COL4A1 is associated with arterial stiffness by genome-wide association scan.
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.
Tarasov
Kirill V
KV
Laboratory of Cardiovascular Science, Laboratory of Genetics, Clinical Research Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Sanna
Serena
S
Scuteri
Angelo
A
Strait
James B
JB
Orrù
Marco
M
Parsa
Afshin
A
Lin
Ping-I
PI
Maschio
Andrea
A
Lai
Sandra
S
Piras
Maria Grazia
MG
Masala
Marco
M
Tanaka
Toshiko
T
Post
Wendy
W
O'Connell
Jeffrey R
JR
Schlessinger
David
D
Cao
Antonio
A
Nagaraja
Ramaiah
R
Mitchell
Braxton D
BD
Abecasis
Gonçalo R
GR
Shuldiner
Alan R
AR
Uda
Manuela
M
Lakatta
Edward G
EG
Najjar
Samer S
SS
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
C547475:COL4A1 protein, human; D024141:Collagen Type IV