COL4A1 Is Associated With Arterial Stiffness By Genome Wide Association Scan.
Background—Pulse wave velocity (PWV), a non-invasive 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 4,221 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 1,828 individuals, using a custom-chip designed to include the top 43 non-redundant 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 two 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.
- Received September 22, 2008.
- Accepted January 26, 2009.
- Copyright © 2009, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited