Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B-Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population.
Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B-Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population.
复制标题
DOI：
10.1161/circgenetics.117.001713
复制
发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Perola M
中科院分区：
文献类型：
--
作者：
Salo PP;Havulinna AS;Tukiainen T;Raitakari O;Lehtimäki T;Kähönen M;Kettunen J;Männikkö M;Eriksson JG;Jula A;Blankenberg S;Zeller T;Salomaa V;Kristiansson K;Perola M
文本中提供了补充数字内容。心肌细胞响应机械拉伸而分泌心房钠尿肽 (ANP) 和 B 型钠尿肽 (BNP)，使它们成为有用的心脏应激临床生物标志物。人类和动物研究均表明 ANP 具有血压调节作用，而 BNP 的结果却相互矛盾。我们使用全基因组关联分析（n=6296）来研究遗传变异对循环利钠肽浓度的影响，并比较利钠肽相关遗传变异对血压的影响（n=27 059）。 2 个已知基因座（NPPA-NPPB 和 POC1B-GALNT4）和 1 个新基因座（PPP3CC）中的 8 个独立遗传变异与中区 proANP (MR-proANP)、BNP、氨基末端 proBNP (NT-proBNP) 或 BNP:NT-proBNP 比率相关。包含编码 ANP 和 BNP 的相邻基因的 NPPA-NPPB 基因座具有 4 个独立的顺式变体，对中区 proANP 或 BNP 具有特异性作用，并且 NT-proBNP 中罕见的错义单核苷酸多态性严重改变了其测量结果。钙调磷酸酶催化亚基 γ 基因 PPP3CC 和多肽 N-乙酰半乳糖胺基转移酶 4 基因 GALNT4 附近的变体与 BNP:NT-proBNP 比率相关，但与 BNP 或中区 proANP 无关，表明对 proBNP 的翻译后调节有影响。在 8 个个体变异中，只有那些与中区 proANP 相关的变异对血压有统计学上的显着影响，尽管影响微弱。这3个单核苷酸多态性的综合作用也与高血压风险相关（P=8.2×10−4）。影响与血压相关的 ANP 循环浓度的常见基因差异，而影响 BNP 的基因差异则不然，这凸显了 ANP 在一般人群中的降血压作用。
Supplemental Digital Content is available in the text. Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP. We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide–associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (NPPA-NPPB and POC1B-GALNT4) and 1 novel locus (PPP3CC) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The NPPA-NPPB locus containing the adjacent genes encoding ANP and BNP harbored 4 independent cis variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene PPP3CC and the polypeptide N-acetylgalactosaminyltransferase 4 gene GALNT4 associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (P=8.2×10−4). Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure–lowering effect of ANP in the general population.