Lieb Wolfgang, Chen Ming-Huei, Teumer Alexander, de Boer Rudolf A, Lin Honghuang, Fox Ervin R, Musani Solomon K, Wilson James G, Wang Thomas J, Völzke Henry, Petersen Ann-Kristin, Meisinger Christine, Nauck Matthias, Schlesinger Sabrina, Li Yong, Menard Jöel, Hercberg Serge, Wichmann H-Erich, Völker Uwe, Rawal Rajesh, Bidlingmaier Martin, Hannemann Anke, Dörr Marcus, Rettig Rainer, van Gilst Wiek H, van Veldhuisen Dirk J, Bakker Stephan J L, Navis Gerjan, Wallaschofski Henri, Meneton Pierre, van der Harst Pim, Reincke Martin, Vasan Ramachandran S
Circ Cardiovasc Genet. 2015 Feb;8(1):131-40. doi: 10.1161/CIRCGENETICS.114.000613. Epub 2014 Dec 4.
The renin-angiotensin-aldosterone system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood.
We meta-analyzed genome-wide association data for plasma renin activity (n=5275), plasma renin concentrations (n=8014), and circulating aldosterone (n=13289) from ≤4 population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6487). Single-nucleotide polymorphisms (SNPs) in 2 independent loci displayed associations with plasma renin activity at genome-wide significance (P<5×10(-8)). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], P=5.5×10(-8)). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: P=0.001 for plasma renin, P=0.024 for plasma aldosterone concentration; and rs4253311 with P<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911; P=8.81×10(-9)), but did not replicate (P=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in blacks.
We identified 2 genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS.
肾素-血管紧张素-醛固酮系统（RAAS）对血压调节和液体平衡至关重要，并影响心血管重塑。RAAS失调会导致心血管和肾脏疾病。循环RAAS成分的遗传结构尚未完全明确。
我们对来自≤4个欧洲和欧美血统人群队列的血浆肾素活性（n = 5275）、血浆肾素浓度（n = 8014）和循环醛固酮（n = 13289）的全基因组关联数据进行荟萃分析，并在一个独立样本（n = 6487）中评估了顶级结果的重复性。2个独立位点的单核苷酸多态性（SNP）在全基因组水平上显示出与血浆肾素活性相关（P < 5×10⁻⁸）。第三个位点接近此阈值（激肽释放酶B [KLKB1]中的rs4253311，P = 5.5×10⁻⁸）。其中2个位点在一个独立样本中对血浆肾素和醛固酮浓度均有重复性（激肽原1 [KNG1]中的SNP rs5030062：血浆肾素P = 0.001，血浆醛固酮浓度P = 0.024；rs4253311对血浆肾素和醛固酮浓度均P < 0.001）。NEBL基因中的SNP在发现样本中对血浆肾素浓度达到全基因组显著性（顶级SNP rs3915911；P = 8.81×10⁻⁹），但未重复（P = 0.81）。没有位点对醛固酮达到全基因组显著性。SNP rs5030062和rs4253311与血压或肾脏性状无关；在一项配套研究中，激肽释放酶B位点的变异与黑人的B型利钠肽浓度相关。
我们鉴定出2个影响RAAS关键成分的遗传位点（激肽原1和激肽释放酶B）,这与激肽释放酶-激肽系统和RAAS之间的密切相互关系一致。
