Genome-wide association analysis of plasma B-type natriuretic peptide in blacks: the Jackson Heart Study.
Genome-wide association analysis of plasma B-type natriuretic peptide in blacks: the Jackson Heart Study.
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黑色血浆B型纳地尿肽的基因组全基因组关联分析：杰克逊心脏研究。
DOI：
10.1161/circgenetics.114.000900
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Vasan RS
中科院分区：
文献类型：
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作者：
Musani SK;Fox ER;Kraja A;Bidulescu A;Lieb W;Lin H;Beecham A;Chen MH;Felix JF;Fox CS;Kao WH;Kardia SL;Liu CT;Nalls MA;Rundek T;Sacco RL;Smith J;Sun YV;Wilson G;Zhang Z;Mosley TH;Taylor HA;Vasan RS
大量实验研究表明，b型利钠肽（BNP）具有心脏保护作用，但在临床研究中，血浆BNP浓度升高与心血管疾病的发生和左心室质量（LVM）升高有关。遗传关联研究可以使我们确定真正的因果方向，而不受补偿机制的干扰。我们对来自2790名非裔美国人的两个全基因组关联（GWA）结果进行了荟萃分析。我们假设了一个加性遗传模型，对输入的250万个SNP剂量与由控制相关协变量和群体分层的多变量调整对数转换BNP产生的残差进行关联分析。两个基因座具有全基因组显著性，一个候选基因座NPPB （rs198389， p值=1.18×10−09）和KLKB1基因座的新错意变异（rs3733402， p值=1.75×10−11）分别解释了0.4%和1.9%的对数BNP浓度变异。观察到BNP浓度的增加与有效等位基因拷贝数成正比，平均增加8.1 pg/dl与两个等位基因拷贝相关。该位点的snp随后与欧洲血统个体醛固酮-肾素比值的GWA结果交叉检查，只有rs3733402具有全基因组显著性（p<5.0×10−8），表明这两条通路可能具有共同的遗传结构。这些snp的其他有统计学意义的关系包括：黑人rs198389与收缩压（COGENT联盟），白人rs198389和rs3733402与LVM （EchoGEN联盟）。这些发现提高了我们对非裔美国人BNP变异遗传基础的认识，证明了BNP与ARR可能共享的等位基因结构，并激发了对潜在机制的进一步研究。
Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective, yet in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass (LVM). Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. We performed meta-analysis of two genome-wide association (GWA) results from a total of 2,790 African Americans. We assumed an additive genetic model in association analysis of imputed 2.5 million SNP dosages with residuals generated from multivariable-adjusted logarithmically-transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, p-value=1.18×10−09) and novel missense variant in the KLKB1 locus (rs3733402, p-value=1.75×10−11) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, an average of 8.1 pg/dl increase associated with two allele copies. SNPs in this loci were subsequently cross-checked with GWA results for the aldosterone-to-renin ratio in individuals of European ancestry, and only rs3733402 was genome-wide significant (p<5.0×10−8), suggesting possible shared genetic architecture for these two pathways. Other statistically significant relations for these SNPs included: rs198389 with systolic blood pressure in blacks (COGENT consortium) rs198389 and rs3733402 with LVM in whites (EchoGEN consortium). These findings improve our knowledge of the genetic basis of BNP variation in African Americans, demonstrate possible shared allelic architecture for BNP with ARR and motivate further studies of underlying mechanisms.