02796nas a2200361 4500008004100000022001400041245010300055210006900158260001300227300001000240490000700250520173200257653002201989653000902011653001902020653001602039653004002055653001102095653002202106653001902128653001102147653001702158653000902175653002402184653001702208653004702225653001802272100002202290700002102312700001802333710004702351856003602398 2009 eng d a0161-810500aInsomnia did not predict incident hypertension in older adults in the cardiovascular health study.0 aInsomnia did not predict incident hypertension in older adults i c2009 Jan a65-720 v323 a
STUDY OBJECTIVE: We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction.
DESIGN: This is a prospective cohort study over a 6-year period of follow-up.
SETTING: This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland.
PARTICIPANTS: The study analyzed data from 1419 older individuals (baseline mean age 73.4 +/- 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline.
INTERVENTIONS: none.
MEASUREMENTS: We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination.
RESULTS: Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans.
CONCLUSIONS: Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.
10aAfrican Americans10aAged10aCohort Studies10aComorbidity10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHealth Surveys10aHumans10aHypertension10aMale10aProspective Studies10aRisk Factors10aSleep Initiation and Maintenance Disorders10aUnited States1 aPhillips, Barbara1 aBůzková, Petra1 aEnright, Paul1 aCardiovascular Health Study Research Group uhttps://chs-nhlbi.org/node/107602286nas a2200337 4500008004100000022001400041245008400055210006900139260001300208300001000221490000700231520139500238653000901633653001101642653001801653653001801671653001101689653001401700653000901714653001701723653001801740100001901758700002101777700002001798700002101818700001501839700001501854700002201869700002101891856003601912 2010 eng d a1522-964500aHip fractures and heart failure: findings from the Cardiovascular Health Study.0 aHip fractures and heart failure findings from the Cardiovascular c2010 Jan a77-840 v313 aAIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis.
METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone.
CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.
10aAged10aFemale10aHeart Failure10aHip Fractures10aHumans10aIncidence10aMale10aRisk Factors10aUnited States1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aLee, Jennifer, S1 aChen, Zhao1 aAhmed, Ali1 aParashar, Susmita1 aRobbins, John, R uhttps://chs-nhlbi.org/node/114303251nas a2200445 4500008004100000022001400041245007900055210006900134260001600203300001200219490000800231520205700239653000902296653001102305653002202316653001802338653001102356653002002367653001902387653001402406653000902420653002602429653003202455653002402487653001702511653002102528653001602549653001802565100002102583700002102604700002002625700001502645700001902660700001502679700001702694700001902711700002102730700001802751856003602769 2010 eng d a1538-367900aSubclinical thyroid dysfunction and incident hip fracture in older adults.0 aSubclinical thyroid dysfunction and incident hip fracture in old c2010 Nov 22 a1876-830 v1703 aBACKGROUND: Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture.
METHODS: Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline.
RESULTS: During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women.
CONCLUSIONS: Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.
10aAged10aFemale10aFollow-Up Studies10aHip Fractures10aHumans10aHyperthyroidism10aHypothyroidism10aIncidence10aMale10aMultivariate Analysis10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Distribution10aThyrotropin10aUnited States1 aLee, Jennifer, S1 aBůzková, Petra1 aFink, Howard, A1 aVu, Joseph1 aCarbone, Laura1 aChen, Zhao1 aCauley, Jane1 aBauer, Doug, C1 aCappola, Anne, R1 aRobbins, John uhttps://chs-nhlbi.org/node/124603263nas a2200553 4500008004100000022001400041245011200055210006900167260001300236300001100249490000600260520171300266653000901979653002201988653003402010653002102044653001102065653003402076653001102110653000902121653001602130653003602146653002402182100002302206700001602229700002102245700002002266700001902286700001202305700002102317700002302338700002102361700002102382700001602403700001902419700001802438700002302456700001902479700002202498700001702520700001902537700001902556700002102575700001702596700002402613700001702637700001902654856003602673 2011 eng d a1942-326800aAssociation of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.0 aAssociation of genetic variants and incident coronary heart dise c2011 Dec a661-720 v43 aBACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.
METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.
CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
10aAged10aAged, 80 and over10aContinental Population Groups10aCoronary Disease10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aFranceschini, Nora1 aCarty, Cara1 aBůzková, Petra1 aReiner, Alex, P1 aGarrett, Tiana1 aLin, Yi1 aVöckler, Jens-S1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBoerwinkle, Eric1 aLin, Dan-Yu1 aBookman, Ebony1 aBest, Lyle, G1 aBella, Jonathan, N1 aEaton, Charles1 aGreenland, Philip1 aJenny, Nancy1 aNorth, Kari, E1 aTaverna, Darin1 aYoung, Alicia, M1 aDeelman, Ewa1 aKooperberg, Charles1 aPsaty, Bruce1 aHeiss, Gerardo uhttps://chs-nhlbi.org/node/134704377nas a2200829 4500008004100000022001400041245014300055210006900198260001300267300001300280490000600293520197700299653001502276653001002291653000902301653002202310653003402332653001102366653001902377653002502396653003402421653001102455653002702466653002102493653002202514653002202536653000902558653001602567653002702583653003602610653002802646653001702674653001802691653001602709100002202725700001902747700001702766700002802783700002302811700002102834700002102855700001802876700002602894700002102920700002802941700002102969700002102990700002503011700001703036700002203053700002003075700002303095700001903118700002303137700002203160700001903182700002503201700001803226700002203244700002103266700002603287700002103313700002103334700002203355700002703377700002303404700001903427700002403446700001903470700002203489856003603511 2011 eng d a1553-740400aGenetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.0 aGenetic determinants of lipid traits in diverse populations from c2011 Jun ae10021380 v73 aFor the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aContinental Population Groups10aFemale10aGene Frequency10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aLipid Metabolism10aLipoproteins, HDL10aLipoproteins, LDL10aMale10aMiddle Aged10aMolecular Epidemiology10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aTriglycerides10aYoung Adult1 aDumitrescu, Logan1 aCarty, Cara, L1 aTaylor, Kira1 aSchumacher, Fredrick, R1 aHindorff, Lucia, A1 aAmbite, José, L1 aAnderson, Garnet1 aBest, Lyle, G1 aBrown-Gentry, Kristin1 aBůzková, Petra1 aCarlson, Christopher, S1 aCochran, Barbara1 aCole, Shelley, A1 aDevereux, Richard, B1 aDuggan, Dave1 aEaton, Charles, B1 aFornage, Myriam1 aFranceschini, Nora1 aHaessler, Jeff1 aHoward, Barbara, V1 aJohnson, Karen, C1 aLaston, Sandra1 aKolonel, Laurence, N1 aLee, Elisa, T1 aMacCluer, Jean, W1 aManolio, Teri, A1 aPendergrass, Sarah, A1 aQuibrera, Miguel1 aShohet, Ralph, V1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/130303420nas a2200517 4500008004100000022001400041245023700055210006900292260001600361300001000377490000600387520182700393653000902220653002202229653002802251653002102279653002102300653004002321653001102361653002502372653003402397653001302431653001102444653000902455653001602464653003602480653001702516653001102533653001802544100001902562700002102581700002002602700002302622700001802645700001902663700002302682700002302705700001402728700002002742700001602762700002002778700001902798700002502817700002402842856003602866 2012 eng d a1942-326800aAssociations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study.0 aAssociations between incident ischemic stroke events and stroke c2012 Apr 01 a210-60 v53 aBACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.
METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.
CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aFemale10aGenetics, Population10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aTriglycerides1 aCarty, Cara, L1 aBůzková, Petra1 aFornage, Myriam1 aFranceschini, Nora1 aCole, Shelley1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHoward, Barbara, V1 aMann, Sue1 aMartin, Lisa, W1 aZhang, Ying1 aMatise, Tara, C1 aPrentice, Ross1 aReiner, Alexander, P1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/137103141nas a2200685 4500008004100000022001400041245018100055210006900236260001300305300001100318490000700329520115600336653001001492653000901502653002201511653001201533653003001545653001101575653003801586653003401624653001301658653001101671653000901682653001701691653001601708653002201724653000901746653001701755100002701772700002501799700002201824700002101846700002201867700001501889700001901904700002301923700002401946700002301970700002401993700002002017700002502037700001902062700002302081700001502104700002102119700002002140700001802160700002402178700002602202700001902228700002202247700002302269700002302292700001902315700001902334700002202353700002302375700002102398856003602419 2012 eng d a1939-327X00aConsistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium.0 aConsistent directions of effect for established type 2 diabetes c2012 Jun a1642-70 v613 aCommon genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
10aAdult10aAged10aAged, 80 and over10aAlleles10aDiabetes Mellitus, Type 210aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMetagenomics10aMiddle Aged10aPopulation Groups10aRisk10aRisk Factors1 aHaiman, Christopher, A1 aFesinmeyer, Megan, D1 aSpencer, Kylee, L1 aBůzková, Petra1 aVoruganti, Saroja1 aWan, Peggy1 aHaessler, Jeff1 aFranceschini, Nora1 aMonroe, Kristine, R1 aHoward, Barbara, V1 aJackson, Rebecca, D1 aFlorez, Jose, C1 aKolonel, Laurence, N1 aBuyske, Steven1 aGoodloe, Robert, J1 aLiu, Simin1 aManson, JoAnn, E1 aMeigs, James, B1 aWaters, Kevin1 aMukamal, Kenneth, J1 aPendergrass, Sarah, A1 aShrader, Peter1 aWilkens, Lynne, R1 aHindorff, Lucia, A1 aAmbite, Jose, Luis1 aNorth, Kari, E1 aPeters, Ulrike1 aCrawford, Dana, C1 aLe Marchand, Loïc1 aPankow, James, S uhttps://chs-nhlbi.org/node/663302996nas a2200433 4500008004100000022001400041245013100055210006900186260001300255300001100268490000700279520163600286653003901922653000901961653002201970653002801992653004002020653001102060653002202071653001102093653004902104653004902153653003302202653002502235653000902260653001402269653003002283653001702313100002202330700002102352700002102373700002502394700002202419700002102441700002102462700002302483700002002506856003602526 2012 eng d a1945-719700aDecline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study.0 aDecline in circulating insulinlike growth factors and mortality c2012 Jun a1970-60 v973 aBACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.
STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.
RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10% decreases over time in IGF-I levels (CM = 29.6%), individuals who had at least 10% increases over time in IGF-I levels (CM = 24.7%), and individuals who had IGF-I levels remaining within ±10% over time (CM = 23.5%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.
CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.
10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aLongitudinal Studies10aMale10aMortality10aPredictive Value of Tests10aRisk Factors1 aKaplan, Robert, C1 aBůzková, Petra1 aCappola, Anne, R1 aStrickler, Howard, D1 aMcGinn, Aileen, P1 aMercer, Laina, D1 aArnold, Alice, M1 aPollak, Michael, N1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/137403528nas a2200721 4500008004100000022001400041245014600055210006900201260000900270300001100279490000600290520139200296653002201688653002801710653004001738653002101778653002101799653002301820653001901843653001901862653003401881653001301915653001101928653002301939653003601962653002801998100001902026700001302045700001902058700001602077700002902093700002202122700002302144700002202167700002302189700002102212700002102233700002202254700002102276700001802297700002202315700002502337700002302362700002202385700001702407700002002424700002402444700001202468700002302480700002002503700002602523700002202549700002802571700002402599700001802623700002102641700002102662700002702683700001902710700002202729700001902751856003602770 2012 eng d a1932-620300aEvaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.0 aEvaluation of the metabochip genotyping array in African America c2012 ae356510 v73 aThe Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
10aAfrican Americans10aCardiovascular Diseases10aCholesterol Ester Transfer Proteins10aCholesterol, HDL10aCholesterol, LDL10aChromosomes, Human10aCohort Studies10aGene Frequency10aGenome-Wide Association Study10aGenotype10aHumans10aMetabolic Diseases10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aBuyske, Steven1 aWu, Ying1 aCarty, Cara, L1 aCheng, Iona1 aAssimes, Themistocles, L1 aDumitrescu, Logan1 aHindorff, Lucia, A1 aMitchell, Sabrina1 aAmbite, Jose, Luis1 aBoerwinkle, Eric1 aBůzková, Petra1 aCarlson, Chris, S1 aCochran, Barbara1 aDuggan, David1 aEaton, Charles, B1 aFesinmeyer, Megan, D1 aFranceschini, Nora1 aHaessler, Jeffrey1 aJenny, Nancy1 aKang, Hyun, Min1 aKooperberg, Charles1 aLin, Yi1 aLe Marchand, Loïc1 aMatise, Tara, C1 aRobinson, Jennifer, G1 aRodriguez, Carlos1 aSchumacher, Fredrick, R1 aVoight, Benjamin, F1 aYoung, Alicia1 aManolio, Teri, A1 aMohlke, Karen, L1 aHaiman, Christopher, A1 aPeters, Ulrike1 aCrawford, Dana, C1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/663402865nas a2200337 4500008004100000022001400041245012600055210006900181260001300250300001200263490000700275520188800282653002202170653001102192653001102203653002502214653000902239653002102248653002702269653001802296653001602314653001402330653002102344100002402365700002102389700002002410700002102430700001902451700002102470856003602491 2012 eng d a1945-719700aLongitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.0 aLongitudinal changes in thyroid function in the oldest old and s c2012 Nov a3944-500 v973 aCONTEXT: Data on thyroid function in the oldest old are sparse, and existing studies show conflicting evidence on the relationship between thyroid function and mortality in this age group.
OBJECTIVE: We describe longitudinal changes in thyroid function in a cohort of elderly individuals and determine the relationship between thyroid function and mortality.
DESIGN, SETTING, AND PARTICIPANTS: Eight hundred forty-three participants in the Cardiovascular Health Study All Stars Study who were not taking thyroid medications and had thyroid function testing in 2005-2006 (mean age 85 yr).
MAIN OUTCOME MEASURE: Thyroid-stimulating hormone (TSH), free T(4) (FT4), total T(3), and thyroid peroxidase antibody status were measured in 1992-1993 and 2005-2006. Deaths were ascertained through February 2011.
RESULTS: There was a statistically significant 13% increase in TSH, 1.7% increase in FT4, and 13% decrease in total T(3) over the 13-yr period. Two hundred eighty-seven deaths occurred over a median follow-up of 5.1 yr. There was no association between subclinical hypothyroidism[hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.66-1.43], TSH level (HR per milliunits per liter 0.94, 95% CI 0.88-1.01), or persistent thyroid peroxidase antibody positivity (HR 1.09, 95% CI 0.62-1.92), and death. However, FT4 was positively associated with death (HR per nanograms per deciliter 2.57, 95% CI 1.32-5.02).
CONCLUSIONS: TSH increased over time in these older individuals. This elevation was not associated with increased or decreased mortality, although higher FT4 levels were associated with death. These findings raise concern for treatment of mild elevations of TSH in advanced age. Further studies are needed to determine the potential benefit of treating age-related changes in thyroid function.
10aAged, 80 and over10aFemale10aHumans10aLongitudinal Studies10aMale10aThyroid Diseases10aThyroid Function Tests10aThyroid Gland10aThyrotropin10aThyroxine10aTriiodothyronine1 aWaring, Avantika, C1 aArnold, Alice, M1 aNewman, Anne, B1 aBůzková, Petra1 aHirsch, Calvin1 aCappola, Anne, R uhttps://chs-nhlbi.org/node/140402763nas a2200493 4500008004100000022001400041245010300055210006900158260001300227300001100240490000700251520140800258653003101666653001601697653000901713653002201722653001001744653002601754653002101780653001101801653002501812653001801837653001901855653001101874653001801885653000901903653002401912653001401936653001701950653003001967653002001997653001702017653002202034653001702056653001802073653002002091653001202111100002602123700002102149700002102170700002202191700002002213856003602233 2012 eng d a1468-283400aPredicting late-life disability and death by the rate of decline in physical performance measures.0 aPredicting latelife disability and death by the rate of decline c2012 Mar a155-610 v413 aBACKGROUND: the rate of performance decline may influence the risk of disability or death.
