Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.
Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.
复制标题
DOI：
10.1161/hypertensionaha.110.153429
复制
发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Miki T
中科院分区：
文献类型：
--
作者：
Tabara Y;Kohara K;Kita Y;Hirawa N;Katsuya T;Ohkubo T;Hiura Y;Tajima A;Morisaki T;Miyata T;Nakayama T;Takashima N;Nakura J;Kawamoto R;Takahashi N;Hata A;Soma M;Imai Y;Kokubo Y;Okamura T;Tomoike H;Iwai N;Ogihara T;Inoue I;Tokunaga K;Johnson T;Caulfield M;Munroe P;Global Blood Pressure Genetics Consortium;Umemura S;Ueshima H;Miki T
高血压是最常见的复杂遗传性疾病之一。我们以前已经描述了38个单核苷酸多态性（SNPs）与日本人高血压的暗示关联。在这项研究中，我们扩展了我们以前的研究结果，分析了大样本的日本人（n=14 - 105）的最相关的SNP。我们还进行了复制分析，在日本的高血压易感基因位点最近确定的全基因组关联研究的欧洲血统。关联分析显示ATP 2B 1 rs 2070759多态性与高血压显著相关（P=5.3×10−5;等位基因优势比：1.17 [95%CI：1.09 - 1.26]）。随后对ATP 2B 1中的其他SNP进行了基因分型，最显著的关联是与rs 11105378（比值比：1.31 [95%CI：1.21 - 1.42]; P=4.1×10−11）。rs 11105378与高血压的相关性通过全球血压遗传学联盟数据集的重复分析进行了交叉验证（比值比：1.13 [95% CI：1.05 - 1.21]; P=5.9×10−4）。在对欧洲血统个体的荟萃分析中，平均调整后的收缩压与相同的SNP高度显著相关（P=1.4×10−18）。结果显示，rs 11105378基因型间脐动脉平滑肌细胞ATP 2B 1 mRNA表达水平差异有统计学意义。在已发表的全基因组关联研究中发现的7个SNP也在日本人群中进行了基因分型。在重复的3个基因FGF 5 rs 1458038、CYP 17 A1、rs 1004467和CSK rs 1378942的联合分析中，与低风险组相比，最高风险组的比值比为2.27（95%CI：1.65至3.12; P=4.6×10−7）。总之，这项研究证实了ATP 2B 1以及FGF 5、CYP 17 A1和CSK的常见遗传变异与血压水平和高血压风险相关。
Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10−5; allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10−11). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10−4). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10−18). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10−7) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.