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 (χ2=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.
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Gong M, Hubner N : Molecular genetics of human hypertension. Clin Sci 2006; 110: 315–326.
Tanira MO, Al Balushi KA : Genetic variations related to hypertension: a review. J Hum Hypertens 2005; 19: 7–19.
Marteau J-B, Zaiou M, Siest G, Visvikis-Siest S : Genetic determination of blood pressure regulation. J Hypertens 2005; 23: 2127–2143.
Agarwal A, Williams GH, Fisher NDL : Genetics of human hypertension. Trends Endocrinol Metab 2005; 16: 127–133.
McBride MW, Graham D, Delles C, Dominiczak AF : Functional genomics in hypertension. Curr Opin Nephrol Hypertens 2006; 15: 145–151.
Williams SM, Addy JH, Phillips JA 3rd, et al: Combinations of variations in multiple genes are associated with hypertension. Hypertension 2000; 36: 2–6.
Williams SM, Ritchie MD, Phillips JA 3rd, et al: Multilocus analysis of hypertension: a hierarchical approach. Hum Hered 2004; 57: 28–38.
Caulfield M, Munroe P, Pembroke J, et al: MRC British Genetics of Hypertension Study. Genome-wide mapping of human loci for essential hypertension. Lancet 2003; 361: 2118–2123.
Nebert DW : Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 1997; 60: 265–271.
Izawa H, Yamada Y, Okada T, Tanaka M, Hirayama H, Yokota M : Prediction of genetic risk for hypertension. Hypertension 2003; 41: 1035–1040.
Kokubo Y, Tomoike H, Tanaka C, et al: Association of sixty-one non-synonymous polymorphisms in forty-one hypertension candidate genes with blood pressure variation and hypertension. Hypertens Res 2006; 29: 611–619.
Kosachunhanun N, Hunt SC, Hopkins PN, et al: Genetic determinants of nonmodulating hypertension. Hypertension 2003; 42: 901–908.
Agachan B, Isbir T, Yilmaz H, Akoglu E : Angiotensin converting enzyme I/D, angiotensinogen T174M–M235T and angiotensin II type 1 receptor A1166C gene polymorphisms in Turkish hypertensive patients. Exp Mol Med 2003; 35: 545–549.
Vasku A, Soucek M, Znojil V, et al: Angiotensin I–converting enzyme and angiotensinogen gene interaction and prediction of essential hypertension. Kidney Int 1998; 53: 1479–1482.
Giner V, Poch E, Bragulat E, et al: Renin-angiotensin system genetic polymorphism and salt sensitivity in essential hypertension. Hypertension 2000; 35: 512–517.
Tsai CT, Fallin D, Chiang FT, et al: Angiotensinogen gene haplotype and hypertension: interaction with ACE gene I allele. Hypertension 2003; 41: 9–15.
Dominiczak AF, Graham D, McBride MW, et al: Corcoran Lecture. Cardiovascular genomics and oxidative stress. Hypertension 2005; 45: 636–642.
Haga H, Yamada R, Ohnishi Y, Nakamura Y, Tanaka T : Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variations in the human genome. Single-nucleotide polymorphism. J Hum Genet 2002; 47: 605–610.
Tamaki S, Nakamura Y, Tabara Y, et al: Relationship between metabolic syndrome and Trp64Arg polymorphism of the β-adrenergic receptor gene in a general sample: the Shigaraki study. Hypertens Res 2006; 29: 891–896.
Sugimoto K, Katsuya T, Ohkubo T, et al: Association between angiotensin II type 1 receptor gene polymorphism and essential hypertension: the Ohasama Study. Hypertens Res 2004; 27: 551–556.
Tabara Y, Tachibana-Iimori R, Yamamoto M, et al: Hypotension associated with prone body position: a possible overlooked postural hypotension. Hypertens Res 2005; 28: 741–746.