METHODS: for 4,182 Cardiovascular Health Study participants, we used multinomial Poisson log-linear models to assess the contribution of physical performance in 1998-99, and the rate of performance change between 1992-93 and 1998-99, to the risk of death or disability in 2005-06 in three domains: mobility, upper-extremity function (UEF) and activities of daily living (ADL). We evaluated performance in finger-tapping, grip strength, stride length, gait speed and chair stands separately and together for each outcome, adjusting for age, gender, race and years of disability in that outcome between 1992-93 and 1998-99.
RESULTS: participants' age averaged 79.4 in 1998-99; 1,901 died over 7 years. Compared with the lowest change quintile in stride length, the highest quintile had a 1.32 relative risk (RR) of ADL disability (95% CI: 1.16 -1.96) and a 1.27 RR of death (95% CI: 1.07 -1.51). The highest change quintile for grip strength increased the risk of ADL disability by 35% (95% CI: 1.13 -1.61) and death by 31% (95% CI: 1.16 -1.49), compared with the lowest quintile. The annual change in stride length and grip strength also predicted disability in mobility and UEF.
CONCLUSION: performance trajectories independently predict death and disability.
10aActivities of Daily Living10aAge Factors10aAged10aAged, 80 and over10aAging10aDisability Evaluation10aDisabled Persons10aFemale10aGeriatric Assessment10aHand Strength10aHealth Surveys10aHumans10aLinear Models10aMale10aMobility Limitation10aMortality10aMotor Skills10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aSurvival Analysis10aTime Factors10aUnited States10aUpper Extremity10aWalking1 aHirsch, Calvin, Hayes1 aBůzková, Petra1 aRobbins, John, A1 aPatel, Kushang, V1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/135703502nas a2200481 4500008004100000022001400041245014100055210006900196260001600265300001000281490000800291520213900299653000902438653002402447653002802471653002702499653001502526653001802541653001102559653001102570653001402581653000902595653001602604653003202620653002002652653001702672653001602689653001802705100001702723700002202740700002102762700001902783700001802802700002302820700002002843700002402863700001902887700001702906700002102923700002102944700001902965856003602984 2013 eng d a2168-611400aAtrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study.0 aAtrial fibrillation and the risk of sudden cardiac death the ath c2013 Jan 14 a29-350 v1733 aBACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.
METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.
RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.
CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.
10aAged10aAtrial Fibrillation10aCardiovascular Diseases10aDeath, Sudden, Cardiac10aDemography10aEthnic Groups10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aSex Factors10aUnited States1 aChen, Lin, Y1 aSotoodehnia, Nona1 aBůzková, Petra1 aLopez, Faye, L1 aYee, Laura, M1 aHeckbert, Susan, R1 aPrineas, Ronald1 aSoliman, Elsayed, Z1 aAdabag, Selcuk1 aKonety, Suma1 aFolsom, Aaron, R1 aSiscovick, David1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/585003734nas a2200745 4500008004100000022001400041245012200055210006900177260001600246300000600262490000700268520160700275653001501882653001001897653002201907653000901929653005001938653002001988653004002008653001102048653003802059653001102097653000902108653002202117653001602139653001202155653003602167653001302203653001702216653001202233653001602245100002502261700001902286700001502305700002102320700002202341700002202363700002002385700001802405700002002423700002202443700001602465700002802481700002102509700002002530700002102550700002402571700001902595700002202614700001502636700003002651700002402681700002402705700002202729700002502751700002102776700001802797700002302815700002302838700002202861700002702883700002302910700001902933856003602952 2013 eng d a1471-235000aEffects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.0 aEffects of smoking on the genetic risk of obesity the population c2013 Jan 11 a60 v143 aBACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.
METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.
RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).
CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.
CLINICAL TRIAL REGISTRATION: NCT00000611.
10aAdolescent10aAdult10aAfrican Americans10aAged10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHumans10aMale10aMembrane Proteins10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aSmoking10aYoung Adult1 aFesinmeyer, Megan, D1 aNorth, Kari, E1 aLim, Unhee1 aBůzková, Petra1 aCrawford, Dana, C1 aHaessler, Jeffrey1 aGross, Myron, D1 aFowke, Jay, H1 aGoodloe, Robert1 aLove, Shelley-Ann1 aGraff, Misa1 aCarlson, Christopher, S1 aKuller, Lewis, H1 aMatise, Tara, C1 aHong, Ching-Ping1 aHenderson, Brian, E1 aAllen, Melissa1 aRohde, Rebecca, R1 aMayo, Ping1 aSchnetz-Boutaud, Nathalie1 aMonroe, Kristine, R1 aRitchie, Marylyn, D1 aPrentice, Ross, L1 aKolonel, Lawrence, N1 aManson, JoAnn, E1 aPankow, James1 aHindorff, Lucia, A1 aFranceschini, Nora1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/606503280nas a2200469 4500008004100000022001400041245013300055210006900188260001300257300001200270490000700282520195800289653000902247653002202256653001702278653001102295653003002306653001802336653001102354653002502365653000902390653001602399653002402415653000902439653002102448100002102469700002102490700002102511700001802532700002002550700002002570700002202590700001602612700001902628700001802647700002202665700002402687700002002711700002402731700001902755856003602774 2013 eng d a1945-719700aFibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study.0 aFibroblast growth factor 23 bone mineral density and risk of hip c2013 Aug a3323-310 v983 aCONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.
OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.
DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease.
PARTICIPANTS: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit.
MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.
RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions).
CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.
10aAged10aAged, 80 and over10aBone Density10aFemale10aFibroblast Growth Factors10aHip Fractures10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aProspective Studies10aRisk10aSpinal Fractures1 aJovanovich, Anna1 aBůzková, Petra1 aChonchol, Michel1 aRobbins, John1 aFink, Howard, A1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aKatz, Ronit1 aCarbone, Laura1 aLee, Jennifer1 aLaughlin, Gail, A1 aMukamal, Kenneth, J1 aFried, Linda, F1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/599604096nas a2200901 4500008004100000022001400041245007000055210006900125260001500194300001100209490000700220520164400227653001001871653002201881653000901903653002201912653002001934653001101954653001701965653003801982653001802020653003402038653001302072653001102085653002702096653000902123653001602132653001202148653003602160653001602196100001502212700002502227700001502252700002302267700001902290700001902309700002802328700002102356700002102377700002002398700001702418700002102435700002102456700002502477700002002502700001702522700001602539700002002555700002502575700002102600700001602621700002102637700001602658700001902674700001802693700001902711700001702730700002602747700002002773700002202793700002102815700002002836700002402856700001502880700002002895700001602915700003002931700002202961700002102983700002403004700002003028700002303048700002203071700002703093700001903120700001903139856003603158 2013 eng d a1537-660500aFine Mapping and Identification of BMI Loci in African Americans.0 aFine Mapping and Identification of BMI Loci in African Americans c2013 Oct 3 a661-710 v933 aGenome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aBody Mass Index10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aYoung Adult1 aGong, Jian1 aSchumacher, Fredrick1 aLim, Unhee1 aHindorff, Lucia, A1 aHaessler, Jeff1 aBuyske, Steven1 aCarlson, Christopher, S1 aRosse, Stephanie1 aBůzková, Petra1 aFornage, Myriam1 aGross, Myron1 aPankratz, Nathan1 aPankow, James, S1 aSchreiner, Pamela, J1 aCooper, Richard1 aEhret, Georg1 aGu, Charles1 aHouston, Denise1 aIrvin, Marguerite, R1 aJackson, Rebecca1 aKuller, Lew1 aHenderson, Brian1 aCheng, Iona1 aWilkens, Lynne1 aLeppert, Mark1 aLewis, Cora, E1 aLi, Rongling1 aNguyen, Khanh-Dung, H1 aGoodloe, Robert1 aFarber-Eger, Eric1 aBoston, Jonathan1 aDilks, Holli, H1 aRitchie, Marylyn, D1 aFowke, Jay1 aPooler, Loreall1 aGraff, Misa1 aFernandez-Rhodes, Lindsay1 aCochrane, Barbara1 aBoerwinkle, Eric1 aKooperberg, Charles1 aMatise, Tara, C1 aLe Marchand, Loïc1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aNorth, Kari, E1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/662603914nas a2200673 4500008004100000022001400041245016900055210006900224260001300293300001100306490000700317520191200324653001202236653002002248653001802268653001902286653001702305653003802322653003402360653001102394653002702405653001702432653001202449653001402461653003602475653001702511100002502528700001902553700002402572700001502596700002302611700002202634700002002656700002102676700002002697700002102717700003002738700001402768700001802782700001702800700002802817700002202845700002102867700002102888700002002909700002102929700002502950700002302975700002502998700002403023700002403047700002203071700002303093700001903116700002703135700002303162700001903185856003603204 2013 eng d a1930-739X00aGenetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study.0 aGenetic risk factors for BMI and obesity in an ethnically divers c2013 Apr a835-460 v213 aOBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.
DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.
RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.
CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.
10aAlleles10aBody Mass Index10aEthnic Groups10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMetagenomics10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aFesinmeyer, Megan, D1 aNorth, Kari, E1 aRitchie, Marylyn, D1 aLim, Unhee1 aFranceschini, Nora1 aWilkens, Lynne, R1 aGross, Myron, D1 aBůzková, Petra1 aGlenn, Kimberly1 aQuibrera, Miguel1 aFernandez-Rhodes, Lindsay1 aLi, Qiong1 aFowke, Jay, H1 aLi, Rongling1 aCarlson, Christopher, S1 aPrentice, Ross, L1 aKuller, Lewis, H1 aManson, JoAnn, E1 aMatise, Tara, C1 aCole, Shelley, A1 aChen, Christina, T L1 aHoward, Barbara, V1 aKolonel, Laurence, N1 aHenderson, Brian, E1 aMonroe, Kristine, R1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aBuyske, Steven1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/663103932nas a2200769 4500008004100000022001400041245020400055210006900259260001600328300000700344490000700351520160000358653004101958653001001999653002202009653000902031653001202040653003702052653001802089653003002107653004002137653001102177653001902188653001702207653003402224653001302258653002302271653001102294653002802305653001202333653000902345653001602354653003602370653004202406100002502448700002002473700001902493700002802512700002102540700002302561700002202584700002002606700002202626700003102648700002302679700002102702700002502723700001502748700002102763700002402784700002102808700002002829700002602849700001702875700001502892700002202907700002302929700002302952700001902975700002002994700002203014700002303036700002703059700001903086700002103105856003603126 2013 eng d a1471-235000aGenetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aGenetic variants associated with fasting glucose and insulin con c2013 Sep 25 a980 v143 aBACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.
METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.
RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.
CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.
10aAdaptor Proteins, Signal Transducing10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBlood Glucose10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGenomics10aHispanic Americans10aHumans10aIndians, North American10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factor 7-Like 2 Protein1 aFesinmeyer, Megan, D1 aMeigs, James, B1 aNorth, Kari, E1 aSchumacher, Fredrick, R1 aBůzková, Petra1 aFranceschini, Nora1 aHaessler, Jeffrey1 aGoodloe, Robert1 aSpencer, Kylee, L1 aVoruganti, Venkata, Saroja1 aHoward, Barbara, V1 aJackson, Rebecca1 aKolonel, Laurence, N1 aLiu, Simin1 aManson, JoAnn, E1 aMonroe, Kristine, R1 aMukamal, Kenneth1 aDilks, Holli, H1 aPendergrass, Sarah, A1 aNato, Andrew1 aWan, Peggy1 aWilkens, Lynne, R1 aLe Marchand, Loïc1 aAmbite, Jose, Luis1 aBuyske, Steven1 aFlorez, Jose, C1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aHaiman, Christopher, A1 aPeters, Ulrike1 aPankow, James, S uhttps://chs-nhlbi.org/node/629004246nas a2200769 4500008004100000022001400041245015300055210006900208260001300277300001000290490000600300520206100306653002202367653000902389653001902398653001302417653002102430653004002451653001102491653003402502653001302536653001002549653001102559653000902570653001602579653001402595653003602609653001202645100001802657700002302675700001902698700001902717700001302736700002402749700002302773700002102796700002202817700001902839700002002858700002102878700002302899700002502922700002202947700002302969700001602992700002103008700001903029700001303048700001803061700002503079700002003104700002903124700002103153700002403174700002203198700002403220700001903244700001803263700002203281700002203303700002203325700002003347700002303367700002303390700002703413856003603440 2013 eng d a1942-326800aGenome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study.0 aGenomewide association study of cardiac structure and systolic f c2013 Feb a37-460 v63 aBACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.
METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.
CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
10aAfrican Americans10aAged10aCohort Studies10aDiastole10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aMusani, Solomon, K1 aBarbalic, Maja1 aLin, Honghuang1 aYu, Bing1 aOgunyankin, Kofo, O1 aSmith, Nicholas, L1 aKutlar, Abdullah1 aGlazer, Nicole, L1 aPost, Wendy, S1 aPaltoo, Dina, N1 aDries, Daniel, L1 aFarlow, Deborah, N1 aDuarte, Christine, W1 aKardia, Sharon, L1 aMeyers, Kristin, J1 aSun, Yan, V1 aArnett, Donna, K1 aPatki, Amit, A1 aSha, Jin1 aCui, Xiangqui1 aSamdarshi, Tandaw, E1 aPenman, Alan, D1 aBibbins-Domingo, Kirsten1 aBůzková, Petra1 aBenjamin, Emelia, J1 aBluemke, David, A1 aMorrison, Alanna, C1 aHeiss, Gerardo1 aCarr, Jeffrey1 aTracy, Russell, P1 aMosley, Thomas, H1 aTaylor, Herman, A1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCappola, Thomas, P1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/663203572nas a2200745 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520148800271653001501759653001001774653000901784653002201793653001001815653002001825653001901845653002801864653004001892653001101932653003201943653001901975653001101994653000902005653001602014653001202030653003602042653001302078653001802091653001602109100002202125700002502147700001502172700001802187700002102205700002202226700002202248700002402270700002402294700002202318700001602340700002102356700002102377700002302398700002102421700002502442700001902467700002402486700001902510700002002529700002002549700002302569700002802592700001902620700002102639700002302660700002002683700002202703700002702725700001902752700001902771856003602790 2013 eng d a1939-327X00aThe influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study.0 ainfluence of obesityrelated single nucleotide polymorphisms on B c2013 May a1763-70 v623 aEvidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAging10aBody Mass Index10aCohort Studies10aCross-Sectional Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aHealth Surveys10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins10aUnited States10aYoung Adult1 aGraff, Mariaelisa1 aGordon-Larsen, Penny1 aLim, Unhee1 aFowke, Jay, H1 aLove, Shelly-Ann1 aFesinmeyer, Megan1 aWilkens, Lynne, R1 aVertilus, Shawyntee1 aRitchie, Marilyn, D1 aPrentice, Ross, L1 aPankow, Jim1 aMonroe, Kristine1 aManson, JoAnn, E1 aLe Marchand, Loïc1 aKuller, Lewis, H1 aKolonel, Laurence, N1 aHong, Ching, P1 aHenderson, Brian, E1 aHaessler, Jeff1 aGross, Myron, D1 aGoodloe, Robert1 aFranceschini, Nora1 aCarlson, Christopher, S1 aBuyske, Steven1 aBůzková, Petra1 aHindorff, Lucia, A1 aMatise, Tara, C1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aPeters, Ulrike1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/663003673nas a2200601 4500008004100000022001400041245015800055210006900213260000900282300000700291490000700298520191500305653001102220653002602231653001802257653003402275653001102309653001102320653000902331653003602340653002202376100002002398700001902418700002202437700002102459700002102480700002002501700002402521700002202545700002102567700002102588700002202609700002402631700001902655700002302674700002202697700002102719700002102740700001602761700002202777700002602799700002102825700002302846700002402869700002302893700002402916700002202940700001902962700001902981700002003000710001503020856003603035 2013 eng d a1471-215600aInvestigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study.0 aInvestigation of genebysex interactions for lipid traits in dive c2013 a330 v143 aBACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.
RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.
CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
10aFemale10aGenetic Heterogeneity10aGenome, Human10aGenome-Wide Association Study10aHumans10aLipids10aMale10aPolymorphism, Single Nucleotide10aPopulation Groups1 aTaylor, Kira, C1 aCarty, Cara, L1 aDumitrescu, Logan1 aBůzková, Petra1 aCole, Shelley, A1 aHindorff, Lucia1 aSchumacher, Fred, R1 aWilkens, Lynne, R1 aShohet, Ralph, V1 aQuibrera, Miguel1 aJohnson, Karen, C1 aHenderson, Brian, E1 aHaessler, Jeff1 aFranceschini, Nora1 aEaton, Charles, B1 aDuggan, David, J1 aCochran, Barbara1 aCheng, Iona1 aCarlson, Chris, S1 aBrown-Gentry, Kristin1 aAnderson, Garnet1 aAmbite, Jose, Luis1 aHaiman, Christopher1 aLe Marchand, Loïc1 aKooperberg, Charles1 aCrawford, Dana, C1 aBuyske, Steven1 aNorth, Kari, E1 aFornage, Myriam1 aPAGE Study uhttps://chs-nhlbi.org/node/662704131nas a2200697 4500008004100000022001400041245021700055210006900272260001300341300001000354490000800364520200300372653002202375653000902397653002502406653002602431653002802457653003502485653002102520653004002541653001102581653001902592653003202611653003802643653001102681653002802692653001802720653002002738653000902758653002202767653001602789653001502805653001402820653003602834653003002870653002002900653001702920653001802937100001602955700002102971700002502992700001903017700001903036700002203055700002103077700002903098700002103127700001703148700002003165700001803185700001903203700002003222700002303242700002003265700002203285700002303307700002403330700002303354700002003377856003603397 2013 eng d a1879-148400aLack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aLack of associations of ten candidate coronary heart disease ris c2013 Jun a390-90 v2283 aBACKGROUND: A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
METHODS: Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
RESULTS: None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3809 AA, and 5353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10(-5)), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
CONCLUSIONS: We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
10aAfrican Americans10aAged10aAnkle Brachial Index10aAsymptomatic Diseases10aCarotid Artery Diseases10aCarotid Intima-Media Thickness10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Association Studies10aGenetic Predisposition to Disease10aHumans10aIndians, North American10aLinear Models10aLogistic Models10aMale10aMexican Americans10aMiddle Aged10aOdds Ratio10aPhenotype10aPolymorphism, Single Nucleotide10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aUnited States1 aZhang, Lili1 aBůzková, Petra1 aWassel, Christina, L1 aRoman, Mary, J1 aNorth, Kari, E1 aCrawford, Dana, C1 aBoston, Jonathan1 aBrown-Gentry, Kristin, D1 aCole, Shelley, A1 aDeelman, Ewa1 aGoodloe, Robert1 aWilson, Sarah1 aHeiss, Gerardo1 aJenny, Nancy, S1 aJorgensen, Neal, W1 aMatise, Tara, C1 aMcClellan, Bob, E1 aNato, Alejandro, Q1 aRitchie, Marylyn, D1 aFranceschini, Nora1 aKao, Linda, W H uhttps://chs-nhlbi.org/node/609402686nas a2200697 4500008004100000022001400041245012800055210006900183260001300252300001200265490000800277520066900285653002100954653002100975653001900996653001801015653001101033653001901044653003301063653002501096653003401121653001101155653002101166653000901187653003601196653001501232653001201247653001801259653001601277100002201293700001901315700002301334700002301357700002101380700002101401700002801422700002201450700002301472700002101495700001901516700002101535700002401556700001601580700002201596700002201618700002201640700002601662700002301688700002101711700002101732700002301753700002201776700002301798700002701821700001901848700002401867700001901891700002001910700002201930856003601952 2013 eng d a1432-120300aNo evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population.0 aNo evidence of interaction between known lipidassociated genetic c2013 Dec a1427-310 v1323 aGenome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aEthnic Groups10aFemale10aGene Frequency10aGene-Environment Interaction10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aMale10aPolymorphism, Single Nucleotide10aPrevalence10aSmoking10aTriglycerides10aYoung Adult1 aDumitrescu, Logan1 aCarty, Cara, L1 aFranceschini, Nora1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBůzková, Petra1 aSchumacher, Fredrick, R1 aEaton, Charles, B1 aGoodloe, Robert, J1 aDuggan, David, J1 aHaessler, Jeff1 aCochran, Barbara1 aHenderson, Brian, E1 aCheng, Iona1 aJohnson, Karen, C1 aCarlson, Chris, S1 aLove, Shelly-Anne1 aBrown-Gentry, Kristin1 aNato, Alejandro, Q1 aQuibrera, Miguel1 aShohet, Ralph, V1 aAmbite, Jose, Luis1 aWilkens, Lynne, R1 aLe Marchand, Loïc1 aHaiman, Christopher, A1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aFornage, Myriam1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/629203380nas a2200673 4500008004100000022001400041245020100055210006900256260001300325300001100338490000700349520133800356653001001694653000901704653004001713653001101753653003201764653003401796653001101830653001101841653000901852653001601861653003601877653002801913653003401941653001701975100002201992700001902014700002302033700002302056700002102079700002102100700002802121700002202149700002302171700002102194700001902215700002102234700002402255700001602279700002202295700002202317700002102339700002602360700002302386700002102409700002102430700002102451700002302472700002202495700002202517700002702539700001902566700002402585700001902609700002002628700002202648856003602670 2013 eng d a1469-180900aPost-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aPostgenomewide association study challenges for lipid traits des c2013 Sep a416-250 v773 aNumerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
10aAdult10aAged10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aLipids10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors1 aDumitrescu, Logan1 aCarty, Cara, L1 aFranceschini, Nora1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBůzková, Petra1 aSchumacher, Fredrick, R1 aEaton, Charles, B1 aGoodloe, Robert, J1 aDuggan, David, J1 aHaessler, Jeff1 aCochran, Barbara1 aHenderson, Brian, E1 aCheng, Iona1 aJohnson, Karen, C1 aCarlson, Chris, S1 aLove, Shelly-Ann1 aBrown-Gentry, Kristin1 aNato, Alejandro, Q1 aQuibrera, Miguel1 aAnderson, Garnet1 aShohet, Ralph, V1 aAmbite, Jose, Luis1 aWilkens, Lynne, R1 aLe Marchand, Loic1 aHaiman, Christopher, A1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aFornage, Myriam1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/611103693nas a2200421 4500008004100000022001400041245007800055210006900133260001600202300001200218490000600230520248800236653000902724653002802733653001902761653002802780653001102808653002502819653001902844653001102863653004902874653004902923653003302972653000903005653002103014653001003035653002903045653001703074653001803091100001603109700001403125700001803139700001803157700002103175700001703196700002203213856003603235 2013 eng d a1550-939700aSleep and insulin-like growth factors in the Cardiovascular Health Study.0 aSleep and insulinlike growth factors in the Cardiovascular Healt c2013 Dec 15 a1245-510 v93 aSTUDY OBJECTIVES: Sleep and sleep disordered breathing (obstructive sleep apnea [OSA]) are known to affect the growth hormone/insulin-like growth factor (GH/IGF) axis. There are few relevant population studies in this area, particularly in the elderly. We conducted this study to investigate the relationship between sleep (architecture and OSA) and circulating IGF-I (insulin-like growth factor-1), IGFBP-1 (insulin-like growth factor binding protein-1), and IGFBP-3 (insulin-like growth factor binding protein-3) levels in an elderly population.
DESIGN SETTING: Cross-sectional analysis of participants from the year 9 visit of the Cardiovascular Health Study (CHS) who were enrolled in the Sleep Heart Health Study (SHHS).
PATIENTS OR PARTICIPANTS: 1,233 elderly participants from the CHS and SHHS.
MEASUREMENTS AND RESULTS: The mean age of males (n = 526) and females (n = 697) was 77 years. The mean value of IGF-I (ng/mL) in males was 112.4 vs. 97.1 in females (p < 0.01). Mean IGFBP-1 and IGFBP-3 levels were higher in females than males (p < 0.01). As expected, slow wave sleep was better preserved in females compared to males (22% total sleep time vs. 9% total sleep time, p < 0.01). Furthermore, as expected, OSA (apneahypopnea index [AHI] ≥ 5/h) was more prevalent in males compared to females (60% vs. 46%, p < 0.01). Multivariable linear regression was used to determine the relationship between objective sleep parameters and circulating IGF-I, IGFBP-1, and IGFBP-3 levels, with adjustment for age, sex, race, BMI, diabetes, estrogen use, progestin use, and physical activity. We did not detect a significant association between slow wave sleep (SWS) (per 5 min) and IGF-I, IGFBP-1, and IGFBP-3 levels (ng/mL). We found no significant linear association between OSA (AHI ≥ 5/h) and IGF-I, IGFBP-1, and IGFBP-3 levels. Gender-stratification of the entire cohort did not alter these findings. Sensitivity analyses excluding diabetics revealed that moderate OSA (AHI ≥ 5 and < 15) is inversely associated with IGFBP-3 levels in women. Conclusions The relationship between SWS and GH/IGF system is not significant in the elderly. Furthermore, OSA does not appear to adversely influence the GH/IGF axis, as reported in younger individuals. Whether our study findings are due to diminished GH/IGF-I axis activity in elderly needs further investigation by replication in other large population based elderly cohorts.
10aAged10aCardiovascular Diseases10aCohort Studies10aCross-Sectional Studies10aFemale10aGeriatric Assessment10aHealth Surveys10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aSex Distribution10aSleep10aSleep Apnea, Obstructive10aSomatomedins10aUnited States1 aShah, Neomi1 aRice, Tom1 aTracy, Daniel1 aRohan, Thomas1 aBůzková, Petra1 aNewman, Anne1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/618904247nas a2200757 4500008004100000022001400041245023300055210006900288260000900357300001300366490000600379520199400385653004102379653001002420653002202430653000902452653002202461653001202483653002002495653002302515653003402538653004002572653001102612653003802623653003402661653001102695653002702706653000902733653001702742653001602759653001202775653001302787100001902800700001902819700002402838700001802862700001902880700001502899700002502914700002402939700001902963700002502982700001503007700001603022700002103038700001903059700001703078700001603095700001703111700002603128700002003154700001903174700001803193700002503211700001603236700002003252700002103272700002103293700002003314700002303334700002303357700002203380700002703402700002403429856003603453 2013 eng d a1553-740400aA systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.0 asystematic mapping approach of 16q122FTO and BMI in more than 20 c2013 ae10031710 v93 aGenetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
10aAdaptor Proteins, Signal Transducing10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAlleles10aBody Mass Index10aChromosome Mapping10aContinental Population Groups10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMale10aMetagenomics10aMiddle Aged10aObesity10aProteins1 aPeters, Ulrike1 aNorth, Kari, E1 aSethupathy, Praveen1 aBuyske, Steve1 aHaessler, Jeff1 aJiao, Shuo1 aFesinmeyer, Megan, D1 aJackson, Rebecca, D1 aKuller, Lew, H1 aRajkovic, Aleksandar1 aLim, Unhee1 aCheng, Iona1 aSchumacher, Fred1 aWilkens, Lynne1 aLi, Rongling1 aMonda, Keri1 aEhret, Georg1 aNguyen, Khanh-Dung, H1 aCooper, Richard1 aLewis, Cora, E1 aLeppert, Mark1 aIrvin, Marguerite, R1 aGu, Charles1 aHouston, Denise1 aBůzková, Petra1 aRitchie, Marylyn1 aMatise, Tara, C1 aLe Marchand, Loïc1 aHindorff, Lucia, A1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/662805266nas a2201201 4500008004100000022001400041245015400055210006900209260001300278300001300291490000600304520181500310653002202125653002202147653002102169653002102190653004002211653003402251653001102285653002202296653002202318653002702340653002602367653001802393100001302411700002202424700002102446700002102467700001902488700001802507700002102525700002102546700002502567700001902592700001602611700002102627700003002648700002202678700002202700700002302722700001702745700002402762700002302786700001402809700002002823700002202843700001802865700002302883700001202906700002202918700002802940700002502968700001902993700002603012700002103038700002503059700002003084700001703104700001803121700002003139700001903159700001903178700002103197700002003218700002803238700002103266700002603287700002403313700001803337700002103355700001703376700001703393700002003410700002003430700002303450700002603473700002203499700001903521700001903540700001403559700002103573700002003594700002003614700002103634700001903655700002403674700002103698700002203719700002003741700002303761700002003784700002003804700002103824700002703845700002103872700002403893700002903917700002203946700002003968700001903988700002104007856003604028 2013 eng d a1553-740400aTrans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.0 aTransethnic finemapping of lipid loci identifies populationspeci c2013 Mar ae10033790 v93 aGenome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
10aAfrican Americans10aApolipoproteins A10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aLipoproteins, HDL10aLipoproteins, LDL10aProprotein Convertases10aSerine Endopeptidases10aTriglycerides1 aWu, Ying1 aWaite, Lindsay, L1 aJackson, Anne, U1 aSheu, Wayne, H-H1 aBuyske, Steven1 aAbsher, Devin1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aCarty, Cara, L1 aCheng, Iona1 aCochran, Barbara1 aCroteau-Chonka, Damien, C1 aDumitrescu, Logan1 aEaton, Charles, B1 aFranceschini, Nora1 aGuo, Xiuqing1 aHenderson, Brian, E1 aHindorff, Lucia, A1 aKim, Eric1 aKinnunen, Leena1 aKomulainen, Pirjo1 aLee, Wen-Jane1 aLe Marchand, Loïc1 aLin, Yi1 aLindström, Jaana1 aLingaas-Holmen, Oddgeir1 aMitchell, Sabrina, L1 aNarisu, Narisu1 aRobinson, Jennifer, G1 aSchumacher, Fred1 aStančáková, Alena1 aSundvall, Jouko1 aSung, Yun-Ju1 aSwift, Amy, J1 aWang, Wen-Chang1 aWilkens, Lynne1 aWilsgaard, Tom1 aYoung, Alicia, M1 aAdair, Linda, S1 aBallantyne, Christie, M1 aBůzková, Petra1 aChakravarti, Aravinda1 aCollins, Francis, S1 aDuggan, David1 aFeranil, Alan, B1 aHo, Low-Tone1 aHung, Yi-Jen1 aHunt, Steven, C1 aHveem, Kristian1 aJuang, Jyh-Ming, J1 aKesäniemi, Antero, Y1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLee, I-Te1 aLeppert, Mark, F1 aMatise, Tara, C1 aMoilanen, Leena1 aNjølstad, Inger1 aPeters, Ulrike1 aQuertermous, Thomas1 aRauramaa, Rainer1 aRotter, Jerome, I1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aWang, Tzung-Dau1 aBoehnke, Michael1 aHaiman, Christopher, A1 aChen, Yii-der, I1 aKooperberg, Charles1 aAssimes, Themistocles, L1 aCrawford, Dana, C1 aHsiung, Chao, A1 aNorth, Kari, E1 aMohlke, Karen, L uhttps://chs-nhlbi.org/node/662902795nas a2200409 4500008004100000022001400041245013000055210007300185260000900258300001100267490000700278520162600285653001601911653000901927653001101936653002201947653003701969653001802006653001102024653001402035653001102049653000902060653002402069653002602093653001702119100002402136700002102160700002102181700002002202700001802222700001902240700002202259700002402281700002002305700002402325856003602349 2014 eng d a1523-468100aCirculating levels of carboxy‐methyl‐lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study.0 aCirculating levels of carboxy‐methyl‐lysine CML are associated w c2014 a1061-60 v293 aAdvanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy‐methyl‐lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68–102 years; 39.8% male) for a median of 9.22 years (range, 0.01–12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow‐up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant‐years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95% confidence interval [CI], 1.16–1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95% CI, 1.05–1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.
