Wang Laiyuan, Li Hongfan, Yang Bin, Guo Liwei, Han Xikun, Li Lin, Li Mengting, Huang Jianfeng, Gu Dongfeng
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Am J Hypertens. 2017 Feb;30(2):202-208. doi: 10.1093/ajh/hpw127. Epub 2016 Oct 25.
The large-scale meta-analysis of genome-wide association study (GWAS) recently identified a genomic locus where the genetic variant at rs820430 was strongly associated with hypertension in Chinese Han population, with its T allele conferred increased risks. However, the biological and disease-relevant mechanisms for this association remain elusive.
A group of 275 participants from rural district of Shandong Province were enrolled, rs820430 was genotyped using genomic DNA with the fluorogenic 5'-nuclease TaqMan allelic discrimination assay system (Applied Biosystems, CA). In vitro experiments were performed in this study, such as luciferase reporter assays, gel mobility shift assays (electrophoretic mobility shift assay), and chromatin immunoprecipitation.
We found the risk T allele of rs820430 was associated with higher SLC4A7 mRNA level in cohort population. Furthermore, we characterized a cis-regulatory mechanism that the T allele of rs820430 distinctively increased c-Fos transcription factor binding, by which leading to increased SLC4A7 expression.
The present study indicated that the disease-associated T allele of a new hypertension risk variant rs820430 linked increased hypertension risk through higher SLC4A7 expression, and rs820430 functioned as an enhancer of SLC4A7 transcription by allele distinctively increased c-Fos transcription factor binding.
全基因组关联研究（GWAS）的大规模荟萃分析最近确定了一个基因组位点，其中rs820430处的基因变异与中国汉族人群的高血压密切相关，其T等位基因会增加患病风险。然而，这种关联的生物学和疾病相关机制仍不清楚。
招募了一组来自山东省农村地区的275名参与者，使用荧光5'-核酸酶TaqMan等位基因鉴别分析系统（应用生物系统公司，加利福尼亚州）对基因组DNA进行rs820430基因分型。本研究进行了体外实验，如荧光素酶报告基因检测、凝胶迁移率变动分析（电泳迁移率变动分析）和染色质免疫沉淀。
我们发现rs820430的风险T等位基因与队列人群中较高的SLC4A7 mRNA水平相关。此外，我们确定了一种顺式调节机制，即rs820430的T等位基因显著增加c-Fos转录因子结合，从而导致SLC4A7表达增加。
本研究表明，新的高血压风险变异rs820430的疾病相关T等位基因通过更高的SLC4A7表达与增加的高血压风险相关联，并且rs820430通过等位基因特异性增加c-Fos转录因子结合而作为SLC4A7转录的增强子发挥作用。
