Salo Perttu P, Havulinna Aki S, Tukiainen Taru, Raitakari Olli, Lehtimäki Terho, Kähönen Mika, Kettunen Johannes, Männikkö Minna, Eriksson Johan G, Jula Antti, Blankenberg Stefan, Zeller Tanja, Salomaa Veikko, Kristiansson Kati, Perola Markus
Circ Cardiovasc Genet. 2017 Dec;10(6):e001713. doi: 10.1161/CIRCGENETICS.117.001713.
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 ( and ) and 1 novel locus () associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The locus containing the adjacent genes encoding ANP and BNP harbored 4 independent 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 and the polypeptide N-acetylgalactosaminyltransferase 4 gene 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 (=8.2×10).
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.
心肌细胞在受到机械拉伸时会分泌心房利钠肽（ANP）和B型利钠肽（BNP），使其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具有调节血压的作用，但关于BNP的研究结果存在冲突。
我们使用全基因组关联分析（n = 6296）来研究基因变异对循环利钠肽浓度的影响，并比较利钠肽相关基因变异对血压的影响（n = 27059）。在2个已知基因座（ 和 ）和1个新基因座（ ）中发现了8个独立的基因变异，这些变异与中段前体ANP（MR-proANP）、BNP、氨基末端前体BNP（NT-proBNP）或BNP:NT-proBNP比值相关。包含相邻的编码ANP和BNP基因的基因座含有4个独立的 变异，其对中段前体ANP或BNP具有特异性影响，并且NT-proBNP中一个罕见的错义单核苷酸多态性严重改变了其测量结果。钙调神经磷酸酶催化亚基γ基因 附近和多肽N-乙酰半乳糖胺基转移酶4基因 附近的变异与BNP:NT-proBNP比值相关，但与BNP或中段前体ANP无关，提示对前体BNP的翻译后调节有影响。在这8个个体变异中，只有那些与中段前体ANP相关的变异对血压有统计学上显著但较弱的影响。这3个单核苷酸多态性的联合效应也与高血压风险相关（ = 8.2×10）。
影响ANP循环浓度的常见基因差异与血压相关，而影响BNP的基因差异则不然，这突出了ANP在普通人群中的降压作用。
