02708nas a2200469 4500008004100000022001400041245014600055210006900201260001300270300001100283490000800294520133100302653002201633653000901655653001201664653002301676653002801699653001901727653004001746653001101786653001901797653003801816653002201854653001101876653001801887653001201905653002501917653000901942653003601951653003001987100002302017700002002040700001802060700001802078700001702096700001702113700002002130700001902150700001702169700001702186856003502203 2007 eng d a1432-120300aIL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study.0 aIL6 gene variation is associated with IL6 and Creactive protein c2007 Dec a485-940 v1223 a
Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.
10aAfrican Americans10aAged10aAlleles10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenetic Variation10aHumans10aInterleukin-610aIntrons10aLongitudinal Studies10aMale10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic1 aWalston, Jeremy, D1 aFallin, Daniele1 aCushman, Mary1 aLange, Leslie1 aPsaty, Bruce1 aJenny, Nancy1 aBrowner, Warren1 aTracy, Russell1 aDurda, Peter1 aReiner, Alex uhttps://chs-nhlbi.org/node/98203243nas a2200625 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520141500253653002701668653002001695653003801715653004001753653001701793653003401810653001101844653003801855653001501893100001901908700001901927700001901946700001901965700002201984700002402006700001702030700002102047700002302068700002002091700001302111700002202124700001802146700001702164700002002181700001802201700002202219700002702241700002202268700002202290700002802312700002302340700001702363700002302380700002002403700002102423700001902444700002102463700002002484700002802504700002502532700002402557856003602581 2010 eng d a1460-208300aLarge-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels.0 aLargescale genomic studies reveal central role of ABO in sPselec c2010 May 01 a1863-720 v193 aP-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.
10aABO Blood-Group System10aBlood Platelets10aEnzyme-Linked Immunosorbent Assay10aEuropean Continental Ancestry Group10aFluorescence10aGenome-Wide Association Study10aHumans10aIntercellular Adhesion Molecule-110aP-Selectin1 aBarbalic, Maja1 aDupuis, Josée1 aDehghan, Abbas1 aBis, Joshua, C1 aHoogeveen, Ron, C1 aSchnabel, Renate, B1 aNambi, Vijay1 aBretler, Monique1 aSmith, Nicholas, L1 aPeters, Annette1 aLu, Chen1 aTracy, Russell, P1 aAleksic, Nena1 aHeeriga, Jan1 aKeaney, John, F1 aRice, Kenneth1 aLip, Gregory, Y H1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aLarson, Martin, G1 aUitterlinden, André, G1 aYamamoto, Jennifer1 aDurda, Peter1 aHaritunians, Talin1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aHofman, Albert1 aKoenig, Wolfgang1 aJenny, Nancy, S1 aWitteman, Jacqueline, C1 aBallantyne, Christie1 aBenjamin, Emelia, J uhttps://chs-nhlbi.org/node/116903628nas a2200529 4500008004100000022001400041245010700055210006900162260001300231300001100244490000700255520202700262653001002289653002202299653000902321653002202330653002402352653002502376653001902401653002702420653001102447653002202458653001102480653000902491653001602500653004002516653002402556653001702580653002402597100002302621700001902644700002402663700001902687700001702706700001702723700002802740700002202768700002202790700002302812700002402835700001802859700002402877700002502901700002202926710011402948856003603062 2014 eng d a1540-816700aA common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans.0 acommon SCN5A variant is associated with PR interval and atrial f c2014 Nov a1150-70 v253 aOBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.
BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.
METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).
RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).
CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAtrial Fibrillation10aCase-Control Studies10aCohort Studies10aDeath, Sudden, Cardiac10aFemale10aGenetic Variation10aHumans10aMale10aMiddle Aged10aNAV1.5 Voltage-Gated Sodium Channel10aProspective Studies10aRisk Factors10aSingle-Blind Method1 aIlkhanoff, Leonard1 aArking, Dan, E1 aLemaitre, Rozenn, N1 aAlonso, Alvaro1 aChen, Lin, Y1 aDurda, Peter1 aHesselson, Stephanie, E1 aKerr, Kathleen, F1 aMagnani, Jared, W1 aMarcus, Gregory, M1 aSchnabel, Renate, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aReiner, Alexander, P1 aSotoodehnia, Nona1 aCandidate-Gene Association Resource (CARE) Consortium and the Cardiac Arrest Blood Study (CABS) Investigators uhttps://chs-nhlbi.org/node/657004043nas a2200769 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520183700298653001002135653002202145653000902167653001502176653002302191653002802214653001802242653001102260653001702271653003802288653002502326653003402351653001102385653002702396653001602423653003602439653001702475100001802492700002002510700001202530700001902542700001802561700002302579700002402602700001702626700001802643700002302661700001702684700001802701700002302719700002402742700002102766700001702787700002002804700001902824700001502843700002702858700002302885700002102908700002102929700002802950700002202978700002803000700002003028700002203048700002103070700001903091700002103110700002203131700001903153700002003172700002403192700002103216856003603237 2014 eng d a1432-120300aLarge multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.0 aLarge multiethnic Candidate Gene Study for Creactive protein lev c2014 Aug a985-950 v1333 aC-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
10aAdult10aAfrican Americans10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCD36 Antigens10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetics, Population10aGenome-Wide Association Study10aHumans10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aEllis, Jaclyn1 aLange, Ethan, M1 aLi, Jin1 aDupuis, Josée1 aBaumert, Jens1 aWalston, Jeremy, D1 aKeating, Brendan, J1 aDurda, Peter1 aFox, Ervin, R1 aPalmer, Cameron, D1 aMeng, Yan, A1 aYoung, Taylor1 aFarlow, Deborah, N1 aSchnabel, Renate, B1 aMarzi, Carola, S1 aLarkin, Emma1 aMartin, Lisa, W1 aBis, Joshua, C1 aAuer, Paul1 aRamachandran, Vasan, S1 aGabriel, Stacey, B1 aWillis, Monte, S1 aPankow, James, S1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBallantyne, Christie, M1 aGross, Myron, D1 aLettre, Guillaume1 aWilson, James, G1 aPeters, Ulrike1 aKoenig, Wolfgang1 aTracy, Russell, P1 aRedline, Susan1 aReiner, Alex, P1 aBenjamin, Emelia, J1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/655804252nas 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/636005955nas 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/657703704nas a2200589 4500008004100000022001400041245013900055210007000194260001300264300001200277490000700289520197000296653001002266653002202276653002102298653000902319653002802328653001902356653002802375653001102403653003802414653003402452653001102486653001402497653004102511653002602552653000902578653001602587653003602603653003202639653002402671653002002695653002102715653002202736100001702758700002102775700002002796700001902816700002602835700002502861700001202886700002002898700002202918700002002940700002002960700001702980700001802997700002003015700002203035700002103057856003603078 2015 eng d a1524-463600aPlasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.0 aPlasma Levels of Soluble Interleukin2 Receptor α Associations Wi c2015 Oct a2246-530 v353 aOBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.
APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.
CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.
10aAdult10aAfrican Americans10aAge Distribution10aAged10aCardiovascular Diseases10aCohort Studies10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aIncidence10aInterleukin-2 Receptor alpha Subunit10aKaplan-Meier Estimate10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aSex Distribution10aSurvival Analysis1 aDurda, Peter1 aSabourin, Jeremy1 aLange, Ethan, M1 aNalls, Mike, A1 aMychaleckyj, Josyf, C1 aJenny, Nancy, Swords1 aLi, Jin1 aWalston, Jeremy1 aHarris, Tamara, B1 aPsaty, Bruce, M1 aValdar, William1 aLiu, Yongmei1 aCushman, Mary1 aReiner, Alex, P1 aTracy, Russell, P1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/680902593nas a2200325 4500008004100000022001400041245014800055210006900203260001300272300001300285490000600298520161100304100002301915700003101938700002001969700002101989700001702010700001402027700001502041700002102056700001902077700001902096700002302115700001702138700002302155700001902178700001802197700001602215856003602231 2017 eng d a2375-254800aThe GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.0 aGH receptor exon 3 deletion is a marker of malespecific exceptio c2017 Jun ae16020250 v33 aAlthough both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.
