Identification of hypertension-susceptibility genes and pathways by a systemic multiple candidate gene approach: The millennium genome project for hypertension

Katsuhiko Kohara, Yasuharu Tabara, Jun Nakura, Yutaka Imai, Takayoshi Ohkubo, Akira Hata, Masayoshi Soma, Tomohiro Nakayama, Satoshi Umemura, Nobuhito Hirawa, Hirotsuga Ueshima, Yoshikuni Kita, Toshio Ogihara, Tomohiro Katsuya, Norio Takahashi, Katsushi Tokunaga, Tetsuro Miki

研究成果: Article査読

52 被引用数 (Scopus)


A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p<0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GN12, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n=9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension (X2= 9.93, p=0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension (p=0.0052). Furthermore, the high-risk genotype was associated with a significantly higher systolic blood pressure (133.08±19.46 vs. 132.25±19.19 mmHg, p=0.04) and diastolic blood pressure (79.65±11.49 vs. 79.01±11.32 mmHg, p=0.019) in the total population. In conclusion, a systemic multiple candidate gene approach can be used to identify not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.

ジャーナルHypertension Research
出版ステータスPublished - 2008 2月

ASJC Scopus subject areas

  • 内科学
  • 生理学
  • 循環器および心血管医学


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