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RESEARCH PRODUCT
Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies
Gerardo HeissBarbara RantnerBrenda W.j.h. PenninxJeffrey R. O'connellLambertus A. KiemeneyShih-jen HwangLuigi FerrucciKarl J. LacknerAnne B. NewmanSarah H. WildMegan E. RudockMeinhard HaltmayerPim Van Der HarstChrista MeisingerJerome I. RotterNora FranceschiniMarcus DörrJames F. WilsonOzren PolasekLinda BroerPhilipp S. WildJennifer E. HuffmanMaja BarbalićDavid CouperDavid M. HerringtonAnna MurrayDavid MelzerVijay NambiIngrid B. BoreckiMonika SummererStephen B. KritchevskyXiaohui LiLina ZgagaLina ZgagaWalter PalmasYongmei LiuGrgo GunjacaMichael H. CriquiFriedrich OberhollenzerAndrew R. WoodChristopher J. O'donnellStefan BlankenbergJingzhong DingMarietta StadlerBraxton D. MitchellDevin AbsherL. Adrienne CupplesMaryam KavousiAlan F. WrightMary F. FeitosaChristine Espinola-kleinBenjamin DieplingerJohann WilleitAlbert HofmanAstrid PetersmannQuince GibsonAaron R. FolsomGustav FraedrichJeffrey W. OlinJeffrey W. OlinEmile R. MohlerTatijana ZemunikKenneth RiceJoanne M. MurabitoJoanne M. MurabitoYan V. SunMartin Den HeijerNajaf AminMatthew A. AllisonWolfgang LiebIlja M. NolteVeronique VitartStephan B. FelixThomas MünzelAndré G. UitterlindenJohn P. CookeEric BoerwinkleCornelia M. Van DuijnBen A. OostraSuzanne HolewijnSuzanne HolewijnAlice M. ArnoldIvana MudnićThemistocles L. AssimesThomas MuellerTanja ZellerRuth Frikke-schmidtH.-erich WichmannAndrea SenftChristina L. WasselDana C. CrawfordAlan R. ShuldinerFernando RivadeneiraHarold SniederWiek H. Van GilstKristin Brown-gentryCaroline HaywardFolkert W. AsselbergsStefan CoassinKurt LohmanFlorian KronenbergAlexander TeumerStefan KiechlToshiko TanakaSharon L.r. KardiaClaudia LaminaMladen BobanJacqueline C.m. WittemanArne KiebackRobert GoodloeAdrie SeldenrijkAbbas DehghanLindsay L. WaiteMargot HaunMay E. MontasserBarbara KolleritsIvana KolcicSita H. VermeulenBruce M. PsatyIftikhar J. KulloJacqueline De GraafGerjan NavisUwe VölkerHarry CampbellAnne Tybjærg-hansenIgor RudanIgor RudanAndreas ZieglerYurii S. AulchenkoStefania BandinelliArne SchillertCharles C. WhiteJoshua C. BisKari E. Northsubject
Malegenetic associationGenome-wide association studyAetiology screening and detection [ONCOL 5]030204 cardiovascular system & hematologyBioinformaticsCohort Studies0302 clinical medicineRisk FactorsGenotypeCARDIOVASCULAR RISK-FACTORSInternational HapMap ProjectGenetics (clinical)POPULATIONGeneticsAged 80 and overPeripheral Vascular Diseases0303 health scienceseducation.field_of_studyAge FactorsMiddle AgedPhenotypeperipheral vascular diseaseMeta-analysiscardiovascular system/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_beingCORONARY-ARTERY-DISEASEFemaleCardiology and Cardiovascular MedicineChromosomes Human Pair 9AdultSUSCEPTIBILITY LOCIGenotypePopulationHapMap ProjectBiologyPolymorphism Single NucleotideArticleMolecular epidemiology [NCEBP 1]03 medical and health sciencesSex FactorsSDG 3 - Good Health and Well-beingGeneticscohort studyHumansAnkle Brachial Indexcardiovascular diseasesAlleleeducationHealth aging / healthy living Cardiovascular diseases [IGMD 5]AllelesMolecular epidemiology Aetiology screening and detection [NCEBP 1]030304 developmental biologyGenetic associationAgedCyclin-Dependent Kinase Inhibitor p15ABDOMINAL AORTIC-ANEURYSMcohort study ; genetic association ; genome-wide association study ; meta-analysis ; peripheral vascular diseasegenome-wide association studyMORTALITYChromosomeGENEmeta-analysisbody regionsLogistic ModelsMYOCARDIAL-INFARCTIONATHEROSCLEROSISSEQUENCE VARIANThuman activitiesdescription
Background— 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-02-01 |