10aAge Factors10aAged10aFemale10aFollow-Up Studies10aGlycation End Products, Advanced10aHip Fractures10aHumans10aIncidence10aLysine10aMale10aProspective Studies10aRetrospective Studies10aRisk Factors1 aBarzilay, Joshua, I1 aBůzková, Petra1 aZieman, Susan, J1 aKizer, Jorge, R1 aDjoussé, Luc1 aIx, Joachim, H1 aTracy, Russell, P1 aSiscovick, David, S1 aCauley, Jane, A1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/637503624nas a2200613 4500008004100000022001400041245010500055210006900160260001500229300001200244490000700256520193600263653001002199653000902209653002202218653002402240653000802264653001802272653001102290653001902301653003802320653001302358653001102371653002502382653000902407653001602416653001402432653003602446653001502482653002402497653001302521653001702534653001802551100002402569700002202593700002002615700002202635700001902657700002102676700002002697700002302717700002002740700002302760700002402783700001802807700001802825700002002843700002302863700001802886700002402904700002402928700002202952856003602974 2014 eng d a1552-578300aGenetic determinants of age-related macular degeneration in diverse populations from the PAGE study.0 aGenetic determinants of agerelated macular degeneration in diver c2014 Sep 9 a6839-500 v553 aPURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.
METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.
RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.
CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.
10aAdult10aAged10aAged, 80 and over10aComplement Factor H10aDNA10aEthnic Groups10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aMacular Degeneration10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aPrevalence10aProspective Studies10aProteins10aRisk Factors10aUnited States1 aRestrepo, Nicole, A1 aSpencer, Kylee, L1 aGoodloe, Robert1 aGarrett, Tiana, A1 aHeiss, Gerardo1 aBůzková, Petra1 aJorgensen, Neal1 aJensen, Richard, A1 aMatise, Tara, C1 aHindorff, Lucia, A1 aKlein, Barbara, E K1 aKlein, Ronald1 aWong, Tien, Y1 aCheng, Ching-Yu1 aCornes, Belinda, K1 aTai, E-Shyong1 aRitchie, Marylyn, D1 aHaines, Jonathan, L1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/701902712nas a2200457 4500008004100000022001400041245012000055210006900175260001300244300001500257490000700272520143400279653001001713653000901723653002001732653001601752653002101768653002701789653001101816653001101827653001701838653001401855653000901869653001601878653002801894653002401922653001701946100002601963700001901989700002102008700001902029700001702048700002202065700002402087700002402111700001902135700001902154700002102173700002402194856003602218 2014 eng d a1873-258500aHeight and risk of sudden cardiac death: the Atherosclerosis Risk in Communities and Cardiovascular Health studies.0 aHeight and risk of sudden cardiac death the Atherosclerosis Risk c2014 Mar a174-179.e20 v243 aPURPOSE: Sudden cardiac death (SCD) is an important cause of mortality in the adult population. Height has been associated with cardiac hypertrophy and an increased risk of arrhythmias but also with decreased risk of coronary heart disease, suggesting a complex association with SCD.
METHODS: We examined the association of adult height with the risk of physician-adjudicated SCD in two large population-based cohorts: the Cardiovascular Health Study and the Atherosclerosis Risk in Communities study.
RESULTS: Over an average follow-up time of 11.7 years in Cardiovascular Health Study, there were 199 (3.6%) cases of SCD among 5556 participants. In Atherosclerosis Risk in Communities study, over 12.6 years, there were 227 (1.5%) cases of SCD among 15,633 participants. In both cohorts, there was a trend toward decreased SCD with taller height. In fixed effects meta-analysis, the pooled hazard ratio per 10 cm of height was 0.84; 95% confidence interval, 0.73-0.98; P = .03. The association of increased height with lower risk of SCD was slightly attenuated after inclusion of risk factors associated with height, such as hypertension and left ventricular hypertrophy. The association appeared stronger among men than women in both cohorts.
CONCLUSIONS: In two population-based prospective cohorts of different ages, greater height was associated with lower risk of SCD.
10aAdult10aAged10aAtherosclerosis10aBody Height10aCoronary Disease10aDeath, Sudden, Cardiac10aFemale10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPopulation Surveillance10aProspective Studies10aRisk Factors1 aRosenberg, Michael, A1 aLopez, Faye, L1 aBůzková, Petra1 aAdabag, Selcuk1 aChen, Lin, Y1 aSotoodehnia, Nona1 aKronmal, Richard, A1 aSiscovick, David, S1 aAlonso, Alvaro1 aBuxton, Alfred1 aFolsom, Aaron, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/618704252nas a2200745 4500008004100000022001400041245016200055210006900217260001300286300001100299490000600310520207600316653001002392653003902402653000902441653003702450653002302487653001102510653002202521653003402543653002302577653001102600653002802611653001702639653000902656653001602665653003602681653001802717653001602735100002602751700002602777700001902803700002102822700002802843700001602871700001702887700002302904700001702927700001902944700001502963700002602978700002003004700002603024700001803050700001803068700002103086700002103107700002103128700002203149700002103171700002303192700002003215700002203235700002703257700002503284700002003309700001603329700002103345700002303366700002303389700002203412700001703434700001903451856003603470 2014 eng d a1942-326800aMultiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.0 aMultiancestral analysis of inflammationrelated genetic variants c2014 Apr a178-880 v73 aBACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).
CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
10aAdult10aAfrican Continental Ancestry Group10aAged10aAsian Continental Ancestry Group10aC-Reactive Protein10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHispanic Americans10aHumans10aIndians, North American10aInflammation10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aUnited States10aYoung Adult1 aKocarnik, Jonathan, M1 aPendergrass, Sarah, A1 aCarty, Cara, L1 aPankow, James, S1 aSchumacher, Fredrick, R1 aCheng, Iona1 aDurda, Peter1 aAmbite, Jose, Luis1 aDeelman, Ewa1 aCook, Nancy, R1 aLiu, Simin1 aWactawski-Wende, Jean1 aHutter, Carolyn1 aBrown-Gentry, Kristin1 aWilson, Sarah1 aBest, Lyle, G1 aPankratz, Nathan1 aHong, Ching-Ping1 aCole, Shelley, A1 aVoruganti, Saroja1 aBůzková, Petra1 aJorgensen, Neal, W1 aJenny, Nancy, S1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aKolonel, Laurence, N1 aLaCroix, Andrea1 aNorth, Kari1 aJackson, Rebecca1 aLe Marchand, Loïc1 aHindorff, Lucia, A1 aCrawford, Dana, C1 aGross, Myron1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/636002895nas a2200385 4500008004100000022001400041245010400055210006900159260001300228300001200241490000700253520181800260653000902078653002202087653001602109653001502125653001302140653001102153653001802164653001102182653001402193653003102207653000902238653003002247653002902277653002402306653000902330100002102339700002402360700002002384700002102404700002002425700002802445856003602473 2014 eng d a1945-719700aRatio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk.0 aRatio of urine albumin to creatinine attenuates the association c2014 Nov a4116-230 v993 aCONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50% of people with a hip fracture have cognitive impairment.
OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [≥ 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.
SETTING: The Cardiovascular Health Cognition Study.
PATIENTS: Three thousand, one-hundred six participants (mean age, ∼ 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).
MAIN OUTCOME MEASURE: Incident hip fracture.
RESULTS: There were 488 participants (16%) with mild cognitive impairment (MCI) and 564 (18%) with dementia. There were 337 incident hip fractures, of which 19% occurred in participants with MCI and 26% in participants with dementia. Adjusted hazard ratios (HR) and 95% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.
CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.
10aAged10aAged, 80 and over10aAlbuminuria10aCreatinine10aDementia10aFemale10aHip Fractures10aHumans10aIncidence10aMagnetic Resonance Imaging10aMale10aMild Cognitive Impairment10aNeuropsychological Tests10aProspective Studies10aRisk1 aBůzková, Petra1 aBarzilay, Joshua, I1 aFink, Howard, A1 aRobbins, John, A1 aCauley, Jane, A1 aFitzpatrick, Annette, L uhttps://chs-nhlbi.org/node/662503001nas a2200397 4500008004100000022001400041245012100055210006900176260001300245300001300258490000700271520187200278653001002150653000902160653002202169653002802191653001702219653002802236653001102264653002202275653002002297653001102317653001402328653000902342653002302351100002002374700002102394700002502415700002402440700002002464700002002484700002402504700002002528700001902548856003602567 2015 eng d a1523-468100aAssociation of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study.0 aAssociation of FetuinA With Incident Fractures in CommunityDwell c2015 Aug a1394-4020 v303 aFetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women ≥65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture.
10aAdult10aAged10aAged, 80 and over10aalpha-2-HS-Glycoprotein10aBone Density10aCross-Sectional Studies10aFemale10aFollow-Up Studies10aFractures, Bone10aHumans10aIncidence10aMale10aModels, Biological1 aFink, Howard, A1 aBůzková, Petra1 aGarimella, Pranav, S1 aMukamal, Kenneth, J1 aCauley, Jane, A1 aKizer, Jorge, R1 aBarzilay, Joshua, I1 aJalal, Diana, I1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/666603082nas a2200409 4500008004100000022001400041245012400055210006900179260001300248300001000261490000700271520181300278653000902091653001802100653001902118653003002137653001102167653001102178653004902189653004902238653003302287653000902320653002602329100002502355700002902380700002602409700002102435700002402456700002802480700002002508700002102528700002002549700002002569700002502589700002202614856003602636 2015 eng d a1532-541500aChanges in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults.0 aChanges in insulinlike growth factorI and its binding proteins a c2015 May a902-90 v633 aOBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.
DESIGN: Retrospective analysis of a cohort study.
SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.
PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).
MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).
RESULTS: At baseline, mean age was 76.3±3.6, and 18.5% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3% for IGF-I, 59.7% for IGFBP-1, -13.4% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7% for IGF-I, 25.6% for IGFBP-1, -6.4% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.
CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.
10aAged10aBlood Glucose10aCohort Studies10aDiabetes Mellitus, Type 210aFemale10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aRetrospective Studies1 aAneke-Nash, Chino, S1 aParrinello, Christina, M1 aRajpathak, Swapnil, N1 aRohan, Thomas, E1 aStrotmeyer, Elsa, S1 aKritchevsky, Stephen, B1 aPsaty, Bruce, M1 aBůzková, Petra1 aKizer, Jorge, R1 aNewman, Anne, B1 aStrickler, Howard, D1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/673702646nas a2200433 4500008004100000022001400041245009700055210006900152260001300221300001100234490000700245520147400252653000901726653002201735653002001757653001901777653003301796653001101829653001901840653001801859653001101877653002601888653000901914653002401923653000901947653001601956653001801972653001401990100001702004700002102021700002002042700002102062700002002083700001802103700002002121700001802141700001702159856003602176 2015 eng d a1532-860000aSerum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study.0 aSerum urate levels and the risk of hip fractures data from the C c2015 Mar a438-460 v643 aPURPOSE: Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults.
METHODS: 1963 men and 2729 women ≥65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori.
RESULTS: There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women.
CONCLUSION: In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.
10aAged10aAged, 80 and over10aBody Mass Index10aCohort Studies10aEstrogen Replacement Therapy10aFemale10aHealth Surveys10aHip Fractures10aHumans10aKaplan-Meier Estimate10aMale10aProspective Studies10aRisk10aSex Factors10aUnited States10aUric Acid1 aMehta, Tapan1 aBůzková, Petra1 aSarnak, Mark, J1 aChonchol, Michel1 aCauley, Jane, A1 aWallace, Erin1 aFink, Howard, A1 aRobbins, John1 aJalal, Diana uhttps://chs-nhlbi.org/node/662401276nas a2200205 4500008004100000245008600041210006900127260000900196490000700205520064800212653001000860653003400870653002700904653002500931653001800956653002000974100002100994700001901015856003601034 2015 eng d00aTime to diagnosis: accounting for differential follow-up times in cohort studies.0 aTime to diagnosis accounting for differential followup times in c20150 v443 aCox regression is widely used to analyze discrete survival time data. Differential endpoint follow-up across sub-cohorts where distribution of a covariate varies may cause typical estimators to be biased or inefficient. We demonstrate that with Cardiovascular Health Study data for incident type 2 diabetes. Two cohorts with extremely different race distribution have differential follow-up for fasting glucose levels. We study various scenarios of Cox regression. We suggest an alternative approach, Poisson generalized estimating equations with an offset to accommodate the differential follow-up. We use simulations to contrast the methods.10a62N0110aCovariate-dependent follow-up10aDiscrete survival data10aMulti-cohort studies10aPrimary 62N0210aSecondary 62H121 aBůzková, Petra1 aLumley, Thomas uhttps://chs-nhlbi.org/node/673902547nas a2200229 4500008004100000022001400041245016500055210006900220260001300289300000900302490000700311520179200318100002502110700002702135700002102162700001402183700001702197700002002214700002502234700002202259856003602281 2016 eng d a1532-223800aAgreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies.0 aAgreement between circulating IGFI IGFBP1 and IGFBP3 levels meas c2016 Feb a11-60 v263 aOBJECTIVE: Levels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available.
DESIGN: In a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS).
RESULTS: Results were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X-1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated.
CONCLUSIONS: Care is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.
1 aAneke-Nash, Chino, S1 aDominguez-Islas, Clara1 aBůzková, Petra1 aQi, Qibin1 aXue, XiaoNan1 aPollak, Michael1 aStrickler, Howard, D1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/695202680nas a2200289 4500008004100000022001400041245011600055210006900171260001600240300001500256520179300271100002202064700002202086700002202108700002702130700002102157700002202178700001802200700002002218700001802238700002002256700001802276700002302294700002002317700001702337856003602354 2016 eng d a1945-719700aInsulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: CHS cohort.0 aInsulinlike growth factor binding protein1 and ghrelin predict h c2016 Nov 07 ajc201627793 aCONTEXT: Multiple diseases may explain the association of the growth hormone / insulinlike growth factor-I (GH/IGF-I) axis with longevity.
OBJECTIVE: To relate circulating GH/IGF-I system protein levels with major health events.
DESIGN: Cohort study Setting: Four US communities Participants: Adults (n=2268) 65 years and older free of diabetes and cardiovascular disease.
MEASUREMENTS: We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiologic covariates.
RESULTS: During 13,930 person-years of follow-up, 48.1% individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-h ghrelin were associated with a 27% higher (95% CI: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-h IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite endpoint. Similarly, higher mortality was significantly associated with higher fasting and 2-h ghrelin level, and with 2-h IGFBP-1 level. When examined together, 2-h post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels.
CONCLUSIONS: Circulating IGFBP-1 and ghrelin measured during an OGTT predict major health events and death in older adults, which may explain the influence of the GH-IGF-axis on lifespan and health.
