Original Article

Hypertension Research (2008) 31, 203–212; doi:10.1291/hypres.31.203

Identification of Hypertension-Susceptibility Genes and Pathways by a Systemic Multiple Candidate Gene Approach: The Millennium Genome Project for Hypertension

Katsuhiko Kohara1, Yasuharu Tabara2, Jun Nakura1, Yutaka Imai3, Takayoshi Ohkubo3, Akira Hata4, Masayoshi Soma5, Tomohiro Nakayama5, Satoshi Umemura6, Nobuhito Hirawa6, Hirotsugu Ueshima7, Yoshikuni Kita7, Toshio Ogihara8, Tomohiro Katsuya8, Norio Takahashi9, Katsushi Tokunaga10 and Tetsuro Miki1

  1. 1Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Japan
  2. 2Department of Basic Medical Research and Education, Ehime University School of Medicine, Toon, Japan
  3. 3Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Medicine, Sendai, Japan
  4. 4Department of Public Health, Chiba University Graduate School of Medicine, Chiba, Japan
  5. 5Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
  6. 6Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  7. 7Department of Health Science, Shiga University of Medical Science, Otsu, Japan
  8. 8Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan
  9. 9Radiation Effects Research Foundation, Hiroshima, Japan
  10. 10Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Correspondence: Katsuhiko Kohara, M.D., Ph.D., Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. E-mail: koharak@m.ehime-u.ac.jp

Received 2 May 2007; Accepted 24 August 2007.

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Abstract

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 (GNI2, 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 (chi2=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 (133.08plusminus19.46 vs. 132.25plusminus19.19 mmHg, p=0.04) and diastolic blood pressure (79.65plusminus11.49 vs. 79.01plusminus11.32 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.

Keywords:

hypertension, candidate gene, association study, gene–gene interaction, pathways

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Identification of Hypertension-Susceptibility Genes and Pathways by a Systemic Multiple Candidate Gene Approach: The Millennium Genome Project for Hypertension

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