1 aBen-Avraham, Danny1 aGovindaraju, Diddahally, R1 aBudagov, Temuri1 aFradin, Delphine1 aDurda, Peter1 aLiu, Bing1 aOtt, Sandy1 aGutman, Danielle1 aSharvit, Lital1 aKaplan, Robert1 aBougnères, Pierre1 aReiner, Alex1 aShuldiner, Alan, R1 aCohen, Pinchas1 aBarzilai, Nir1 aAtzmon, Gil uhttps://chs-nhlbi.org/node/755206570nas a2201753 4500008004100000022001400041245007100055210006900126260001200195300001200207490000800219520164100227100002301868700002501891700002601916700002201942700001701964700002401981700002002005700001902025700002602044700001902070700001602089700002002105700002902125700002702154700001602181700002202197700002002219700002002239700002502259700002402284700001902308700002002327700001902347700002002366700002402386700002002410700002602430700002702456700002502483700002402508700001402532700002202546700002302568700002102591700002302612700001902635700002302654700001702677700002302694700001802717700002102735700001902756700002302775700002502798700002202823700002402845700002402869700001902893700002702912700001902939700001702958700002202975700001902997700002103016700001903037700002203056700001903078700001903097700002003116700002203136700002203158700002503180700001903205700002103224700002303245700002103268700002303289700002303312700002203335700001903357700001803376700002203394700002103416700002203437700002103459700002103480700002003501700001903521700002003540700002203560700001803582700002203600700002003622700001703642700001703659700001603676700001503692700002703707700002303734700001703757700002403774700002103798700002003819700002103839700002403860700002503884700002403909700002303933700002503956700002303981700002104004700001904025700002004044700001904064700002804083700001804111700002104129700002104150700002304171700001804194700002004212700002304232700001804255700002404273700002104297700002504318700002104343700001704364700001704381700001804398700002104416700002204437700002104459700001704480700002204497700002004519700002304539700002304562700002504585700002404610700002204634700002304656700002204679700002304701710005604724856003604780 2020 eng d a1476-468700aInherited causes of clonal haematopoiesis in 97,691 whole genomes.0 aInherited causes of clonal haematopoiesis in 97691 whole genomes c2020 10 a763-7680 v5863 aAge is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aNandakumar, Satish, K1 aFulco, Charles, P1 aBao, Erik, L1 aZekavat, Seyedeh, M1 aSzeto, Mindy, D1 aLiao, Xiaotian1 aLeventhal, Matthew, J1 aNasser, Joseph1 aChang, Kyle1 aLaurie, Cecelia1 aBurugula, Bala, Bharathi1 aGibson, Christopher, J1 aLin, Amy, E1 aTaub, Margaret, A1 aAguet, Francois1 aArdlie, Kristin1 aMitchell, Braxton, D1 aBarnes, Kathleen, C1 aMoscati, Arden1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aSilverman, Edwin, K1 aWeiss, Scott, T1 aPalmer, Nicholette, D1 aVasan, Ramachandran, S1 aBurchard, Esteban, G1 aKardia, Sharon, L R1 aHe, Jiang1 aKaplan, Robert, C1 aSmith, Nicholas, L1 aArnett, Donna, K1 aSchwartz, David, A1 aCorrea, Adolfo1 ade Andrade, Mariza1 aGuo, Xiuqing1 aKonkle, Barbara, A1 aCuster, Brian1 aPeralta, Juan, M1 aGui, Hongsheng1 aMeyers, Deborah, A1 aMcGarvey, Stephen, T1 aChen, Ida Yii-Der1 aShoemaker, Benjamin1 aPeyser, Patricia, A1 aBroome, Jai, G1 aGogarten, Stephanie, M1 aWang, Fei, Fei1 aWong, Quenna1 aMontasser, May, E1 aDaya, Michelle1 aKenny, Eimear, E1 aNorth, Kari, E1 aLauner, Lenore, J1 aCade, Brian, E1 aBis, Joshua, C1 aCho, Michael, H1 aLasky-Su, Jessica1 aBowden, Donald, W1 aCupples, Adrienne, L1 aC Y Mak, Angel1 aBecker, Lewis, C1 aSmith, Jennifer, A1 aKelly, Tanika, N1 aAslibekyan, Stella1 aHeckbert, Susan, R1 aTiwari, Hemant, K1 aYang, Ivana, V1 aHeit, John, A1 aLubitz, Steven, A1 aJohnsen, Jill, M1 aCurran, Joanne, E1 aWenzel, Sally, E1 aWeeks, Daniel, E1 aRao, Dabeeru, C1 aDarbar, Dawood1 aMoon, Jee-Young1 aTracy, Russell, P1 aButh, Erin, J1 aRafaels, Nicholas1 aLoos, Ruth, J F1 aDurda, Peter1 aLiu, Yongmei1 aHou, Lifang1 aLee, Jiwon1 aKachroo, Priyadarshini1 aFreedman, Barry, I1 aLevy, Daniel1 aBielak, Lawrence, F1 aHixson, James, E1 aFloyd, James, S1 aWhitsel, Eric, A1 aEllinor, Patrick, T1 aIrvin, Marguerite, R1 aFingerlin, Tasha, E1 aRaffield, Laura, M1 aArmasu, Sebastian, M1 aWheeler, Marsha, M1 aSabino, Ester, C1 aBlangero, John1 aWilliams, Keoki1 aLevy, Bruce, D1 aSheu, Wayne, Huey-Herng1 aRoden, Dan, M1 aBoerwinkle, Eric1 aManson, JoAnn, E1 aMathias, Rasika, A1 aDesai, Pinkal1 aTaylor, Kent, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aKooperberg, Charles1 aLaurie, Cathy, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aZhao, Hongyu1 aLange, Ethan1 aLange, Leslie1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aScheet, Paul1 aKitzman, Jacob, O1 aLander, Eric, S1 aEngreitz, Jesse, M1 aEbert, Benjamin, L1 aReiner, Alexander, P1 aJaiswal, Siddhartha1 aAbecasis, Goncalo1 aSankaran, Vijay, G1 aKathiresan, Sekar1 aNatarajan, Pradeep1 aNHLBI Trans-Omics for Precision Medicine Consortium uhttps://chs-nhlbi.org/node/862104776nas a2201261 4500008004100000022001400041245010300055210006900158260001500227300000900242490000700251520104900258653001001307653002201317653000901339653002201348653005001370653002901420653002401449653001101473653002201484653001701506653003801523653003401561653001101595653005001606653000901656653000901665653001601674653003601690653004101726653004301767653004001810653004601850653002801896100001701924700001601941700001801957700001801975700001501993700001502008700001702023700001902040700001702059700003002076700002902106700002202135700002302157700001302180700002102193700001902214700001902233700001502252700002002267700001902287700002302306700002002329700002502349700002002374700002002394700002402414700002002438700002702458700002102485700002002506700001702526700001902543700002002562700001702582700001702599700002202616700002302638700002002661700002502681700002802706700002202734700002402756700001702780700002602797700002002823700002302843700003102866700002502897700001902922700002002941700002102961700002402982700001903006700002003025700002103045700002403066700002503090700002403115700002203139700002003161700002103181700002503202700002303227700002603250700002503276700002403301700001703325700002003342700002103362710006503383710003003448856003603478 2020 eng d a2041-172300aWhole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.0 aWhole genome sequence analysis of pulmonary function and COPD in c2020 10 14 a51820 v113 aChronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aCalcium-Binding Proteins10aFeasibility Studies10aFemale10aFollow-Up Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aIntracellular Signaling Peptides and Proteins10aLung10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Inhibitors of Activated STAT10aPulmonary Disease, Chronic Obstructive10aRespiratory Physiological Phenomena10aSmall Ubiquitin-Related Modifier Proteins10aWhole Genome Sequencing1 aZhao, Xutong1 aQiao, Dandi1 aYang, Chaojie1 aKasela, Silva1 aKim, Wonji1 aMa, Yanlin1 aShrine, Nick1 aBatini, Chiara1 aSofer, Tamar1 aTaliun, Sarah, A Gagliano1 aSakornsakolpat, Phuwanat1 aBalte, Pallavi, P1 aProkopenko, Dmitry1 aYu, Bing1 aLange, Leslie, A1 aDupuis, Josée1 aCade, Brian, E1 aLee, Jiwon1 aGharib, Sina, A1 aDaya, Michelle1 aLaurie, Cecelia, A1 aRuczinski, Ingo1 aCupples, Adrienne, L1 aLoehr, Laura, R1 aBartz, Traci, M1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aWilson, James, G1 aTaylor, Kent, D1 aDurda, Peter1 aJohnson, Craig1 aCornell, Elaine1 aGuo, Xiuqing1 aLiu, Yongmei1 aTracy, Russell, P1 aArdlie, Kristin, G1 aAguet, Francois1 