■先前对200,000个外显子组测序的英国生物银行参与者进行的一项研究,以测试稀有编码变异与高血压的关联,其中两个基因具有外显子组意义。DNMT3A和FES。总共42个基因具有未校正的p值<0.001。这些结果在470,000个外显子组测序参与者的更大样本中进行了随访。
■对这42个基因进行了97,050例病例和172,263个对照的新样本中的稀有编码变体的加权负荷分析。然后在167,127例病例和302,691例对照的合并样本中分析了显示关联证据的那些。
■在新样本中复制了DNMT3A和FES与高血压的关联,它们和先前涉及的基因NPR1,该基因编码膜结合的鸟苷酸环化酶,在合并的样本中,所有外显子都是显著的。此外,作为高血压风险基因的全外显子组显著的是GUCY1A1、ASXL1和SMAD6,而GUCY1B1的名义p值<0.0001。GUCY1A1和GUCY1B1编码可溶性鸟苷酸环化酶的亚基。对于两个基因,DBH,编码多巴胺β羟化酶,和INPPL1,预测会损害基因功能的罕见编码变异对高血压有保护作用,再次具有广泛的意义。
■这些发现为高血压的生物危险因素提供了新的见解,这可能是进一步研究的主题。特别是,预测遗传变异会损害膜结合的鸟苷酸环化酶的功能,被利钠肽激活,或可溶性鸟苷酸环化酶,被一氧化氮激活,增加高血压的风险。相反,损害多巴胺β羟化酶功能的变体,负责去甲肾上腺素的合成,降低高血压风险。
UNASSIGNED: A previous study of 200,000 exome-sequenced UK Biobank participants to test for association of rare coding variants with hypertension implicated two genes at exome-wide significance, DNMT3A and FES. A total of 42 genes had an uncorrected p value <0.001. These results were followed up in a larger sample of 470,000 exome-sequenced participants.
UNASSIGNED: Weighted burden analysis of rare coding variants in a new sample of 97,050 cases and 172,263 controls was carried out for these 42 genes. Those showing evidence for association were then analysed in the combined sample of 167,127 cases and 302,691 controls.
UNASSIGNED: The association of DNMT3A and FES with hypertension was replicated in the new sample and they and the previously implicated gene
NPR1, which codes for a membrane-bound guanylate cyclase, were all exome-wide significant in the combined sample. Also exome-wide significant as risk genes for hypertension were GUCY1A1, ASXL1, and SMAD6, while GUCY1B1 had a nominal p value of <0.0001. GUCY1A1 and GUCY1B1 code for subunits of a soluble guanylate cyclase. For two genes, DBH, which codes for dopamine beta hydroxylase, and INPPL1, rare coding variants predicted to impair gene function were protective against hypertension, again with exome-wide significance.
UNASSIGNED: The findings offer new insights into biological risk factors for hypertension which could be the subject of further investigation. In particular, genetic variants predicted to impair the function of either membrane-bound guanylate cyclase, activated by natriuretic peptides, or soluble guanylate cyclase, activated by nitric oxide, increase risk of hypertension. Conversely, variants impairing the function of dopamine beta hydroxylase, responsible for the synthesis of norepinephrine, reduce hypertension risk.