Published online before print February 18, 2009, doi: 10.1161/CIRCGENETICS.108.823245
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Original Articles |
COL4A1 Is Associated With Arterial Stiffness by Genome-Wide Association Scan
From the Laboratory of Cardiovascular Science (K.V.T., J.B.S., E.G.L., S.S.N.), Laboratory of Genetics (K.V.T., J.B.S., D.S., R.N.), Clinial Research Branch (T.T.), Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md; Istituto di Neurogenetica e Neurofarmacologia (INN) (S.S., M.O., A.M., S.L., G.P., M.M., A.C., M.U.), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monseratto, Monserrato, Cagliari, Italy; Unitá Operativa Geriatria (A.S.), Istituto Nazionale Ricovero e Cura per Anziani (INRCA) IRCCS, Rome, Italy; Divisions of Nephrology (A.P.) and Endocrinology, Diabetes and Nutrition (P.-I.L., J.R.O., B.D.M., A.R.S.), Department of Medicine, University of Maryland School of Medicine, Baltimore, Md; Maryland Psychiatric Research Center (P.-I.L.), Department of Psychiatry, University of Maryland School of Medicine, Catonsville, Md; Division of Cardiology (W.P.), Department of Medicine, Johns Hopkins School of Medicine; Department of Epidemiology (W.P.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md; Department of Biostatistics (G.R.A.), Center for Statistical Genetics, University of Michigan, Ann Arbor, Mich; and Geriatrics Research and Education Clinical Center (A.R.S.), Veterans Administration Medical Center, Baltimore, Md.
Correspondence to Samer S. Najjar, MD, NIA/ASTRA Unit, Harbor Hospital, 5th floor, 3001 South Hanover St, Baltimore, MD 21225. E-mail NajjarSa{at}mail.nih.gov
Received September 22, 2008; accepted January 26, 2009.
Background— Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV.
Methods and Results— The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age2, and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the COL4A1 gene on chromosome 13 and SNP rs1495448 in the MAGI1 gene on chromosome 3 were successfully replicated (P=7.08x10–7 and P=1.06x10–5, respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (P=0.02) in an independent population, the Old-Order Amish, leading to an overall P=5.16x10–8.
Conclusions— A genome-wide association study identified a SNP in the COL4A1 gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness.
Key Words: arterial stiffness • pulse wave velocity • genome-wide association scan • COL4A1, MAGI1 • nonsynomous SNP
CLINICAL PERSPECTIVE
*The first 2 authors contributed equally to this work.The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.823245/DC1.
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