1 aKaplan, Robert, C1 aStrizich, Garrett1 aAneke-Nash, Chino1 aDominguez-Islas, Clara1 aBůzková, Petra1 aStrickler, Howard1 aRohan, Thomas1 aPollak, Michael1 aKuller, Lewis1 aKizer, Jorge, R1 aCappola, Anne1 aLi, Christopher, I1 aPsaty, Bruce, M1 aNewman, Anne uhttps://chs-nhlbi.org/node/725801955nas a2200217 4500008004100000022001400041245014500055210006900200260001300269300001200282490000800294520125300302100002201555700002101577700002001598700002101618700002001639700002101659700002101680856003601701 2017 eng d a1432-082700aAssociation of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study.0 aAssociation of Plasma SDF1 with Bone Mineral Density Body Compos c2017 Jun a599-6080 v1003 aAging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.
1 aCarbone, Laura, D1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBethel, Monique1 aHamrick, Mark, W1 aHill, William, D uhttps://chs-nhlbi.org/node/734104297nas a2200889 4500008004100000022001400041245007400055210006900129260001300198490000700211520176700218653002501985653001502010653001502025653002402040653001702064653003402081653001302115653001602128653001102144653004002155653004002195653002602235100003002261700002202291700001702313700001802330700001802348700001902366700002602385700002202411700002202433700001502455700002202470700001902492700002202511700001802533700003002551700002302581700001902604700002002623700002202643700001702665700002202682700002302704700002202727700002102749700002302770700002602793700001702819700002602836700002002862700002202882700002402904700002402928700002002952700001902972700002402991700002203015700002003037700002403057700001903081700002003100700002203120700002203142700001803164700001203182700001903194700002403213700001903237700002103256700002303277700002403300700002303324700002403347856003603371 2017 eng d a1942-326800aFifteen Genetic Loci Associated With the Electrocardiographic P Wave.0 aFifteen Genetic Loci Associated With the Electrocardiographic P c2017 Aug0 v103 aBACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.
METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.
CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.
10aArrhythmias, Cardiac10aCaveolin 110aCaveolin 210aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHumans10aNAV1.5 Voltage-Gated Sodium Channel10aNAV1.8 Voltage-Gated Sodium Channel10aT-Box Domain Proteins1 aChristophersen, Ingrid, E1 aMagnani, Jared, W1 aYin, Xiaoyan1 aBarnard, John1 aWeng, Lu-Chen1 aArking, Dan, E1 aNiemeijer, Maartje, N1 aLubitz, Steven, A1 aAvery, Christy, L1 aDuan, Qing1 aFelix, Stephan, B1 aBis, Joshua, C1 aKerr, Kathleen, F1 aIsaacs, Aaron1 aMüller-Nurasyid, Martina1 aMüller, Christian1 aNorth, Kari, E1 aReiner, Alex, P1 aTinker, Lesley, F1 aKors, Jan, A1 aTeumer, Alexander1 aPetersmann, Astrid1 aSinner, Moritz, F1 aBůzková, Petra1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVölker, Uwe1 aWaldenberger, Melanie1 aPeters, Annette1 aMeitinger, Thomas1 aLimacher, Marian, C1 aWilhelmsen, Kirk, C1 aPsaty, Bruce, M1 aHofman, Albert1 aUitterlinden, Andre1 aKrijthe, Bouwe, P1 aZhang, Zhu-Ming1 aSchnabel, Renate, B1 aKääb, Stefan1 aDuijn, Cornelia1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aDörr, Marcus1 aLi, Yun1 aChung, Mina, K1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aWhitsel, Eric, A1 aStricker, Bruno, H1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/755702478nas a2200241 4500008004100000022001400041245012400055210007000179260001600249300000700265490000700272520174300279100001702022700002102039700002002060700001802080700002102098700002402119700002102143700001902164700001702183856003602200 2017 eng d a1471-236900aHigher plasma transforming growth factor (TGF)-β is associated with kidney disease in older community dwelling adults.0 aHigher plasma transforming growth factor TGFβ is associated with c2017 Mar 21 a980 v183 aBACKGROUND: TGF-β is induced in the vasculature with aging suggesting that high plasma TGF-β levels may be a risk factor for chronic kidney disease (CKD) in older adults.
METHODS: We conducted a cross-sectional analysis of the association between plasma TGF-β levels and CKD including data for 1722 older adults who had participated in the 1996/97 visit of the Cardiovascular Health Study (CHS). Prevalent CKD was defined as eGFR < 60 mL/min/1.73 m(2) or urinary albumin/creatinine ratio (ACR) ≥30 mg/g. We also evaluated whether baseline TGF-β levels predicted change in eGFR, cardiovascular (CV) events, or mortality in longitudinal analysis.
RESULTS: Plasma TGF-β levels were significantly and independently associated with lower eGFR in cross-sectional analysis. Doubling of TGF-β was significantly associated with lower eGFR (β estimate after adjusting for CV risk factors = -1.18, 95% CI -2.03, -0.32). We observed no association with albuminuria. There was no association between baseline TGF-β and change in eGFR, but each doubling of TGF-β at baseline was associated with increased risk of a composite outcome of CV events and mortality, adjusted HR 1.10 (95% C.I. 1.02- 1.20, p = 0.006).
CONCLUSION: In this large cohort of community-dwelling older individuals, high plasma TGF-β levels are modestly, but independently associated with lower eGFR but not with albuminuria in cross-sectional analysis. In addition, TGF-β levels are associated with increased risk of CV events and mortality. Further research is needed to determine the direction of association between plasma TGF-β and the risk of CKD and CKD-associated morbidities in older adults.
1 aMehta, Tapan1 aBůzková, Petra1 aKizer, Jorge, R1 aDjoussé, Luc1 aChonchol, Michel1 aMukamal, Kenneth, J1 aShlipak, Michael1 aIx, Joachim, H1 aJalal, Diana uhttps://chs-nhlbi.org/node/735102586nas a2200289 4500008004100000022001400041245011400055210006900169260001600238520170000254100002601954700002101980700002402001700002302025700002002048700002002068700002002088700001802108700002202126700001902148700002002167700001302187700001902200700001702219700002402236856003602260 2017 eng d a1523-468100aSoluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study.0 aSoluble Inflammatory Markers and Risk of Incident Fractures in O c2017 Oct 043 aSeveral in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95% CI, 1.02 to 1.30) overall and HR 1.17 (95% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95% CI, 1.01 to 1.06) overall and HR 1.06 (95% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. © 2017 American Society for Bone and Mineral Research.
1 aStojanović, Danijela1 aBůzková, Petra1 aMukamal, Kenneth, J1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aFink, Howard, A1 aCauley, Jane, A1 aWallace, Erin1 aCurtis, Lesley, H1 aHirsch, Calvin1 aBudoff, Matthew1 aLi, Dong1 aYoung, Rebekah1 aJalal, Diana1 aDelaney, Joseph, Ac uhttps://chs-nhlbi.org/node/759204643nas a2200985 4500008004100000022001400041245023800055210006900293260001300362300001200375490000800387520178500395653002002180653001802200653002502218653001102243653001202254100003002266700001502296700002202311700002302333700002202356700002802378700001602406700002502422700002202447700002102469700002002490700002402510700001902534700001702553700002002570700002102590700001302611700001802624700002702642700002102669700002202690700002002712700001602732700001702748700002602765700001902791700001802810700002502828700001502853700002702868700002302895700002502918700001902943700001802962700002402980700002003004700002103024700001703045700001803062700001403080700001703094700001803111700001603129700002003145700001403165700001603179700002003195700002403215700002303239700002203262700002603284700002003310700002203330700001903352700002103371700002103392700002403413700002003437700002503457700002503482700001703507700002003524700001903544700002003563700001903583700001903602856003603621 2017 eng d a1432-120300aTrans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.0 aTransethnic finemapping of genetic loci for body mass index in t c2017 Jun a771-8000 v1363 aMost body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.
10aBody Mass Index10aEthnic Groups10aGenetics, Population10aHumans10aObesity1 aFernandez-Rhodes, Lindsay1 aGong, Jian1 aHaessler, Jeffrey1 aFranceschini, Nora1 aGraff, Mariaelisa1 aNishimura, Katherine, K1 aWang, Yujie1 aHighland, Heather, M1 aYoneyama, Sachiko1 aBush, William, S1 aGoodloe, Robert1 aRitchie, Marylyn, D1 aCrawford, Dana1 aGross, Myron1 aFornage, Myriam1 aBůzková, Petra1 aTao, Ran1 aIsasi, Carmen1 aAvilés-Santa, Larissa1 aDaviglus, Martha1 aMackey, Rachel, H1 aHouston, Denise1 aGu, Charles1 aEhret, Georg1 aNguyen, Khanh-Dung, H1 aLewis, Cora, E1 aLeppert, Mark1 aIrvin, Marguerite, R1 aLim, Unhee1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aSchumacher, Fredrick1 aWilkens, Lynne1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J L1 aSheu, Wayne, H-H1 aGuo, Xiuqing1 aLee, Wen-Jane1 aHai, Yang1 aHung, Yi-Jen1 aAbsher, Devin1 aWu, I-Chien1 aTaylor, Kent, D1 aLee, I-Te1 aLiu, Yeheng1 aWang, Tzung-Dau1 aQuertermous, Thomas1 aJuang, Jyh-Ming, J1 aRotter, Jerome, I1 aAssimes, Themistocles1 aHsiung, Chao, A1 aChen, Yii-Der Ida1 aPrentice, Ross1 aKuller, Lewis, H1 aManson, JoAnn, E1 aKooperberg, Charles1 aSmokowski, Paul1 aRobinson, Whitney, R1 aGordon-Larsen, Penny1 aLi, Rongling1 aHindorff, Lucia1 aBuyske, Steven1 aMatise, Tara, C1 aPeters, Ulrike1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/746503363nas a2200241 4500008004100000022001400041245014100055210006900196260001600265300001200281490000800293520258100301100003002882700002102912700001802933700001902951700002002970700002102990700002103011700001503032710003803047856003603085 2018 eng d a1873-276300aAssociation of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study.0 aAssociation of bone mineral density with hemoglobin and change i c2018 Nov 15 a321-3260 v1203 aPURPOSE: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD).
METHODS: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use.
RESULTS: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10 g/cmper 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10 g/cmper 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10 g/cmper 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women.
CONCLUSIONS: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement.
1 aValderrábano, Rodrigo, J1 aBůzková, Petra1 aChang, Po-Yin1 aZakai, Neil, A1 aFink, Howard, A1 aRobbins, John, A1 aLee, Jennifer, S1 aWu, Joy, Y1 aCardiovascular Health Study group uhttps://chs-nhlbi.org/node/793002502nas a2200241 4500008004100000245014200041210006900183260001200252300000900264490000700273520173500280653002502015653001702040653000902057653003202066100001702098700002102115700001702136700002002153700002002173700001802193856004902211 2018 eng d00aThe associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults.0 aassociations of subclinical atherosclerotic cardiovascular disea c08/2018 a22300 v293 aIn the absence of clinically recognized cardiovascular disease, increased carotid artery intimal medial thickness was associated with higher hip fracture risk in older adults, despite its association with higher bone mineral density (BMD). Low ankle brachial index and aortic wall thickness were not associated with fracture risk or BMD. INTRODUCTION: Clinically recognized cardiovascular disease (CVD) is associated with osteoporosis and hip fracture risk, but the relationship of subclinical atherosclerosis to bone health is not certain. METHODS: We followed 3385 participants from the Cardiovascular Health Study (mean age 74.7 ± 5.3 years) with a median time to fracture of 12.1 years who underwent baseline carotid artery and aortic wall ultrasound scanning and ankle brachial blood pressure index (ABI) determinations. A subset underwent bone mineral density (BMD) testing. RESULTS: There were 494 hip fractures during follow-up. Among persons without clinical CVD, an average standard-deviation increase in a composite score of maximal common and internal carotid artery intimal medial thickness (cIMT) was associated with increased risk of hip fracture [(HR 1.18 [1.04, 1.35]), even though cIMT was positively associated with BMD. Neither aortic wall thickness nor ABI were associated with hip fracture risk or BMD. Among participants with clinical CVD, cIMT and aortic wall thickness, but not ABI, were associated with increased hip fracture risk. CONCLUSION: Subclinical cIMT is associated with an increased risk of hip fractures despite being associated with increased BMD. This finding suggests that vascular health, even in its early stages, is linked to bone health, by pathways other than BMD.10aBone mineral density10aHip fracture10aRisk10aSubclinical atherosclerosis1 aBarzilay, JI1 aBůzková, Petra1 aCauley, J, A1 aRobbins, J., A.1 aFink, Howard, A1 aMukamal, K, J uhttps://www.ncbi.nlm.nih.gov/pubmed/3013202703689nas a2200553 4500008004100000022001400041245023400055210006900289260001600358300001400374490000700388520195100395100002602346700002102372700001602393700002202409700002002431700001902451700001902470700002502489700002202514700002802536700002302564700002902587700001902616700002102635700001802656700001302674700001902687700002502706700002402731700003002755700001902785700002102804700002102825700001802846700002302864700001602887700002202903700002302925700002002948700001902968700001902987700002703006700001903033700002303052700002403075856003603099 2018 eng d a1460-208300aDiscovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aDiscovery finemapping and conditional analyses of genetic varian c2018 Aug 15 a2940-29530 v273 aC-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.
1 aKocarnik, Jonathan, M1 aRichard, Melissa1 aGraff, Misa1 aHaessler, Jeffrey1 aBien, Stephanie1 aCarlson, Chris1 aCarty, Cara, L1 aReiner, Alexander, P1 aAvery, Christy, L1 aBallantyne, Christie, M1 aLaCroix, Andrea, Z1 aAssimes, Themistocles, L1 aBarbalic, Maja1 aPankratz, Nathan1 aTang, Weihong1 aTao, Ran1 aChen, Dongquan1 aTalavera, Gregory, A1 aDaviglus, Martha, L1 aChirinos-Medina, Diana, A1 aPereira, Rocio1 aNishimura, Katie1 aBůzková, Petra1 aBest, Lyle, G1 aAmbite, Jose, Luis1 aCheng, Iona1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aFornage, Myriam1 aHeiss, Gerardo1 aNorth, Kari, E1 aHaiman, Christopher, A1 aPeters, Ulrike1 aLe Marchand, Loïc1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/779802272nas a2200205 4500008004100000022001400041245009900055210006900154260001600223520160700239100002601846700002101872700002401893700002101917700002101938700002401959700002301983700002402006856003602030 2018 eng d a1932-873700aSerum Androgens and Risk of Atrial Fibrillation in Older Men: The Cardiovascular Health Study.0 aSerum Androgens and Risk of Atrial Fibrillation in Older Men The c2018 Apr 193 aBACKGROUND: Decline in serum androgens is common among older men and has been associated with cardiovascular disease, although its role in risk of atrial fibrillation (AF) has not been well defined.
HYPOTHESIS: Low serum androgens are associated with an increased risk of AF.
METHODS: We examined the prospective associations between testosterone, its more active metabolite dihydrotestosterone (DHT), and sex-hormone binding globulin (SHBG) with risk of AF among 1019 otherwise healthy men of average age 76.3±4.9 years in the Cardiovascular Health Study.
RESULTS: After median follow-up of 9.5 years, 304 (30%) men developed AF. We detected a nonlinear association with risk of incident AF in both free and total DHT, in which subjects with the lowest levels had a higher risk of incident AF. After adjustment for demographics, clinical risk factors, left atrial diameter, and serum NT-proBNP levels, men with free DHT less than 0.16 ng/dL were at increased risk compared with men with higher levels (HR 1.48, CI 1.01-2.17, p<0.05). Sensitivity analyses confirmed that the increased risk was not cutpoint-specific, with a significant association noted up to cutpoints less than ~0.2 ng/dL. We also detected a complex nonlinear association between SHBG and incident AF, in which subjects in the middle quintile (52.9 - 65.3 nmol/L) had increased risk.
