03311nas a2200601 4500008004100000022001400041245020900055210006900264260001600333300001100349490000800360520151200368653001001880653002201890653000901912653002801921653001901949653004001968653001102008653001502019653003802034653001502072653001102087653000902098653001602107653001402123653003602137653001702173100002502190700002102215700002402236700002002260700002302280700002002303700001902323700002302342700002002365700001202385700001602397700002302413700001802436700002102454700001902475700002202494700002102516700002202537700002102559700002102580700001702601700003002618700002502648856003602673 2011 eng d a1528-002000aAssociation of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe).0 aAssociation of genomic loci from a cardiovascular gene SNP array c2011 Jan 06 a268-750 v1173 a
Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aWassel, Christina, L1 aLange, Leslie, A1 aKeating, Brendan, J1 aTaylor, Kira, C1 aJohnson, Andrew, D1 aPalmer, Cameron1 aHo, Lindsey, A1 aSmith, Nicholas, L1 aLange, Ethan, M1 aLi, Yun1 aYang, Qiong1 aDelaney, Joseph, A1 aTang, Weihong1 aTofler, Geoffrey1 aRedline, Susan1 aTaylor, Herman, A1 aWilson, James, G1 aTracy, Russell, P1 aJacobs, David, R1 aFolsom, Aaron, R1 aGreen, David1 aO'Donnell, Christopher, J1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156207377nas a2201945 4500008004100000022001400041245014700055210006900202260001600271300001100287490000600298520192200304653001002226653001602236653000902252653002202261653001202283653002502295653003102320653001902351653004202370653001102412653003402423653001302457653001902470653001102489653002002500653000902520653001602529653003302545653001402578653003602592653001702628653001602645100002402661700002202685700002002707700001602727700002102743700001702764700002002781700002002801700002002821700001902841700001702860700002202877700002302899700002502922700001702947700002202964700002502986700002003011700001903031700002303050700002203073700001903095700002103114700001803135700002203153700001503175700002203190700002203212700002003234700002503254700002103279700002403300700001603324700001803340700002703358700002103385700002503406700001903431700001803450700002603468700002103494700002303515700001903538700002403557700002503581700002003606700001803626700003003644700002203674700002003696700002103716700002203737700001903759700002003778700001803798700002403816700001903840700001903859700001803878700002703896700001803923700002303941700002803964700002103992700001604013700001904029700001704048700002304065700001804088700002104106700001804127700002004145700001804165700002904183700002104212700002004233700003004253700001904283700002304302700002304325700001904348700002004367700002104387700001404408700002604422700002204448700002204470700002204492700002104514700002004535700002604555700002804581700001904609700002304628700001904651700002104670700002004691700001804711700002204729700001604751700002904767700002404796700002104820700002004841700001904861700002504880700002204905700002404927700002504951700001704976700002004993700002005013700001905033700001605052700002305068700002005091700002305111700001705134700002005151700002205171700002105193700003005214700001705244700002205261700002305283700002105306700001905327700002505346700002405371856003605395 2012 eng d a1942-326800aAssociation between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.0 aAssociation between chromosome 9p21 variants and the anklebrachi c2012 Feb 01 a100-120 v53 aBACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAlleles10aAnkle Brachial Index10aChromosomes, Human, Pair 910aCohort Studies10aCyclin-Dependent Kinase Inhibitor p1510aFemale10aGenome-Wide Association Study10aGenotype10aHapMap Project10aHumans10aLogistic Models10aMale10aMiddle Aged10aPeripheral Vascular Diseases10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aSex Factors1 