Tarasov Kirill V, Sanna Serena, Scuteri Angelo, Strait James B, Orrù Marco, Parsa Afshin, Lin Ping-I, Maschio Andrea, Lai Sandra, Piras Maria Grazia, Masala Marco, Tanaka Toshiko, Post Wendy, O'Connell Jeffrey R, Schlessinger David, Cao Antonio, Nagaraja Ramaiah, Mitchell Braxton D, Abecasis Gonçalo R, Shuldiner Alan R, Uda Manuela, Lakatta Edward G, Najjar Samer S
Laboratory of Cardiovascular Science, Laboratory of Genetics, Clinical Research Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Circ Cardiovasc Genet. 2009 Apr;2(2):151-8. doi: 10.1161/CIRCGENETICS.108.823245. Epub 2009 Feb 18.
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.
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).
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.
脉搏波速度（PWV）是反映中心动脉僵硬度的一项无创指标，是心血管疾病死亡率和发病率的有力预测指标。遗传力和连锁研究表明存在影响PWV的遗传因素。我们开展了一项全基因组关联研究，以鉴定与PWV相关的单核苷酸多态性（SNP）。
研究队列包括来自撒丁岛研究（SardiNIA study）且有PWV测量值的参与者。对4221名个体进行基因分型，使用Affymetrix 500K或Affymetrix 10K基因分型芯片组（对缺失基因型进行填补）。采用包含年龄、年龄平方和性别作为协变量的加性遗传模型评估与PWV的关联。在一个由1828名个体组成独立的撒丁岛内部队列中，使用定制芯片对研究结果进行验证，该芯片设计包含与PWV相关的前43个非冗余SNP。在检测与PWV关联的基因座中，13号染色体上COL4A1基因的非同义SNP rs3742207和3号染色体上MAGI1基因的SNP rs1495448成功得到验证（联合分析时P值分别为7.08×10⁻⁷和1.06×10⁻⁵）。rs3742207与PWV之间的关联在另一个独立人群——旧秩序阿米什人（Old-Order Amish）中也成功得到验证（P = 0.02），总体P值为5.16×10⁻⁸。
一项全基因组关联研究在两个群体中鉴定出COL4A1基因中的一个SNP与PWV显著相关。IV型胶原是基底膜的主要结构成分，这表明此前未被认识到的细胞-基质相互作用可能在调节动脉僵硬度中发挥重要作用。