CONCLUSION: Among older men, low free DHT is associated with an increased risk of incident atrial fibrillation. Further studies are needed to explore mechanisms for this association.
1 aRosenberg, Michael, A1 aShores, Molly, M1 aMatsumoto, Alvin, M1 aBůzková, Petra1 aLange, Leslie, A1 aKronmal, Richard, A1 aHeckbert, Susan, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/767003015nas a2200241 4500008004100000022001400041245013700055210006900192260001300261300001200274490000800286520225700294100001402551700002102565700002102586700002002607700002002627700002202647700002202669700002402691700002202715856003602737 2019 eng d a1432-082700aThe Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.0 aAssociation of Aromatic Amino Acids with Incident Hip Fracture a c2019 Aug a161-1720 v1053 aIn 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (n = 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p ≤ 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.
1 aLe, Brian1 aBůzková, Petra1 aRobbins, John, A1 aFink, Howard, A1 aRaiford, Mattie1 aIsales, Carlos, M1 aShikany, James, M1 aCoughlin, Steven, S1 aCarbone, Laura, D uhttps://chs-nhlbi.org/node/810402689nas a2200217 4500008004100000022001400041245012900055210006900184260001600253520198000269100002202249700002102271700002002292700002002312700001402332700002202346700002202368700002402390700002102414856003602435 2019 eng d a1523-468100aAssociation of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study.0 aAssociation of Dietary Niacin Intake With Incident Hip Fracture c2019 Jan 193 aInterest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women ≥65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95% CI, 1.04 to 1.66) and highest (HR 1.53; 95% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. © 2018 American Society for Bone and Mineral Research.
1 aCarbone, Laura, D1 aBůzková, Petra1 aFink, Howard, A1 aRaiford, Mattie1 aLe, Brian1 aIsales, Carlos, M1 aShikany, James, M1 aCoughlin, Steven, S1 aRobbins, John, A uhttps://chs-nhlbi.org/node/796702544nas a2200229 4500008004100000022001400041245011800055210006900173260001600242520180400258100002002062700002102082700001902103700002202122700002402144700002302168700002402191700001802215700002002233700002502253856003602278 2019 eng d a1440-179700aAssociation of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study.0 aAssociation of serum and urinary uromodulin and their correlates c2019 Dec 173 aUromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (β = 1.3 [1.1-1.6]), log2 C-reactive protein (β = -4.2 [-6.8 to -1.6]) and male sex (β = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (β = 3700 [400-7000]), while diabetes (β = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.
1 aSteubl, Dominik1 aBůzková, Petra1 aIx, Joachim, H1 aDevarajan, Prasad1 aBennett, Michael, R1 aChaves, Paolo, H M1 aShlipak, Michael, G1 aBansal, Nisha1 aSarnak, Mark, J1 aGarimella, Pranav, S uhttps://chs-nhlbi.org/node/827902803nas a2200229 4500008004100000022001400041245012600055210006900181260001600250520205500266100002002321700002102341700002502362700001902387700002202406700002402428700002302452700002402475700001802499700002002517856003602537 2019 eng d a1460-238500aAssociation of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study.0 aAssociation of serum uromodulin with mortality and cardiovascula c2019 Mar 213 aBACKGROUND: Uromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults.
METHODS: We measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL.
RESULTS: The mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)].
CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.
1 aSteubl, Dominik1 aBůzková, Petra1 aGarimella, Pranav, S1 aIx, Joachim, H1 aDevarajan, Prasad1 aBennett, Michael, R1 aChaves, Paulo, H M1 aShlipak, Michael, G1 aBansal, Nisha1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/800700665nas a2200181 4500008004100000022001400041245019100055210006900246260001200315300000900327490000700336653003000343653001800373653001100391100002100402700002400423856003600447 2019 eng d a1935-554800aComment on Davis et al. Development and Validation of a Simple Hip Fracture Risk Prediction Tool for Type 2 Diabetes: The Fremantle Diabetes Study Phase I. Diabetes Care 2018;42:102-109.0 aComment on Davis et al Development and Validation of a Simple Hi c2019 06 ae1000 v4210aDiabetes Mellitus, Type 210aHip Fractures10aHumans1 aBůzková, Petra1 aBarzilay, Joshua, I uhttps://chs-nhlbi.org/node/825802522nas a2200217 4500008004100000022001400041245019500055210006900250260001300319300001200332490000700344520176800351100002102119700002402140700002002164700002102184700002002205700001902225700002402244856003602268 2019 eng d a2048-850500aHigher albumin:creatinine ratio and lower estimated glomerular filtration rate are potential risk factors for decline of physical performance in the elderly: the Cardiovascular Health Study.0 aHigher albumincreatinine ratio and lower estimated glomerular fi c2019 Dec a788-7940 v123 aIntroduction: Mildly reduced renal function and elevated urine protein levels are each prospectively associated with hip fracture risk in older adults. Here we determine whether these markers are associated with reduced appendicular muscle performance.
Methods: We prospectively examined the associations of urine albumin:creatinine ratio (ACR) and reduced estimated glomerular filtration rate (eGFR) with longitudinal changes in grip strength and gait speed >2 years in 2317 older community-dwelling men and women (median age 77 years). The median ACR was 9.8 [interquartile range (IQR) 5.40-21.50] mg/g creatinine and the median eGFR was 71.6 (IQR 59.1-83.56) mL/min/1.73 m. Models were adjusted for demographic factors, clinical history and biochemical measures in four candidate pathways: diabetes, oxidative stress, inflammation and fibrosis.
Results: In demographic- and covariate-adjusted models, a 2-fold higher baseline urine ACR was associated with longitudinal changes of -0.17 kg [95% confidence interval (CI) -0.29 to -0.06) in grip strength and -1.10 cm/s (95% CI -1.67 to -0.53) gait speed per year. Corresponding estimates for a 10 mL/min/1.73 m lower baseline eGFR were -0.13 kg (95% CI -0.23 to -0.04) and -0.89 cm/s (95% CI -1.37 to -0.40), respectively. The associations of a 2-fold higher baseline ACR and a 10 mL/min/1.73 m lower baseline eGFR using cystatin C with grip strength and gait speed were equivalent to ∼1.2-1.9 additional years of age. Adjustment for covariates in candidate pathways did not attenuate these estimates.
Conclusions: In older adults, higher ACR and lower eGFR are potential risk factors for a decline of physical performance >2 years.
1 aBůzková, Petra1 aBarzilay, Joshua, I1 aFink, Howard, A1 aRobbins, John, A1 aCauley, Jane, A1 aIx, Joachim, H1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/825902027nas a2200217 4500008004100000022001400041245012700055210006900182260001500251300001600266490000700282520132500289100002301614700002101637700002401658700003001682700002101712700002001733700002001753856003601773 2020 eng d a1945-458900aAssociation of skeletal muscle mass, kidney disease and mortality in older men and women: the cardiovascular health study.0 aAssociation of skeletal muscle mass kidney disease and mortality c2020 11 02 a21023-210360 v123 aLow muscle mass (sarcopenia) is a prevalent and major concern in the aging population as well as in patients with chronic kidney disease (CKD). We hypothesized that sarcopenia is an independent predictor of incident and progressive CKD and increased mortality in older men and women (≥65 years) from the Cardiovascular Health Study. Sarcopenia was defined by bioimpedance-estimated skeletal muscle mass index (SMI) as a continuous variable and categorically (normal, class I, and class II). Cox regression hazard ratios (HRs) estimated the risk of incident and prevalent CKD and mortality in individuals with and without CKD. Low SMI was associated with increased prevalence of CKD in men (p<0.001), but lower prevalence of CKD in women (p=0.03). Low muscle mass was not associated with incident CKD or rapid CKD progression (>3 ml/minute/1.73m/year decline in eGFR) in men, but was associated with lower risk of incident CKD in women ([adjusted RR=0.69, 95% (0.51,0.94)]. Low muscle mass (class II) was independently associated with higher mortality only in men [(adjusted HR=1.26, 95% (1.05,1.50)]. Neither definition of sarcopenia was associated with mortality in men or women with CKD. Further studies are needed to understand the mechanisms by which sarcopenia contributes to higher mortality in aging men.
1 aKruse, Nicholas, T1 aBůzková, Petra1 aBarzilay, Joshua, I1 aValderrábano, Rodrigo, J1 aRobbins, John, A1 aFink, Howard, A1 aJalal, Diana, I uhttps://chs-nhlbi.org/node/862702369nas a2200181 4500008004100000022001400041245009300055210006900148260001600217520178500233100002402018700002102042700002402063700001802087700002202105700002402127856003602151 2020 eng d a1758-535X00aHospitalization Rates in Older Adults with Albuminuria: The Cardiovascular Health Study.0 aHospitalization Rates in Older Adults with Albuminuria The Cardi c2020 Jan 223 aBACKGROUND: Albuminuria is highly prevalent among older adults, especially those with diabetes. It is associated with several chronic diseases, but its overall impact on the health of older adults, as measured by hospitalization, has not been quantified.
METHODS: We followed 3110 adults, mean age 78 years, for a median 9.75 years, of whom 654 (21%) had albuminuria (>30 mg albumin / gram creatinine) at baseline. Poisson regression models, adjusted for cardiovascular, renal and demographic factors, were used to evaluate association of albuminuria with all-cause and cause-specific hospitalizations, as defined by ICD, version 9, categories.
RESULTS: The rates of hospitalization per 100 patient-years were 65.85 for participants with albuminuria and 37.55 for participants without albuminuria. After adjustment for covariates, participants with albuminuria were more likely to be hospitalized for any cause than participants without albuminuria (incident rate ratio [IRR], 1.39 [95% confidence intervals, 1.27. 1.53] and to experience more days in hospital (IRR 1.56 [1.37, 1.76]). The association of albuminuria with hospitalization was similar among participants with and without diabetes (adjusted IRR for albuminuria vs no albuminuria: diabetes 1.37 [1.11, 1.70], no diabetes 1.40 [1.26, 1.55]; p interaction NS). Albuminuria was significantly associated with hospitalization for circulatory, endocrine, genitourinary, respiratory, and injury categories.
CONCLUSIONS: Albuminuria in older adults is associated with an increased risk of hospitalization for a broad range of illnesses. Albuminuria in the presence or absence of diabetes appears to mark a generalized vulnerability to diseases of aging among older adults.
1 aBarzilay, Joshua, I1 aBůzková, Petra1 aShlipak, Michael, G1 aBansal, Nisha1 aGarimella, Pranav1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/828302520nas a2200181 4500008004100000022001400041245010500055210006900160260001600229520193100245100002402176700002102200700001802221700001902239700002002258700002402278856003602302 2020 eng d a1758-535X00aNon-Esterified Fatty Acids and Hospitalizations among Older Adults: The Cardiovascular Health Study.0 aNonEsterified Fatty Acids and Hospitalizations among Older Adult c2020 Sep 103 aBACKGROUND: We sought to determine associations between total serum concentrations of non-esterified fatty acids (NEFAs) and incident total and cause-specific hospitalizations in a community-living cohort of elders.
METHODS: We included 4715 participants in the Cardiovascular Health Study who had fasting total serum NEFA measured at the 1992/93 clinic visit and were followed for a median of 12 years. We identified all inpatient admissions requiring at least an overnight hospitalization and used primary diagnostic codes to categorize cause-specific hospitalizations. We used Cox proportional hazards regression models to determine associations with time-to-first hospitalization and Poisson regression for the rate ratios (RR) of hospitalizations and days hospitalized.
RESULTS: We identified 21339 hospitalizations during follow-up. In fully adjusted models, higher total NEFAs were significantly associated with higher risk of incident hospitalization (Hazard Ratio (HR) per SD [0.2 mEq/L]=1.07, 95%CI=1.03-1.10, P&0.001), number of hospitalizations (RR per SD=1.04, 95%CI=1.01-1.07, P=0.01), and total number of days hospitalized (RR per SD=1.06, 95%CI=1.01-1.10, P=0.01). Among hospitalization subtypes, higher NEFA was associated with higher likelihood of mental, neurologic, respiratory, and musculoskeletal causes of hospitalization. Among specific causes of hospitalization, higher NEFA was associated with diabetes, pneumonia, and gastrointestinal hemorrhage.
CONCLUSIONS: Higher fasting total serum NEFAs are associated with a broad array of causes of hospitalization among older adults. While some of these were expected, our results illustrate a possible utility of NEFAs as biomarkers for risk of hospitalization, and total days hospitalized, in older adults. Further research is needed to determine whether interventions based on NEFAs might be feasible.
1 aAhiawodzi, Peter, D1 aBůzková, Petra1 aDjoussé, Luc1 aIx, Joachim, H1 aKizer, Jorge, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/847602530nas a2200229 4500008004100000022001400041245007700055210006900132260001300201300001200214490000700226520185800233100002402091700002102115700002302136700002002159700002102179700002402200700002002224700002002244856003602264 2020 eng d a1532-841400aSoluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults.0 aSoluble CD14 and Risk of Heart Failure and Its Subtypes in Older c2020 May a410-4190 v263 aBACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.
METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as HF with preserved ejection fraction [HFpEF] and 419 as HF with reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (hazard ratio [HR]: 1.56 per doubling, 95% confidence interval [CI]: 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling: 1.10, 95% CI: 1.06-1.15), IL-6 (HR: 1.18, 95% CI: 1.10-1.25), and WBC (HR: 1.24, 95% CI: 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR: 1.50, 95% CI: 1.07-2.10) but not HFrEF (HR: 0.99, 95% CI: 0.67-1.49).
CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.
1 aAl-Kindi, Sadeer, G1 aBůzková, Petra1 aShitole, Sanyog, G1 aReiner, Alex, P1 aGarg, Parveen, K1 aGottdiener, John, S1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/837602582nas a2200241 4500008004100000022001400041245017200055210006900227260001600296300001200312490000700324520177900331100001902110700002102129700002302150700001802173700002202191700002002213700002002233700002402253700002702277856003602304 2021 eng d a2047-998000aAssociations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort.0 aAssociations of Serum Nonesterified Fatty Acids With Coronary He c2021 Mar 16 ae0191350 v103 aBackground Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n-6 and n-3], and fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996-1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow-up of 11.7 years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; =0.0328) and dihomo-γ-linolenic acid (20:3n-6) was positively associated with CHD mortality (HR, 1.34; 95% CI, 1.02-1.76; =0.0351). Elaidic acid (18:1n-7) was positively associated with incident nonfatal MI (HR, 1.46; 95% CI, 1.01-2.12; =0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo-γ-linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.
1 aHuang, Neil, K1 aBůzková, Petra1 aMatthan, Nirupa, R1 aDjoussé, Luc1 aHirsch, Calvin, H1 aKizer, Jorge, R1 aLongstreth, W T1 aMukamal, Kenneth, J1 aLichtenstein, Alice, H uhttps://chs-nhlbi.org/node/870703107nas a2200361 4500008004100000022001400041245010900055210006900164260001500233300000800248490000700256520206700263653000902330653002902339653001102368653001502379653001802394653001102412653001702423653003202440100002202472700002102494700002002515700002102535700002402556700002002580700001902600700001702619700002302636700002602659700002402685856003602709 2021 eng d a1862-351400aCardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study.0 aCardiovascular autonomic nervous system function and hip fractur c2021 10 31 a1630 v163 aAmong 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.
PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.
METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI).
RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.
CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.
