Identification of hypertension-susceptibility genes and pathways by a systemic multiple candidate gene approach: the millennium genome project for hypertension.
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 (133.08+/-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.
Kohara
Katsuhiko
K
Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Japan. koharak@m.ehime-u.ac.jp
Tabara
Yasuharu
Y
Nakura
Jun
J
Imai
Yutaka
Y
Ohkubo
Takayoshi
T
Hata
Akira
A
Soma
Masayoshi
M
Nakayama
Tomohiro
T
Umemura
Satoshi
S
Hirawa
Nobuhito
N
Ueshima
Hirotsugu
H
Kita
Yoshikuni
Y
Ogihara
Toshio
T
Katsuya
Tomohiro
T
Takahashi
Norio
N
Tokunaga
Katsushi
K
Miki
Tetsuro
T
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D016045:Human Genome Project; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics
D020710:RGS Proteins; C087182:RGS2 protein, human; C119109:GNA14 protein, human; D043802:GTP-Binding Protein alpha Subunits, Gq-G11