title: High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project.
abstract: 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 >or= 1.4 and P <or= 0.015 in tier 1) and identified 75 SNPs that showed similar tendency of association in tier 1 and tier 2 samples (P <or= 0.05 for allele frequency and P <or= 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 <or= 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.
authors.affiliation: Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan. nokato@ri.imcj.go.jp
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Tabara
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yanai
authors.forename: Hironori
authors.initials: H
authors.lastname: Hanada
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Jun
authors.initials: J
authors.lastname: Nakura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kohara
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Kita
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Ueshima
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakayama
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujioka
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Miki
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017527:Receptor, IGF Type 2 / Q000235:genetics; D000099291:Adducins
chemical_list: D003598:Cytoskeletal Proteins; D017527:Receptor, IGF Type 2; C501062:ADD2 protein, human; D000099291:Adducins