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 Post; Jeffrey R. O'Connell; David Schlessinger; Antonio Cao; Ramaiah Nagaraja; Braxton D. Mitchell; Gonçalo R. Abecasis; Alan R. Shuldiner; Manuela Uda; Edward G. Lakatta; Samer S. Najjar

doi:10.1161/CIRCGENETICS.108.823245

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 Post, Jeffrey R. O'Connell, David Schlessinger, Antonio Cao, Ramaiah Nagaraja, Braxton D. Mitchell, Gonçalo R. Abecasis, Alan R. ShuldinerManuela Uda, Edward G. Lakatta, Samer S. Najjar

School of Medicine

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

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 language	English (US)
Pages (from-to)	151-158
Number of pages	8
Journal	Circulation: Cardiovascular Genetics
Volume	2
Issue number	2
DOIs	https://doi.org/10.1161/CIRCGENETICS.108.823245
State	Published - Apr 2009

Keywords

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

ASJC Scopus subject areas

Genetics
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1161/CIRCGENETICS.108.823245

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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., 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

Tarasov, KV, Sanna, S, Scuteri, A, Strait, JB, Orrù, M, Parsa, A, Lin, PI, Maschio, A, Lai, S, Piras, MG, Masala, M, Tanaka, T, Post, W, O'Connell, JR, Schlessinger, D, Cao, A, Nagaraja, R, Mitchell, BD, Abecasis, GR, Shuldiner, AR, Uda, M, Lakatta, EG & Najjar, SS 2009, 'COL4A1 is associated with arterial stiffness by genome-wide association scan', Circulation: Cardiovascular Genetics, vol. 2, no. 2, pp. 151-158. https://doi.org/10.1161/CIRCGENETICS.108.823245

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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. 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.",

keywords = "Arterial stiffness, COL4A1, Genome-wide association scan, MAGI1, Nonsynomous SNP, Pulse wave velocity",

author = "Tarasov, {Kirill V.} and Serena Sanna and Angelo Scuteri and Strait, {James B.} and Marco Orr{\`u} and Afshin Parsa and Lin, {Ping I.} and Andrea Maschio and Sandra Lai and Piras, {Maria Grazia} and Marco Masala and Toshiko Tanaka and Wendy Post and O'Connell, {Jeffrey R.} and David Schlessinger and Antonio Cao and Ramaiah Nagaraja and Mitchell, {Braxton D.} and Abecasis, {Gon{\c c}alo R.} and Shuldiner, {Alan R.} and Manuela Uda and Lakatta, {Edward G.} and Najjar, {Samer S.}",

year = "2009",

month = apr,

doi = "10.1161/CIRCGENETICS.108.823245",

language = "English (US)",

volume = "2",

pages = "151--158",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "2",

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T1 - COL4A1 is associated with arterial stiffness by genome-wide association scan

AU - Tarasov, Kirill V.

AU - Sanna, Serena

AU - Scuteri, Angelo

AU - Strait, James B.

AU - Orrù, Marco

AU - Parsa, Afshin

AU - Lin, Ping I.

AU - Maschio, Andrea

AU - Lai, Sandra

AU - Piras, Maria Grazia

AU - Masala, Marco

AU - Tanaka, Toshiko

AU - Post, Wendy

AU - O'Connell, Jeffrey R.

AU - Schlessinger, David

AU - Cao, Antonio

AU - Nagaraja, Ramaiah

AU - Mitchell, Braxton D.

AU - Abecasis, Gonçalo R.

AU - Shuldiner, Alan R.

AU - Uda, Manuela

AU - Lakatta, Edward G.

AU - Najjar, Samer S.

PY - 2009/4

Y1 - 2009/4

N2 - 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.

AB - 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.

KW - Arterial stiffness

KW - COL4A1

KW - Genome-wide association scan

KW - MAGI1

KW - Nonsynomous SNP

KW - Pulse wave velocity

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

Abstract

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