aVanDenBerg, David, J1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBarnes, Kathleen, C1 aJain, Deepti1 aNickerson, Deborah, A1 aMuzny, Donna, M1 aMetcalf, Ginger, A1 aDoddapaneni, Harshavardhan1 aDugan-Perez, Shannon1 aGupta, Namrata1 aGabriel, Stacey1 aRich, Stephen, S1 aO'Connor, George, T1 aRedline, Susan1 aReed, Robert, M1 aLaurie, Cathy, C1 aDaviglus, Martha, L1 aPreudhomme, Liana, K1 aBurkart, Kristin, M1 aKaplan, Robert, C1 aWain, Louise, V1 aTobin, Martin, D1 aLondon, Stephanie, J1 aLappalainen, Tuuli1 aOelsner, Elizabeth, C1 aAbecasis, Goncalo, R1 aSilverman, Edwin, K1 aBarr, Graham1 aCho, Michael, H1 aManichaikul, Ani1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lung Working Group uhttps://chs-nhlbi.org/node/863903432nas a2200457 4500008004100000022001400041245018200055210006900237260001300306300001200319490000700331520203700338653000902375653001702384653004602401653003202447653001502479653002802494653001102522653003402533653001802567653001102585653002502596653000902621100001702630700002302647700002002670700001902690700002502709700001802734700002202752700001802774700001802792700001902810700002602829700002002855700002002875700002202895700002102917856003602938 2022 eng d a2047-998000aCirculating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study.0 aCirculating Soluble CD163 Associations With Cardiovascular Outco c2022 Nov ae0243740 v113 aBackground Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.
10aAged10aAntigens, CD10aAntigens, Differentiation, Myelomonocytic10aAsialoglycoprotein Receptor10aBiomarkers10aCardiovascular Diseases10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aLongitudinal Studies10aMale1 aDurda, Peter1 aRaffield, Laura, M1 aLange, Ethan, M1 aOlson, Nels, C1 aJenny, Nancy, Swords1 aCushman, Mary1 aDeichgraeber, Pia1 aGrarup, Niels1 aJonsson, Anna1 aHansen, Torben1 aMychaleckyj, Josyf, C1 aPsaty, Bruce, M1 aReiner, Alex, P1 aTracy, Russell, P1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/924503779nas a2200673 4500008004100000245013300041210006900174260001600243520177100259100001902030700002202049700001402071700002002085700002002105700001502125700001902140700002202159700002702181700001402208700002102222700002002243700001902263700002102282700001902303700001702322700002202339700002102361700002202382700002502404700002102429700002002450700002502470700002402495700002202519700001902541700001602560700002302576700002002599700001902619700001502638700002102653700002302674700002202697700002402719700002002743700001902763700001902782700001602801700002002817700002402837700002502861700002302886700001602909700001802925700002302943710006502966710003803031856003603069 2023 eng d00aWhole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.0 aWhole Genome Sequencing Based Analysis of Inflammation Biomarker c2023 Sep 123 aInflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
1 aJiang, Min-Zhi1 aGaynor, Sheila, M1 aLi, Xihao1 aVan Buren, Eric1 aStilp, Adrienne1 aButh, Erin1 aWang, Fei, Fei1 aManansala, Regina1 aGogarten, Stephanie, M1 aLi, Zilin1 aPolfus, Linda, M1 aSalimi, Shabnam1 aBis, Joshua, C1 aPankratz, Nathan1 aYanek, Lisa, R1 aDurda, Peter1 aTracy, Russell, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aPsaty, Bruce, M1 aPratte, Katherine, A1 aSilverman, Edwin, K1 aKaplan, Robert, C1 aAvery, Christy1 aNorth, Kari1 aMathias, Rasika, A1 aFaraday, Nauder1 aLin, Honghuang1 aWang, Biqi1 aCarson, April, P1 aNorwood, Arnita, F1 aGibbs, Richard, A1 aKooperberg, Charles1 aLundin, Jessica1 aPeters, Ulrike1 aDupuis, Josée1 aHou, Lifang1 aFornage, Myriam1 aBenjamin, Emelia, J1 aReiner, Alexander, P1 aBowler, Russell, P1 aLin, Xihong1 aAuer, Paul, L1 aRaffield, Laura, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Inflammation Working Group uhttps://chs-nhlbi.org/node/9500