aMurabito, Joanne, M1 aWhite, Charles, C1 aKavousi, Maryam1 aSun, Yan, V1 aFeitosa, Mary, F1 aNambi, Vijay1 aLamina, Claudia1 aSchillert, Arne1 aCoassin, Stefan1 aBis, Joshua, C1 aBroer, Linda1 aCrawford, Dana, C1 aFranceschini, Nora1 aFrikke-Schmidt, Ruth1 aHaun, Margot1 aHolewijn, Suzanne1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aKiechl, Stefan1 aKollerits, Barbara1 aMontasser, May, E1 aNolte, Ilja, M1 aRudock, Megan, E1 aSenft, Andrea1 aTeumer, Alexander1 aHarst, Pim1 aVitart, Veronique1 aWaite, Lindsay, L1 aWood, Andrew, R1 aWassel, Christina, L1 aAbsher, Devin, M1 aAllison, Matthew, A1 aAmin, Najaf1 aArnold, Alice1 aAsselbergs, Folkert, W1 aAulchenko, Yurii1 aBandinelli, Stefania1 aBarbalic, Maja1 aBoban, Mladen1 aBrown-Gentry, Kristin1 aCouper, David, J1 aCriqui, Michael, H1 aDehghan, Abbas1 aHeijer, Martin, den1 aDieplinger, Benjamin1 aDing, Jingzhong1 aDörr, Marcus1 aEspinola-Klein, Christine1 aFelix, Stephan, B1 aFerrucci, Luigi1 aFolsom, Aaron, R1 aFraedrich, Gustav1 aGibson, Quince1 aGoodloe, Robert1 aGunjaca, Grgo1 aHaltmayer, Meinhard1 aHeiss, Gerardo1 aHofman, Albert1 aKieback, Arne1 aKiemeney, Lambertus, A1 aKolcic, Ivana1 aKullo, Iftikhar, J1 aKritchevsky, Stephen, B1 aLackner, Karl, J1 aLi, Xiaohui1 aLieb, Wolfgang1 aLohman, Kurt1 aMeisinger, Christa1 aMelzer, David1 aMohler, Emile, R1 aMudnic, Ivana1 aMueller, Thomas1 aNavis, Gerjan1 aOberhollenzer, Friedrich1 aOlin, Jeffrey, W1 aO'Connell, Jeff1 aO'Donnell, Christopher, J1 aPalmas, Walter1 aPenninx, Brenda, W1 aPetersmann, Astrid1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRantner, Barbara1 aRice, Ken1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeldenrijk, Adrie1 aStadler, Marietta1 aSummerer, Monika1 aTanaka, Toshiko1 aTybjaerg-Hansen, Anne1 aUitterlinden, André, G1 aGilst, Wiek, H1 aVermeulen, Sita, H1 aWild, Sarah, H1 aWild, Philipp, S1 aWilleit, Johann1 aZeller, Tanja1 aZemunik, Tatijana1 aZgaga, Lina1 aAssimes, Themistocles, L1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aCampbell, Harry1 aCooke, John, P1 ade Graaf, Jacqueline1 aHerrington, David1 aKardia, Sharon, L R1 aMitchell, Braxton, D1 aMurray, Anna1 aMünzel, Thomas1 aNewman, Anne, B1 aOostra, Ben, A1 aRudan, Igor1 aShuldiner, Alan, R1 aSnieder, Harold1 aDuijn, Cornelia, M1 aVölker, Uwe1 aWright, Alan, F1 aWichmann, H-Erich1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aLiu, Yongmei1 aHayward, Caroline1 aBorecki, Ingrid, B1 aZiegler, Andreas1 aNorth, Kari, E1 aCupples, Adrienne, L1 aKronenberg, Florian uhttps://chs-nhlbi.org/node/135905476nas a2201057 4500008004100000022001400041245018100055210006900236260001300305300001100318490000800329520232500337653001002662653002202672653000902694653002502703653003402728653002802762653004002790653001102830653001102841653000902852653001602861653003702877653003202914653003602946653001702982653004202999100002503041700002003066700001703086700002003103700002403123700002203147700002103169700002303190700002803213700001903241700001903260700001503279700002203294700002203316700002203338700002403360700002303384700002303407700001703430700002503447700002003472700001903492700002203511700001903533700002203552700002103574700002203595700001903617700001703636700001603653700002303669700002603692700002303718700002603741700002503767700002303792700002103815700002503836700002203861700002003883700002403903700002403927700002103951700002203972700002703994700001804021700002404039700002604063700002004089700002904109700002104138700001904159700002104178700002104199700002504220700002404245700002104269700001904290700002504309700002404334700002404358856003604382 2012 eng d a1879-148400aGenetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.0 aGenetic determinants of the anklebrachial index a metaanalysis o c2012 May a138-470 v2223 aBACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.
METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.
RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
10aAdult10aAfrican Americans10aAged10aAnkle Brachial Index10aAryl Hydrocarbon Hydroxylases10aCytochrome P-450 CYP2B610aEuropean Continental Ancestry Group10aFemale10aHumans10aMale10aMiddle Aged10aOxidoreductases, N-Demethylating10aPeripheral Arterial Disease10aPolymorphism, Single Nucleotide10aRisk Factors10aTranscription Factor 7-Like 2 Protein1 aWassel, Christina, L1 aLamina, Claudia1 aNambi, Vijay1 aCoassin, Stefan1 aMukamal, Kenneth, J1 aGanesh, Santhi, K1 aJacobs, David, R1 aFranceschini, Nora1 aPapanicolaou, George, J1 aGibson, Quince1 aYanek, Lisa, R1 aHarst, Pim1 aFerguson, Jane, F1 aCrawford, Dana, C1 aWaite, Lindsay, L1 aAllison, Matthew, A1 aCriqui, Michael, H1 aMcDermott, Mary, M1 aMehra, Reena1 aCupples, Adrienne, L1 aHwang, Shih-Jen1 aRedline, Susan1 aKaplan, Robert, C1 aHeiss, Gerardo1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aTaylor, Herman, A1 aEraso, Luis, H1 aHaun, Margot1 aLi, Mingyao1 aMeisinger, Christa1 aO'Connell, Jeffrey, R1 aShuldiner, Alan, R1 aTybjærg-Hansen, Anne1 aFrikke-Schmidt, Ruth1 aKollerits, Barbara1 aRantner, Barbara1 aDieplinger, Benjamin1 aStadler, Marietta1 aMueller, Thomas1 aHaltmayer, Meinhard1 aKlein-Weigel, Peter1 aSummerer, Monika1 aWichmann, H-Erich1 aAsselbergs, Folkert, W1 aNavis, Gerjan1 aLeach, Irene, Mateo1 aBrown-Gentry, Kristin1 aGoodloe, Robert1 aAssimes, Themistocles, L1 aBecker, Diane, M1 aCooke, John, P1 aAbsher, Devin, M1 aOlin, Jeffrey, W1 aMitchell, Braxton, D1 aReilly, Muredach, P1 aMohler, Emile, R1 aNorth, Kari, E1 aReiner, Alexander, P1 aKronenberg, Florian1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/586404131nas 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/609405955nas a2201657 4500008004100000022001400041245011000055210006900165260001600234300001100250490000700261520138800268653001001656653000901666653002201675653002101697653001901718653001801737653001001755653001101765653002201776653001901798653001701817653003401834653001301868653001101881653001101892653000901903653001601912653001401928653003601942653002801978653002702006653001902033653002702052653002602079100002102105700001402126700001402140700001602154700002202170700002202192700001702214700002002231700002102251700002102272700001302293700002002306700001702326700001502343700001702358700002002375700001402395700002702409700001802436700002202454700001602476700001902492700001702511700002102528700002302549700002002572700001802592700002202610700001802632700001502650700001202665700001702677700001502694700001802709700001902727700001902746700001902765700002502784700002602809700002102835700002502856700002102881700001902902700002502921700001702946700002502963700001202988700002303000700002003023700002603043700002903069700002303098700002803121700001803149700002003167700002303187700002103210700001903231700001803250700002803268700001903296700002403315700002303339700002803362700001703390700002203407700002203429700002403451700002403475700002003499700002303519700002203542700001603564700001703580700002403597700002003621700001803641700002003659700002103679700001603700700001903716700002203735700002803757700002303785700003003808700001903838700001903857700002503876700002103901700002003922700002103942700002203963700001603985700002004001700002504021700002404046700002104070700002604091700002504117700002104142700002204163700002304185710005304208856003604261 2014 eng d a1537-660500aWhole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.0 aWholeexome sequencing identifies rare and lowfrequency coding va c2014 Feb 06 a233-450 v943 aElevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
