Atrial natriuretic peptide genetic variant rs5065 and risk for cardiovascular disease in the general community: a 9-year follow-up study.
Atrial natriuretic peptide genetic variant rs5065 and risk for cardiovascular disease in the general community: a 9-year follow-up study.
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DOI：
10.1161/hypertensionaha.113.01344
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
Burnett JC Jr
中科院分区：
文献类型：
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作者：
Cannone V;Huntley BK;Olson TM;Heublein DM;Scott CG;Bailey KR;Redfield MM;Rodeheffer RJ;Burnett JC Jr
我们在随机的社区样本中分析了与心钠素(ANP)基因变异rs5065相关的表型。我们还比较了两种浓度的心钠素(10−10−/L，10 mol/L)和由rs5065次要等位基因编码的蛋白变异体ANP-RR对内皮细胞鸟苷酸环化酶-A(GC-A)和B(GC-B)受体的激活、第二信使3‘，5’环鸟苷单磷酸(CGMP)的产生和内皮通透性的影响。对明尼苏达州奥姆斯特德县(n=1623)的横断面成人队列进行了Rs5065基因分型。Rs5065的TT、TC和CC基因频率分别为75%、24%和1%。多因素分析显示，C等位基因与脑血管意外风险增加(危险比1.43；95%可信区间1.09~1.86；p=0.009)和心肌梗死患病率增高(奇比1.82；95%可信区间1.07~3.09；p=0.026)相关。ANP-RR 10−8mol/L可激活GC-A受体(83.07±8.31vs0.18±0.046个/孔，p=0.006)，而ANP-RR 10−/L不能激活GC-A受体。10−8m ol/L和10−10m ol/L均不能激活GC-B受体(p=0.10，p=0.35)。ANP10−8m ol/L和ANP-RR 10−8m ol/L刺激内皮细胞产生cGMP的作用相似(p=0.5 8)。与心钠素相比，两种浓度的心钠素-RR均显著增加人主动脉内皮细胞的通透性(69vs29RFU，p=0.012；58vs39RFU，p=0.015)。Rs5065的微小等位基因与心血管风险增加相关。ANP-RR激活GC-A受体，增加内皮细胞cGMP，与ANP相比，ANP-RR增加内皮细胞通透性。
We analyzed the phenotype associated with the atrial natriuretic peptide (ANP) genetic variant rs5065 in a random community-based sample. We also assessed and compared the biological action of two concentrations (10−10 mol/L, 10−8 mol/L) of ANP and ANP-RR, the protein variant encoded by the minor allele of rs5065, on activation of the guanylyl cyclase-A (GC-A) and B (GC-B) receptors, production of the second messenger 3’,5’cyclic guanosine monophosphate (cGMP) in endothelial cells and endothelial permeability. Rs5065 genotypes were determined in a cross-sectional adult cohort from Olmsted County, MN (n=1623). Genotype frequencies for rs5065 were 75%, 24%, and 1% for TT, TC and CC, respectively. Multivariate analysis showed that the C allele was associated with increased risk of cerebrovascular accident (hazard ratio 1.43; 95% CI, 1.09 to 1.86; p= 0.009) and higher prevalence of myocardial infarction (odd ratio = 1.82; 95% CI, 1.07 to 3.09; p= 0.026). ANP-RR 10−8mol/L activated the GC-A receptor (83.07 ±8.31 vs no treatment 0.18±0.04 6-per well, p=0.006), ANP-RR 10−10mol/L did not. Neither 10−8mol/L nor 10−10mol/L ANP-RR activated GC-B receptor (p=0.10, p= 0.35). ANP 10−8mol/L and ANP-RR 10−8mol/L stimulated cGMP production in endothelial cells similarly (p=0.58). Both concentrations of ANP-RR significantly enhanced human aortic endothelial cell permeability (69 vs 29 RFUs, p=0.012; 58 vs 39 RFUs, p= 0.015) compared to ANP. The minor allele of rs5065 was associated with increased cardiovascular risk. ANP-RR activated the GC-A receptor, increased cGMP in endothelial cells and when compared to ANP, ANP-RR augmented endothelial cell permeability.