Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: The Japanese millennium genome project

Yasuharu Tabara, Katsuhiko Kohara, Yoshikuni Kita, Nobuhito Hirawa, Tomohiro Katsuya, Takayoshi Ohkubo, Yumiko Hiura, Atsushi Tajima, Takayuki Morisaki, Toshiyuki Miyata, Tomohiro Nakayama, Naoyuki Takashima, Jun Nakura, Ryuichi Kawamoto, Norio Takahashi, Akira Hata, Masayoshi Soma, Yutaka Imai, Yoshihiro Kokubo, Tomonori OkamuraHitonobu Tomoike, Naoharu Iwai, Toshio Ogihara, Itsuro Inoue, Katsushi Tokunaga, Toby Johnson, Mark Caulfield, Patricia Munroe, Satoshi Umemura, Hirotsugu Ueshima, Tetsuro Miki

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

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; 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). 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). 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). 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) 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.

Original languageEnglish
Pages (from-to)973-980
Number of pages8
JournalHypertension
Volume56
Issue number5
DOIs
Publication statusPublished - 2010 Nov 1

Keywords

  • ATP2B1
  • Global BPgen
  • Millennium Genome Project
  • genetic variation
  • hypertension

ASJC Scopus subject areas

  • Internal Medicine

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