10aAdult10aAged10aApolipoproteins E10aCholesterol, LDL10aCohort Studies10aDyslipidemias10aExome10aFemale10aFollow-Up Studies10aGene Frequency10aGenetic Code10aGenome-Wide Association Study10aGenotype10aHumans10aLipase10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aProprotein Convertase 910aProprotein Convertases10aReceptors, LDL10aSequence Analysis, DNA10aSerine Endopeptidases1 aLange, Leslie, A1 aHu, Youna1 aZhang, He1 aXue, Chenyi1 aSchmidt, Ellen, M1 aTang, Zheng-Zheng1 aBizon, Chris1 aLange, Ethan, M1 aSmith, Joshua, D1 aTurner, Emily, H1 aJun, Goo1 aKang, Hyun, Min1 aPeloso, Gina1 aAuer, Paul1 aLi, Kuo-Ping1 aFlannick, Jason1 aZhang, Ji1 aFuchsberger, Christian1 aGaulton, Kyle1 aLindgren, Cecilia1 aLocke, Adam1 aManning, Alisa1 aSim, Xueling1 aRivas, Manuel, A1 aHolmen, Oddgeir, L1 aGottesman, Omri1 aLu, Yingchang1 aRuderfer, Douglas1 aStahl, Eli, A1 aDuan, Qing1 aLi, Yun1 aDurda, Peter1 aJiao, Shuo1 aIsaacs, Aaron1 aHofman, Albert1 aBis, Joshua, C1 aCorrea, Adolfo1 aGriswold, Michael, E1 aJakobsdottir, Johanna1 aSmith, Albert, V1 aSchreiner, Pamela, J1 aFeitosa, Mary, F1 aZhang, Qunyuan1 aHuffman, Jennifer, E1 aCrosby, Jacy1 aWassel, Christina, L1 aDo, Ron1 aFranceschini, Nora1 aMartin, Lisa, W1 aRobinson, Jennifer, G1 aAssimes, Themistocles, L1 aCrosslin, David, R1 aRosenthal, Elisabeth, A1 aTsai, Michael1 aRieder, Mark, J1 aFarlow, Deborah, N1 aFolsom, Aaron, R1 aLumley, Thomas1 aFox, Ervin, R1 aCarlson, Christopher, S1 aPeters, Ulrike1 aJackson, Rebecca, D1 aDuijn, Cornelia, M1 aUitterlinden, André, G1 aLevy, Daniel1 aRotter, Jerome, I1 aTaylor, Herman, A1 aGudnason, Vilmundur1 aSiscovick, David, S1 aFornage, Myriam1 aBorecki, Ingrid, B1 aHayward, Caroline1 aRudan, Igor1 aChen, Eugene1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSætrom, Pål1 aHveem, Kristian1 aBoehnke, Michael1 aGroop, Leif1 aMcCarthy, Mark1 aMeitinger, Thomas1 aBallantyne, Christie, M1 aGabriel, Stacey, B1 aO'Donnell, Christopher, J1 aPost, Wendy, S1 aNorth, Kari, E1 aReiner, Alexander, P1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aAltshuler, David1 aKathiresan, Sekar1 aLin, Dan-Yu1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aKooperberg, Charles1 aWilson, James, G1 aNickerson, Deborah, A1 aAbecasis, Goncalo, R1 aRich, Stephen, S1 aTracy, Russell, P1 aWiller, Cristen, J1 aNHLBI Grand Opportunity Exome Sequencing Project uhttps://chs-nhlbi.org/node/657705480nas a2201321 4500008004100000022001400041245007700055210006900132260001600201520175400217100002301971700001901994700002402013700001902037700001802056700002102074700002302095700001702118700002002135700001802155700001702173700002002190700002002210700002802230700002502258700001802283700002402301700001702325700002402342700002102366700002002387700001902407700001302426700003102439700001602470700001702486700002302503700001802526700002202544700002502566700002002591700002102611700001902632700001902651700002102670700002102691700002202712700002202734700002302756700001902779700001802798700001902816700001802835700001902853700002002872700002402892700001902916700002202935700002002957700001902977700002502996700002203021700002303043700002003066700002303086700001903109700002603128700002203154700002103176700002003197700001603217700002503233700002303258700002303281700002203304700002603326700002103352700002203373700002003395700002203415700002003437700002303457700002803480700002203508700002203530700001703552700002303569700002503592700001803617700002403635700002103659700002103680700002103701700002203722700001803744700001903762700002203781700002403803700002203827700002003849700002903869700002003898700002103918700002203939700002103961700002303982700001904005700002204024700002404046700003004070710002204100856003604122 2016 eng d a1942-326800aMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.0 aMultiethnic ExomeWide Association Study of Subclinical Atheroscl c2016 Nov 213 aBACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).
CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
1 aNatarajan, Pradeep1 aBis, Joshua, C1 aBielak, Lawrence, F1 aCox, Amanda, J1 aDörr, Marcus1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIsaacs, Aaron1 aJhun, Min, A1 aKavousi, Maryam1 aLi-Gao, Ruifang1 aLyytikäinen, Leo-Pekka1 aMarioni, Riccardo, E1 aSchminke, Ulf1 aStitziel, Nathan, O1 aTada, Hayato1 avan Setten, Jessica1 aSmith, Albert, V1 aVojinovic, Dina1 aYanek, Lisa, R1 aYao, Jie1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aBaber, Usman1 aBorecki, Ingrid, B1 aCarr, Jeffrey1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 ade Jong, Pim, A1 ade Koning, Harry1 ade Vos, Bob, D1 aDemirkan, Ayse1 aFuster, Valentin1 aFranco, Oscar, H1 aGoodarzi, Mark, O1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHoffmann, Udo1 aHofman, Albert1 aIšgum, Ivana1 aJukema, Wouter1 aKähönen, Mika1 aKardia, Sharon, L R1 aKral, Brian, G1 aLauner, Lenore, J1 aMassaro, Joseph1 aMehran, Roxana1 aMitchell, Braxton, D1 aMosley, Thomas, H1 ade Mutsert, Renée1 aNewman, Anne, B1 aNguyen, Khanh-Dung1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOudkerk, Matthijs1 aPankow, James, S1 aPeloso, Gina, M1 aPost, Wendy1 aProvince, Michael, A1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRivadeneira, Fernando1 aRosendaal, Frits1 aSartori, Samantha1 aTaylor, Kent, D1 aTeumer, Alexander1 aTrompet, Stella1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Lugt, Aad1 aVölker, Uwe1 aWardlaw, Joanna, M1 aWassel, Christina, L1 aWeiss, Stefan1 aWojczynski, Mary, K1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBowden, Donald, W1 aDeary, Ian, J1 aDehghan, Abbas1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aLehtimäki, Terho1 aMathias, Rasika1 aMook-Kanamori, Dennis, O1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRotter, Jerome, I1 aWilson, James, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aKathiresan, Sekar1 aPeyser, Patricia, A1 aO'Donnell, Christopher, J1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/725703442nas a2200469 4500008004100000022001400041245018400055210006900239260001300308300001200321490000700333520199400340100002202334700002502356700002402381700002502405700002002430700001702450700002402467700002002491700002602511700001302537700002302550700002002573700002702593700001902620700002202639700001902661700002102680700002302701700002002724700002102744700002202765700001702787700002102804700001902825700002702844700002202871700002402893700001902917856003602936 2017 eng d a1556-387100aFine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.0 aFine mapping of QT interval regions in global populations refine c2017 Apr a572-5800 v143 aBACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.
OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.
METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.
RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.
CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.
1 aAvery, Christy, L1 aWassel, Christina, L1 aRichard, Melissa, A1 aHighland, Heather, M1 aBien, Stephanie1 aZubair, Niha1 aSoliman, Elsayed, Z1 aFornage, Myriam1 aBielinski, Suzette, J1 aTao, Ran1 aSeyerle, Amanda, A1 aShah, Sanjiv, J1 aLloyd-Jones, Donald, M1 aBuyske, Steven1 aRotter, Jerome, I1 aPost, Wendy, S1 aRich, Stephen, S1 aHindorff, Lucia, A1 aJeff, Janina, M1 aShohet, Ralph, V1 aSotoodehnia, Nona1 aLin, Dan, Yu1 aWhitsel, Eric, A1 aPeters, Ulrike1 aHaiman, Christopher, A1 aCrawford, Dana, C1 aKooperberg, Charles1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/746307247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/7913