10aAged10aAutonomic Nervous System10aFemale10aHeart Rate10aHip Fractures10aHumans10aOsteoporosis10aProportional Hazards Models1 aStein, Phyllis, K1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aMukamal, Kenneth, J1 aCauley, Jane, A1 aCarbone, Laura1 aElam, Rachel1 aMcMillan, David, W1 aValderrabano, Rodrigo1 aBarzilay, Joshua, I uhttps://chs-nhlbi.org/node/900401134nas a2200145 4500008004100000022001400041245007600055210006900131260000900200300001300209490000700222520070200229100002100931856003600952 2021 eng d a1932-620300aCompeting risk of mortality in association studies of non-fatal events.0 aCompeting risk of mortality in association studies of nonfatal e c2021 ae02553130 v163 aIn geriatric research of non-fatal events, participants often die during the study follow-up without having the non-fatal event of interest. Cause-specific (CS) hazard regression and Fine-Gray (FG) subdistribution hazard regression are the two most common estimation approaches addressing such competing risk. We explain how the conventional CS approach and the FG approach differ and why many FG estimates of associations are counter-intuitive. Additionally, we clarify the indirect link between models for hazard and models for cumulative incidence. The methodologies are contrasted on data from the Cardiovascular Health Study, a population-based study in adults aged 65 years and older.
1 aBůzková, Petra uhttps://chs-nhlbi.org/node/882702603nas a2200229 4500008004100000022001400041245010000055210006900155260001600224520188800240100002002128700002002148700002102168700002102189700001902210700002202229700002002251700002202271700002402293700002002317856003602337 2021 eng d a1468-201X00aCumulative burden of clinically significant aortic stenosis in community-dwelling older adults.0 aCumulative burden of clinically significant aortic stenosis in c c2021 Jun 023 aOBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.
METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.
RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]).
CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.
1 aOwens, David, S1 aBartz, Traci, M1 aBůzková, Petra1 aMassera, Daniele1 aBiggs, Mary, L1 aCarlson, Selma, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/878702579nas a2200241 4500008004100000022001400041245008900055210006900144260001600213520182700229100002402056700002102080700002702101700002302128700001902151700002402170700002302194700002202217700002402239700001802263700002002281856003602301 2021 eng d a1468-201X00aIndividual non-esterified fatty acids and incident atrial fibrillation late in life.0 aIndividual nonesterified fatty acids and incident atrial fibrill c2021 Jan 223 aOBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.
METHODS: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.
RESULTS: The study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.
CONCLUSIONS: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.
1 aPellegrini, Cara, N1 aBůzková, Petra1 aLichtenstein, Alice, H1 aMatthan, Nirupa, R1 aIx, Joachim, H1 aSiscovick, David, S1 aHeckbert, Susan, R1 aTracy, Russell, P1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/866503103nas a2200421 4500008004100000022001400041245015900055210006900214260001600283490000700299520182900306653000902135653002202144653002002166653001502186653002002201653002702221653003502248653001502283653003302298653003102331653001102362653001102373653001802384653000902402653002402411653001702435653002002452100001902472700002102491700002302512700001802535700002002553700002402573700002102597700002702618856003602645 2021 eng d a2072-664300aSerum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).0 aSerum NonEsterified Fatty Acids Carotid Artery IntimaMedia Thick c2021 Aug 310 v133 aElevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with ( = 255 for carotid IMT, 301 for FMD) or without ( = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. In multivariable adjusted linear regression models per SD increment, the non-esterified fatty acid conjugated linoleic acid (-18:2 CLA) was positively associated with carotid IMT [β (95% CI): 44.8 (19.2, 70.4), = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), = 1.000]. Non-esterified -palmitoleic acid (16:1n-7) was positively associated with FMD [19.7 (8.34, 31.0), = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.
10aAged10aAged, 80 and over10aAtherosclerosis10aBiomarkers10aBrachial Artery10aCarotid Artery, Common10aCarotid Intima-Media Thickness10aDilatation10aFatty Acids, Monounsaturated10aFatty Acids, Nonesterified10aFemale10aHumans10aLinoleic Acid10aMale10aRegional Blood Flow10aRisk Factors10aUltrasonography1 aHuang, Neil, K1 aBůzková, Petra1 aMatthan, Nirupa, R1 aDjoussé, Luc1 aKizer, Jorge, R1 aMukamal, Kenneth, J1 aPolak, Joseph, F1 aLichtenstein, Alice, H uhttps://chs-nhlbi.org/node/891102736nas a2200265 4500008004100000022001400041245010700055210006900162260001600231520191100247100002402158700002102182700002402203700001902227700001802246700002502264700001902289700002002308700002402328700001802352700001902370700002102389700002402410856003602434 2021 eng d a1532-541500aUrine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.0 aUrine creatinine concentration and clinical outcomes in older ad c2021 Aug 073 aPURPOSE: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.
METHODS: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.
RESULTS: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65).
CONCLUSION: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.
1 aBarzilay, Joshua, I1 aBůzková, Petra1 aShlipak, Michael, G1 aLyles, Mary, F1 aBansal, Nisha1 aGarimella, Pranav, S1 aIx, Joachim, H1 aKizer, Jorge, R1 aStrotmeyer, Elsa, S1 aDjoussé, Luc1 aBiggs, Mary, L1 aSiscovick, David1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/882502915nas a2200241 4500008004100000022001400041245022000055210006900275260001600344520204900360100001802409700002402427700002102451700002002472700002102492700002102513700002702534700001902561700002002580700002002600700001702620856003602637 2022 eng d a1097-679500aThe association of aortic valve sclerosis, aortic annulus increased reflectivity, and mitral annular calcification with subsequent aortic stenosis in older individuals. Findings from the Cardiovascular Health Study.0 aassociation of aortic valve sclerosis aortic annulus increased r c2022 Sep 093 aBACKGROUND: While aortic valve sclerosis (AVS) is well-described as preceding aortic stenosis (AS), the association of AS with antecedent mitral aortic annular calcification and aortic annulus increased reflectivity (MAC and AAIR, respectively) has not been characterized. In a population-based prospective study, we evaluated whether MAC, AAIR, and AVS are associated with the risk of incident AS.
METHODS: Among participants of the Cardiovascular Health Study (CHS) free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three were evaluated in 3041 participants. Cox proportional hazards regression was used to assess the association between the presence of calcification and the incidence of moderate/severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS.
RESULTS: Over a median follow-up of 11.5 years (IQR 6.7 to 17.0), 110 cases of incident moderate/severe AS were ascertained. Strong positive associations with incident moderate/severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (HR=2.90, 95% CI=[1.95, 4.32], p<0.0005), AVS (HR=2.20, 95% CI=[1.44, 3.37], p<0.0005), MAC (HR=1.67, 95% CI=[1.14, 2.45], p=0.008), and the combination of MAC, AAIR, and AVS (HR=2.50, 95% CI=[1.65, 3.78], p<0.0005). In a secondary analysis, the risk of AS increased with the number of sites at which calcification was present.
CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of MAC, AAIR, and AVS with incident moderate/severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS, and potential inclusion in the routine assessment by transthoracic echocardiography.
1 aBarasch, Eddy1 aGottdiener, John, S1 aTressel, William1 aBartz, Traci, M1 aBůzková, Petra1 aMassera, Daniele1 aDeFilippi, Christopher1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aKizer, Jorge, R1 aOwens, David uhttps://chs-nhlbi.org/node/915402657nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520177800240100001702018700002402035700002302059700002202082700002102104700002002125700002002145700001902165700002202184700002002206700002302226700002002249700002202269700001702291700002302308856003602331 2022 eng d a2055-582200aAssociation of immune cell subsets with incident heart failure in two population-based cohorts.0 aAssociation of immune cell subsets with incident heart failure i c2022 Sep 123 aAIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].
METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83-0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.
CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.
1 aSinha, Arjun1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aFohner, Alison, E1 aBůzková, Petra1 aFloyd, James, S1 aHuber, Sally, A1 aOlson, Nels, C1 aNjoroge, Joyce, N1 aKizer, Jorge, R1 aDelaney, Joseph, A1 aShah, Sanjiv, S1 aTracy, Russell, P1 aPsaty, Bruce1 aFeinstein, Matthew uhttps://chs-nhlbi.org/node/917502302nas a2200229 4500008004100000022001400041245010300055210006900158260001600227520158200243100002401825700002101849700002101870700002001891700002001911700001801931700002101949700002201970700002001992700002402012856003602036 2022 eng d a1555-716200aThe Association of Lipids and Lipoproteins with Hip Fracture Risk the Cardiovascular Health Study.0 aAssociation of Lipids and Lipoproteins with Hip Fracture Risk th c2022 Jun 063 aBACKGROUND: It is uncertain if lipids or lipoproteins are associated with osteoporotic fractures. In this study, incident hip fracture risk according to conventional lipid levels and lipoprotein levels and sizes was examined.
METHODS: We followed 5832 participants aged ≥65 years from the Cardiovascular Health Study for hip fracture for a mean of 13.5 (SD 5.7) years. Standard enzymatic methods were used to determine lipid levels (HDL-c, LDL-c, triglycerides). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein fractions (VLDL-P, LDL-P, HDL-P) in a subset of 1849 participants.
RESULTS: We documented 755 incident hip fractures among women (1.19 fractures per 100 participant years [95% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95% CI, 0.41, 1.10]) over an average follow-up. HDL-c and LDL-c levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-c, p=0.009; LDL-c, p=0.02). Triglyceride levels were not significantly associated with hip fracture risk. In fully adjusted conjoint models, higher VLDL-P concentration [HR per 1-standard (SD) increment 1.47 (1.13, 1.91)] and size [HR per 1-SD increment 1.24 [1.05, 1.46]) and higher HDL-P size (HR per 1-SD increment 1.81 [1.25, 2.62]) were all associated with higher hip fracture risk.
CONCLUSIONS: Lipids and lipoproteins are associated with hip fracture risk in older adults. The associations are complex. Mechanistic studies are needed to understand these findings.
1 aBarzilay, Joshua, I1 aBůzková, Petra1 aKuller, Lewis, H1 aCauley, Jane, A1 aFink, Howard, A1 aSheets, Kerry1 aRobbins, John, A1 aCarbone, Laura, D1 aElam, Rachel, E1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/908702793nas a2200253 4500008004100000022001400041245017100055210006900226260001600295520193800311100002102249700002102270700002702291700002302318700001902341700002002360700002202380700001802402700002002420700002102440700001802461700002402479856003602503 2022 eng d a1758-535X00aThe Associations of Individual and Subclasses of Non-Esterified Fatty Acids with Disability, and Mobility Limitation in Older Adults: the Cardiovascular Health Study.0 aAssociations of Individual and Subclasses of NonEsterified Fatty c2022 Sep 263 aBACKGROUND: We sought to determine the associations between individual non-esterified fatty acids (NEFAs) and disability and mobility limitation.
METHODS: We studied 1734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996-1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per-SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors.
RESULTS: Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation [disability: HR per SD of total NEFA (SD=174.70) =1.11, 95%CI=1.04-1.18, p=0.001; mobility limitation: HR per SD of total NEFA=1.09, 95%CI=1.02-1.16, p=0.01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation.
CONCLUSIONS: Higher risks of disability and mobility limitation were observed for pro-inflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs.
1 aAhiawodzi, Peter1 aBůzková, Petra1 aLichtenstein, Alice, H1 aMatthan, Nirupa, R1 aIx, Joachim, H1 aKizer, Jorge, R1 aTracy, Russell, P1 aArnold, Alice1 aNewman, Anne, B1 aSiscovick, David1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/915302519nas a2200217 4500008004100000022001400041245010400055210006900159260001600228520182600244100002402070700002102094700001902115700002302134700002202157700002402179700002402203700001802227700002002245856003602265 2022 eng d a1468-201X00aDysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age.0 aDysregulated carbohydrate and lipid metabolism and risk of atria c2022 Dec 223 aOBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.
METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.
RESULTS: The study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.
CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.
1 aPellegrini, Cara, N1 aBůzková, Petra1 aOesterle, Adam1 aHeckbert, Susan, R1 aTracy, Russell, P1 aSiscovick, David, S1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/925902585nas a2200217 4500008004100000022001400041245012500055210006900180260001600249520188200265100001902147700002102166700002102187700001902208700002202227700002402249700001802273700002002291700002002311856003602331 2022 eng d a1758-535X00aFasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and its Subtypes in Older Adults.0 aFasting and PostLoad Glucose and NonEsterified Fatty Acids and R c2022 Nov 143 aBACKGROUND: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined.
METHODS: Serum glucose and NEFA were measured during fasting and 2 hours post oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary).
RESULTS: Among 2238 participants (age 78±4) with median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (HR=1.11 per SD [95% CI=1.01-1.23], p=0.040) and post-load (HR=1.14 per SD [1.05-1.24], p=0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR=1.11 [1.003-1.22], p=0.044), but not fasting glucose (HR=1.06 [0.94-1.20], p=0.340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity, and were observed specifically for HFrEF, but not HFpEF.
CONCLUSIONS: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life.
1 aOesterle, Adam1 aBůzková, Petra1 aPellegrini, Cara1 aHirsch, Calvin1 aTracy, Russell, P1 aSiscovick, David, S1 aDjoussé, Luc1 aMukamal, Ken, J1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/925703449nas a2200517 4500008004100000022001400041245015400055210006900209260001200278300001000290490000800300520194800308653002002256653003102276653003102307653001402338653001102352653002202363653001102385653001402396653001702410653001802427653002002445653002602465653000902491653001402500653001102514653002502525100002602550700002102576700001902597700002302616700002402639700002202663700002002685700001702705700001702722700002102739700001702760700002502777700002702802700002202829700002002851700002402871856003602895 2022 eng d a1879-148400aMonocyte subsets, T cell activation profiles, and stroke in men and women: The Multi-Ethnic Study of Atherosclerosis and Cardiovascular Health Study.0 aMonocyte subsets T cell activation profiles and stroke in men an c2022 06 a18-250 v3513 aBACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke.
METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models.
RESULTS: We observed associations of intermediate monocytes, early-activated CD4 T cells, and both CD4 and CD8 T cells producing interleukin-4 after cytokine stimulation (T and T, respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women.
CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.
10aAtherosclerosis10aCD4-Positive T-Lymphocytes10aCD8-Positive T-Lymphocytes10aCytokines10aFemale10aFollow-Up Studies10aHumans10aIncidence10aInflammation10aInterleukin-410aIschemic Stroke10aLymphocyte Activation10aMale10aMonocytes10aStroke10aT-Lymphocyte Subsets1 aFeinstein, Matthew, J1 aBůzková, Petra1 aOlson, Nels, C1 aDoyle, Margaret, F1 aSitlani, Colleen, M1 aFohner, Alison, E1 aHuber, Sally, A1 aFloyd, James1 aSinha, Arjun1 aThorp, Edward, B1 aLanday, Alan1 aFreiberg, Matthew, S1 aLongstreth, William, T1 aTracy, Russell, P1 aPsaty, Bruce, M1 aDelaney, Joseph, Ac uhttps://chs-nhlbi.org/node/909003392nas a2200565 4500008004100000022001400041245014400055210006900199260001600268520170200284100002201986700002302008700002302031700001902054700002402073700002002097700001902117700001802136700002102154700002002175700003002195700002602225700002002251700002002271700002202291700002402313700002302337700002002360700002002380700002402400700002002424700002202444700001302466700002402479700002002503700001502523700002302538700002702561700001702588700001602605700002402621700002002645700002402665700002202689700002202711700002202733700001502755700002002770856003602790 2022 eng d a1573-728400aProteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.0 aProteomics and Population Biology in the Cardiovascular Health S c2022 Jul 053 aBACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.
METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.
CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.