Yamamoto M, Jin JJ, Wu Z, et al: Interaction between serotonin 2A receptor and endothelin-1 variants in association with hypertension in Japanese. Hypertens Res 2006; 29: 227–232.
Hirakawa M, Tanaka T, Hashimoto Y, Kuroda M, Takagi T, Nakamura Y : JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res 2002; 30: 158–162.
Kittler R, Stoneking M, Kayser M : A whole genome amplification method to generate long fragments from low quantities of genomic DNA. Anal Biochem 2002; 300: 237–244.
Tachibana-Iimori R, Tabara Y, Kusuhara H, et al: Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab Pharmacokinet 2004; 19: 375–380.
Bannai M, Higuchi K, Akesaka T, et al: Single-nucleotide-polymorphism genotyping for whole-genome-amplified samples using automated fluorescence correlation spectroscopy. Anal Biochem 2004; 327: 215–221.
Ritchie MD, Hahn LW, Roodi N, et al: Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001; 69: 138–147.
Harrap SB : Where are all the blood-pressure genes? Lancet 2003; 361: 2149–2151.
Doris PA : Hypertension genetics, single nucleotide polymorphisms, and the common disease: common variant hypothesis. Hypertension 2002; 39: 323–331.
Liu PY, Zhang YY, Lu Y, et al: A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases. J Med Genet 2005; 42: 221–227.
Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH : Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305: 869–872.
Kostenis E, Waelbroeck M, Milligan G : Techniques: promiscuous Galpha proteins in basic research and drug discovery. Trends Pharmacol Sci 2005; 26: 595–602.
Cabrera-Vera TM, Vanhauwe J, Thomas TO, et al: Insights into G protein structure, function, and regulation. Endocr Rev 2003; 24: 765–781.
Riddle EL, Schwartzman RA, Bond M, Insel PA : Multi-tasking RGS proteins in the heart: the next therapeutic target? Circ Res 2005; 96: 401–411.
Nunn C, Mao H, Chidiac P, Albert PR : RGS17/RGSZ2 and the RZ/A family of regulators of G-protein signaling. Semin Cell Dev Biol 2006; 17: 390–399.
Ho MK, Yung LY, Chan JS, Chan JH, Wong CS, Wong YH : Gα14 links a variety of Gi- and Gs-coupled receptors to the stimulation of phospholipase C. Br J Pharmacol 2001; 132: 1431–1440.
Wang Y, Ho G, Zhang JJ, et al: Regulator of G protein signaling Z1 (RGSZ1) interacts with Gαi subunits and regulates Gαi-mediated cell signaling. J Biol Chem 2002; 277: 48325–48332.
Cho YM, Ritchie MD, Moore JH, et al: Multifactor-dimensionality reduction shows a two-locus interaction associated with type 2 diabetes mellitus. Diabetologia 2004; 47: 549–554.
Tsai CT, Lai LP, Lin JL, et al: Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 2004; 109: 1640–1646.
Colhoun HM, McKeigue PM, Davey Smith G : Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361: 865–872.
Mayeux R : Mapping the new frontier: complex genetic disorders. J Clin Invest 2005; 115: 1404–1407.
Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N : Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 2004; 96: 434–442.
Newton-Cheh C, Hirschohorn JN : Genetic association studies of complex traits: design and analysis issues. Mutat Res 2005; 573: 54–69.
Rudan I, Smolej-Narancic N, Campbell H, et al: Inbreeding and the genetic complexity of human hypertension. Genetics 2003; 163: 1011–1021.
Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP : Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 2006; 163: 300–309.
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Kohara, K., Tabara, Y., Nakura, J. et al. Identification of Hypertension-Susceptibility Genes and Pathways by a Systemic Multiple Candidate Gene Approach: The Millennium Genome Project for Hypertension. Hypertens Res 31, 203–212 (2008). https://doi.org/10.1291/hypres.31.203
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DOI: https://doi.org/10.1291/hypres.31.203
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