Human Molecular Genetics Advance Access originally published online on November 14, 2007
Human Molecular Genetics 2008 17(4):617-627; doi:10.1093/hmg/ddm335
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High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project
1 Department of Gene Diagnostics and Therapeutics 2 Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan 3 National Cardiovascular Center, Suita, Osaka, Japan 4 Department of Basic Medical Research and Education 5 Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan 6 Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 7 Division of Functional Genomics, Jichi Medical University, Shimotsuke-shi, Tochigi, Japan 8 Department of Molecular Pathogenesis, Medical Research Institute 9 Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan 10 Department of Health Science, Shiga University of Medical Science, Otsu, Shiga, Japan 11 Division of Molecular Diagnostics, Advanced Medical Research Center 12 Division of Nephrology and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 13 Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan 14 Amagasaki Health Medical Foundation, Amagasaki, Hyogo, Japan 15 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan 16 SNP Research Center, Institute of Physical and Chemical Research, Tokyo, Japan 17 Genetics Division, National Cancer Center Research Institute, Tokyo, Japan 18 Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan 19 Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan 20 Division of Bioscience, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
* To whom correspondence should be addressed at: Department of Gene Diagnostics and Therapeutics, Research Institute International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Tel: +81 332027181; Fax: +81 332027364; Email: nokato{at}ri.imcj.go.jp
Received August 23, 2007; Accepted November 12, 2007
Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300–900 microsatellite markers but no single study has yielded definitive evidence for ‘principal’ hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio 
1.4 and P 
0.015 in tier 1) and identified 75 SNPs that showed similar tendency of association in tier 1 and tier 2 samples (P 0.05 for allele frequency and P 0.01 for genotype distribution tests). For tier 3 (619 hypertensive and 1406 normotensive subjects), we genotyped the 75 SNPs and found nine SNPs from seven genomic loci to be associated with hypertension (P 0.05). In three of these loci, the lowest P-values were observed for rs3755351 (P = 1.7 x 10–5) in ADD2, rs3794260 (P = 0.0001) in KIAA0789 and rs1805762 (P = 0.0003) in M6PR when case–control comparison was made in the combined data. An SNP (rs3755351) within ADD2 had the lowest P-value and its experiment-wide significance level is 0.13. Thus, these results have nominated several susceptibility genes for hypertension, and independent replication will clarify their etiological relevance.