COL4A1 is associated with arterial stiffness by genome-wide association scan

Kirill V. Tarasov, Serena Sanna, Angelo Scuteri, James B. Strait, Marco Orrù, Afshin Parsa, Ping I. Lin, Andrea Maschio, Sandra Lai, Maria Grazia Piras, Marco Masala, Toshiko Tanaka, Wendy S Post, Jeffrey R. O'Connell, David Schlessinger, Antonio Cao, Ramaiah Nagaraja, Braxton D. Mitchell, Gonçalo R. Abecasis, Alan R. ShuldinerManuela Uda, Edward Lakatta, Samer S. Najjar

Research output: Contribution to journalArticle

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. 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=7.08×10-7 and P=1.06×10 -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=5.16×10 -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.

Original languageEnglish (US)
Pages (from-to)151-158
Number of pages8
JournalCirculation: Cardiovascular Genetics
Volume2
Issue number2
DOIs
StatePublished - Apr 2009

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Keywords

  • Arterial stiffness
  • COL4A1
  • Genome-wide association scan
  • MAGI1
  • Nonsynomous SNP
  • Pulse wave velocity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

Tarasov, K. V., Sanna, S., Scuteri, A., Strait, J. B., Orrù, M., Parsa, A., Lin, P. I., Maschio, A., Lai, S., Piras, M. G., Masala, M., Tanaka, T., Post, W. S., O'Connell, J. R., Schlessinger, D., Cao, A., Nagaraja, R., Mitchell, B. D., Abecasis, G. R., ... Najjar, S. S. (2009). COL4A1 is associated with arterial stiffness by genome-wide association scan. Circulation: Cardiovascular Genetics, 2(2), 151-158. https://doi.org/10.1161/CIRCGENETICS.108.823245