1 aAustin, Thomas, R1 aMcHugh, Caitlin, P1 aBrody, Jennifer, A1 aBis, Joshua, C1 aSitlani, Colleen, M1 aBartz, Traci, M1 aBiggs, Mary, L1 aBansal, Nisha1 aBůzková, Petra1 aCarr, Steven, A1 adeFilippi, Christopher, R1 aElkind, Mitchell, S V1 aFink, Howard, A1 aFloyd, James, S1 aFohner, Alison, E1 aGerszten, Robert, E1 aHeckbert, Susan, R1 aKatz, Daniel, H1 aKizer, Jorge, R1 aLemaitre, Rozenn, N1 aLongstreth, W T1 aMcKnight, Barbara1 aMei, Hao1 aMukamal, Kenneth, J1 aNewman, Anne, B1 aNgo, Debby1 aOdden, Michelle, C1 aVasan, Ramachandran, S1 aShojaie, Ali1 aSimon, Noah1 aSmith, George Davey1 aDavies, Neil, M1 aSiscovick, David, S1 aSotoodehnia, Nona1 aTracy, Russell, P1 aWiggins, Kerri, L1 aZheng, Jie1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/908602689nas a2200217 4500008004100000022001400041245012200055210007100177260001600248520198600264100002402250700002102274700001902295700002702314700001702341700001802358700002002376700001702396700002202413856003602435 2022 eng d a1879-191300aRelation of Cigarette Smoking and Heart Failure in Adults ≥65 Years of Age (From the Cardiovascular Health Study).0 aRelation of Cigarette Smoking and Heart Failure in Adults ≥65 Ye c2022 Jan 163 aCigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.
1 aGottdiener, John, S1 aBůzková, Petra1 aKahn, Peter, A1 aDeFilippi, Christopher1 aShah, Sanjiv1 aBarasch, Eddy1 aKizer, Jorge, R1 aPsaty, Bruce1 aGardin, Julius, M uhttps://chs-nhlbi.org/node/897403034nas a2200409 4500008004100000022001400041245011900055210006900174260001200243300001100255490000800266520189800274653002702172653000902199653001702208653001102225653001802236653001102254653000902265653001702274653001702291100002002308700002102328700002402349700001702373700001502390700002302405700002002428700002002448700001502468700002102483700001502504700002202519700002502541700002202566856003602588 2022 eng d a1873-276300aTrimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.0 aTrimethylamine Noxide and hip fracture and bone mineral density c2022 08 a1164310 v1613 aCONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain.
OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults.
DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study.
PARTICIPANTS: 5019 U.S. adults aged ≥65 years.
EXPOSURE: Plasma TMAO.
MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400).
RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight.
CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.
10aAbsorptiometry, Photon10aAged10aBone Density10aFemale10aHip Fractures10aHumans10aMale10aMethylamines10aRisk Factors1 aElam, Rachel, E1 aBůzková, Petra1 aBarzilay, Joshua, I1 aWang, Zeneng1 aNemet, Ina1 aBudoff, Matthew, J1 aCauley, Jane, A1 aFink, Howard, A1 aLee, Yujin1 aRobbins, John, A1 aWang, Meng1 aHazen, Stanley, L1 aMozaffarian, Dariush1 aCarbone, Laura, D uhttps://chs-nhlbi.org/node/908902059nas a2200181 4500008004100000022001400041245005900055210005700114260001600171520152400187100002101711700002001732700002001752700002101772700002401793700002401817856003601841 2023 eng d a1530-891X00aAge-Related Factors Associated with Hip Fracture Risk.0 aAgeRelated Factors Associated with Hip Fracture Risk c2023 Mar 063 aOBJECTIVES: Advancing age is a powerful risk factor for hip fracture. The biological mechanisms through which aging impacts hip fracture risk have not been well studied.
METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with hip fracture risk are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults ages >65 years with 25 years of follow up.
RESULTS: Five age-related factors were found to be significantly associated with hip fracture risk: (1) microvascular disease of the kidney (albuminuria and / or elevated urine albumin to creatinine ratio) and of the brain (abnormal white matter disease on brain MRI); (2) increased serum levels of carboxymethyl-lysine (CML), an advanced glycation end-product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased trans-fatty acid levels in the blood. Each of these factors was associated with a 10-25%. increased risk of fracture. These associations were independent of traditional risk factors for hip fracture.
CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with hip fracture risk. These same factors may also explain the high risk for mortality following hip fracture.
1 aBůzková, Petra1 aCauley, Jane, A1 aFink, Howard, A1 aRobbins, John, A1 aMukamal, Kenneth, J1 aBarzilay, Joshua, I uhttps://chs-nhlbi.org/node/931803335nas a2200337 4500008004100000022001400041245015100055210006900206260001300275300001000288490000700298520234000305653000902645653002102654653001202675653001802687653001102705653002402716653001702740653001702757100002102774700002102795700001502816700002202831700002002853700002402873700002102897700002302918700002002941856003602961 2023 eng d a1433-296500aAssociation of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.0 aAssociation of covert brain infarcts and white matter hyperinten c2023 Jan a91-990 v343 aUNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture.
INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture.
METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive).
RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90).
CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.
10aAged10aBrain Infarction10aFrailty10aHip Fractures10aHumans10aProspective Studies10aRisk Factors10aWhite Matter1 aSheets, Kerry, M1 aBůzková, Petra1 aChen, Zhao1 aCarbone, Laura, D1 aCauley, Jane, A1 aBarzilay, Joshua, I1 aStarks, Jamie, L1 aMiller, Lindsay, M1 aFink, Howard, A uhttps://chs-nhlbi.org/node/924202665nas a2200313 4500008004100000022001400041245010000055210006900155260001600224520170900240100002001949700002101969700002501990700002002015700002402035700002202059700001502081700002102096700002402117700003002141700002002171700002202191700001902213700002002232700002302252700002002275700002002295856003602315 2023 eng d a1432-082700aAssociation of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.0 aAssociation of Immune Cell Subsets with Incident Hip Fracture Th c2023 Aug 313 aIn this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.
1 aElam, Rachel, E1 aBůzková, Petra1 aDelaney, Joseph, A C1 aFink, Howard, A1 aBarzilay, Joshua, I1 aCarbone, Laura, D1 aSaha, Rick1 aRobbins, John, A1 aMukamal, Kenneth, J1 aValderrábano, Rodrigo, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aOlson, Nels, C1 aHuber, Sally, A1 aDoyle, Margaret, F1 aLanday, Alan, L1 aCauley, Jane, A uhttps://chs-nhlbi.org/node/947802513nas a2200217 4500008004100000022001400041245016600055210006900221260001300290300001100303490000600314520179500320100001902115700002102134700002002155700002102175700002402196700002002220700001902240856003602259 2023 eng d a2473-403900aThe Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study.0 aAssociation of Tryptophan and Its Metabolites With Incident Hip c2023 Oct ae108010 v73 aAmino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( ≥ 0.64), mortality ( ≥ 0.20), or cross-sectional frailty status ( ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBarzilay, Joshua, I1 aElam, Rachel, E1 aIsales, Carlos uhttps://chs-nhlbi.org/node/949902924nas a2200337 4500008004100000022001400041245008300055210006900138260001600207300000700223490000700230520199400237653000902231653001202240653001802252653001102270653002702281653002202308100002402330700002102354700002002375700002002395700001902415700001702434700002102451700001902472700001802491700001702509700002402526856003602550 2023 eng d a1862-351400aThe associations of markers of endothelial dysfunction with hip fracture risk.0 aassociations of markers of endothelial dysfunction with hip frac c2023 Mar 02 a390 v183 aUNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them.
PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk.
METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group.
RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable.
CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.
10aAged10aForearm10aHip Fractures10aHumans10aOsteoporotic Fractures10aVascular Diseases1 aBarzilay, Joshua, I1 aBůzková, Petra1 aFink, Howard, A1 aCauley, Jane, A1 aCarbone, Laura1 aElam, Rachel1 aRobbins, John, A1 aStein, Phyllis1 aSheets, Kerry1 aJalal, Diana1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/931602760nas a2200265 4500008004100000022001400041245008600055210006900141260001600210520197300226100001702199700002102216700001902237700002002256700002002276700002402296700001702320700002002337700001902357700002002376700002402396700001802420700002002438856003602458 2023 eng d a2641-765000aCardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study.0 aCardiac Mechanics and Kidney Function Decline in the Cardiovascu c2023 Mar 083 aBACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.
METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e'). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30% decline in eGFR over 7 years.
RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e' were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30% decline in eGFR.
CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.
1 aMehta, Rupal1 aBůzková, Petra1 aPatel, Harnish1 aCheng, Jeanette1 aKizer, Jorge, R1 aGottdiener, John, S1 aPsaty, Bruce1 aKhan, Sadiya, S1 aIx, Joachim, H1 aIsakova, Tamara1 aShlipak, Michael, G1 aBansal, Nisha1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/932002516nas a2200325 4500008004100000022001400041245014100055210006900196260001300265300000900278490000600287520149900293653001801792653003101810653002401841653002201865653002801887653002301915100001901938700002301957700002101980700002002001700002002021700002402041700002202065700002002087700002402107700002302131856003602154 2023 eng d a2398-923800aCirculating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.0 aCirculating differentiated and senescent lymphocyte subsets and c2023 Jan ae3840 v63 aINTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain.
METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA ), memory (CD45RO ), senescent (CD28 ), and T effector memory RA (TEMRA) (CD28 CD57 CD45RA ) CD4 and CD8 T cells, and memory B cells (CD19 CD27 ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4 and CD8 subsets with incident DM risk.
RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4 , CD8 or CD19 cell phenotypes with incident DM.
CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.
10aCD28 Antigens10aCD8-Positive T-Lymphocytes10aCellular Senescence10aDiabetes Mellitus10aLeukocytes, Mononuclear10aLymphocyte Subsets1 aOlson, Nels, C1 aDoyle, Margaret, F1 aBůzková, Petra1 aHuber, Sally, A1 ade Boer, Ian, H1 aSitlani, Colleen, M1 aTracy, Russell, P1 aPsaty, Bruce, M1 aMukamal, Kenneth, J1 aDelaney, Joseph, A uhttps://chs-nhlbi.org/node/924002472nas a2200241 4500008004100000022001400041245009400055210006900149260001600218520173600234100002101970700002101991700002402012700002002036700002002056700002202076700001502098700002202113700001702135700001802152700002402170856003602194 2023 eng d a1555-716200aMortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease.0 aMortality Following Hip Fracture in Older Adults With and Withou c2023 Apr 243 aBACKGROUND: Comorbidities like coronary heart disease are common among older people who sustain an osteoporotic hip fracture. However, their impact on short- and long-term mortality post-hip fracture is not well quantified.
METHODS: We examined 4092 and 1173 older adults without and with prevalent coronary heart disease, respectively. Post-hip fracture mortality rates were computed with Poisson models and hazard ratios with Cox regression. For perspective, we compared mortality rates among participants with prevalent coronary heart disease who had either a hip fracture or incident heart failure (but no hip fracture).
RESULTS: Among participants without prevalent coronary heart disease, the mortality rate post-hip fracture was 21.83 per 100 participant years, including 49.27 per 100 participant years in the first 6 months following hip fracture. Among participants with prevalent coronary heart disease, the corresponding mortality rates were 32.52 and 79.44 per 100 participant years, respectively. Participants with prevalent coronary heart disease and incident heart failure (but no hip fracture) had corresponding post-incident heart failure mortality rates per 100 participant years of 25.62 overall and 46.4 in the first 6 months. In all 3 groups, the hazard ratio for mortality was similarly elevated: 5- to 7-fold at 6 months and 1.7- to 2.5-fold beyond 5 years.
CONCLUSION: As a case study in the absolute effects of a comorbidity on post-hip fracture mortality, hip fracture in a person with coronary heart disease carries an exceedingly high mortality rate, even higher than that following incident heart failure in individuals with coronary heart disease.
1 aRobbins, John, A1 aBůzková, Petra1 aBarzilay, Joshua, I1 aCauley, Jane, A1 aFink, Howard, A1 aCarbone, Laura, D1 aChen, Zhao1 aStein, Phyllis, K1 aElam, Rachel1 aSheets, Kerry1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/938402552nas a2200217 4500008004100000022001400041245011900055210006900174260001600243520184600259100001902105700002102124700002002145700002102165700002402186700002002210700001902230700002502249700002402274856003602298 2023 eng d a1945-719700aPlasma Levels of Branched Chain Amino Acids, Incident Hip Fractures and Bone Mineral Density of the Hip and Spine.0 aPlasma Levels of Branched Chain Amino Acids Incident Hip Fractur c2023 May 183 aOBJECTIVE: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine and isoleucine and total BCAA (standard deviation of the sum of Z-scores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study (CHS).
DESIGN: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the CHS.
SETTING: Community.
PARTICIPANTS: 1850 men (38% of cohort) and women; mean age 73.
MAIN OUTCOME MEASURES: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck and lumbar spine.
RESULTS: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine or total BCAA per 1 standard deviation higher of each BCAA. Plasma values of leucine but not valine, isoleucine or total BCAA, were positively and significantly associated with BMD of the total hip (p = 0.03) and femoral neck (p = 0.02), but not the lumbar spine (p = 0.07).
CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given lack of a significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.
1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBarzilay, Joshua, I1 aElam, Rachel, E1 aIsales, Carlos1 aConnelly, Margery, A1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/937502808nas a2200205 4500008004100000022001400041245011800055210007100173260001600244520214500260100001802405700002102423700002102444700001802465700001702483700002702500700001902527700002002546856003602566 2024 eng d a1945-719700aAssociation of thyroid dysfunction in individuals ≥ 65 years of age with subclinical cardiac abnormalities.0 aAssociation of thyroid dysfunction in individuals ≥ 65 years of c2024 Jan 063 aCONTEXT: The relationship between thyroid dysfunction and measures of myocardial disease in older individuals remains to be defined.
OBJECTIVE: To evaluate the impact of thyroid dysfunction on structure and function of the left-heart chambers and blood markers of cardiac disease.
DESIGN: Cross-sectional analysis.
SETTING: The Cardiovascular Health Study, a community-based cohort of older individuals recruited from four urban areas in the United States.
PATIENTS: Of 3163 participants studied, 2477 were euthyroid, 465 had subclinical hypothyroidism (SCH), 47 overt hypothyroidism (OH), 45 endogenous (endo) subclinical hyperthyroidism (endo-SCT), and 129 had exogenous (exo) SCT due to thyroid hormone supplementation.
INTERVENTIONS: Clinical evaluation, blood sampling and biomarker measurement, 2-dimensional and speckle-tracking echocardiography.
MAIN OUTCOME MEASURE(S): Left heart myocardial deformation, circulating biomarkers of diastolic overload (NT-proBNP), fibrosis (sST2, gal-3), and cardiomyocyte injury (hs-cTnT).
RESULTS: SCH was associated with higher NT-proBNP (beta = 0.17, p = 0.004), whereas OH was associated with higher hs-cTnT (beta = 0.29, p = 0.005). There were also suggestive associations of SCH with higher sST2, as well as endo-SCT with higher gal-3 and lower (worse) left atrial reservoir strain. Left ventricular longitudinal strain and end-diastolic strain rate did not differ significantly from euthyroid participants in SCH, OH, or exo-SCT.
CONCLUSIONS: In this free-living elderly cohort, subclinical and overt hypothyroidism were associated with abnormalities of blood biomarkers consistent with diastolic overload and myocardial necrosis respectively, whereas subclinical hyperthyroidism tended to be associated with myocardial fibrosis and decreased left atrial strain. Our findings could represent stage B heart failure and illuminate distinct aspects of the pathobiology of heart disease related to thyroid gland dysfunction with potential clinical implications.
1 aBarasch, Eddy1 aGottdiener, John1 aBůzková, Petra1 aCappola, Anne1 aShah, Sanjiv1 aDeFilippi, Christopher1 aGardin, Julius1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/9574