title: COL4A1 is associated with arterial stiffness by genome-wide association scan.
abstract: 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.
  
  
  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, age(2), 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=7.08 x 10(-7) and P=1.06 x 10(-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=5.16 x 10(-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.
authors.affiliation: Laboratory of Cardiovascular Science, Laboratory of Genetics, Clinical Research Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Kirill V
authors.initials: KV
authors.lastname: Tarasov
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Angelo
authors.initials: A
authors.lastname: Scuteri
authors.forename: James B
authors.initials: JB
authors.lastname: Strait
authors.forename: Marco
authors.initials: M
authors.lastname: Orrù
authors.forename: Afshin
authors.initials: A
authors.lastname: Parsa
authors.forename: Ping-I
authors.initials: PI
authors.lastname: Lin
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.forename: Sandra
authors.initials: S
authors.lastname: Lai
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Piras
authors.forename: Marco
authors.initials: M
authors.lastname: Masala
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Wendy
authors.initials: W
authors.lastname: Post
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Ramaiah
authors.initials: R
authors.lastname: Nagaraja
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Samer S
authors.initials: SS
authors.lastname: Najjar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001158:Arteries / Q000503:physiopathology*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D015331:Cohort Studies; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV