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(Hypertension. 2003;41:1035.)
© 2003 American Heart Association, Inc.

Scientific Contribution

Prediction of Genetic Risk for Hypertension

Hideo Izawa; Yoshiji Yamada; Taro Okada; Masashi Tanaka; Haruo Hirayama; Mitsuhiro Yokota

From the Cardiovascular Division, Department of Pathophysiology, Nagoya University Graduate School of Medicine (H.I., M.Y.), Nagoya; Department of Gene Therapy, Gifu International Institute of Biotechnology (Y.Y., M.T.), Mitake; and the Cardiovascular Center, Nagoya Daini Red Cross Hospital (T.O., H.H.), Nagoya, Japan.

Correspondence to Yoshiji Yamada, MD, PhD, FAHA, Department of Gene Therapy, Gifu International Institute of Biotechnology, Yagi Memorial Park, 2193-128 Mitake, Gifu 505-0116, Japan. E-mail yoyamada{at}giib.or.jp

	Abstract

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Although genetic epidemiological studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. The population of the present study comprised 1940 unrelated Japanese individuals, including 1067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that 2 polymorphisms (825CT in the G protein ß3 subunit gene and 190GA in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (-238GA in the tumor necrosis factor gene) was significantly associated with hypertension in women. These results suggest that 2 and 1 genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.

Key Words: hypertension, essential • hypertension, genetic • blood pressure • genetics • polymorphism • population • risk factors

	Introduction

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Hypertension is a complex multifactorial and polygenic disorder that is thought to result from an interaction between an individual’s genetic background and various environmental factors.¹ Given that hypertension is a major risk factor for coronary artery disease (CAD), stroke, and chronic renal failure, prevention of hypertension is an important public health goal. One approach to preventing the development of this condition is to identify disease susceptibility genes. Genetic linkage^2–4 and candidate gene association^5–8 studies have implicated various loci and genes in predisposition to hypertension. Although genetic epidemiological studies have suggested that certain genetic variants, including polymorphisms in the genes encoding angiotensinogen,⁵ -adducin,⁶ the ß3 subunit of G proteins,⁷ and the ß2-adrenergic receptor,⁸ increase the risk of hypertension, the genes that contribute to genetic susceptibility to this condition remain to be identified definitively. In addition, because of ethnic divergence of gene polymorphisms, it is important to construct a database of polymorphisms related to hypertension in each ethnic group.

We have now performed a large-scale association study for 33 single nucleotide polymorphisms (SNPs) of 27 candidate genes and hypertension. Our aim was to predict the genetic risk for hypertension and thereby to contribute to the primary prevention of this condition.

	Methods

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Study Population
The study population comprised 1940 unrelated Japanese individuals (1107 men, 833 women) who either visited outpatient clinics of or were admitted to one of the 15 participating hospitals (Appendix 1) between July 1994 and December 2001. A total of 1067 subjects (574 men, 493 women) either had hypertension (systolic blood pressure [BP] of 140 mm Hg or diastolic BP of 90 mm Hg, or both) or had taken antihypertensive drugs. Individuals with CAD, valvular heart disease, congenital malformations of the heart or vessels, or renal or endocrinologic diseases that cause secondary hypertension were excluded from the study. The 873 control subjects (533 men, 340 women) with normal BP (systolic BP of <140 mm Hg and diastolic BP of <90 mm Hg) were recruited from individuals who were found to have at least one of the conventional risk factors for CAD, including habitual cigarette smoking (10 cigarettes daily), obesity (body mass index [BMI] of 26 kg/m²), diabetes mellitus (fasting blood glucose of 6.93 mmol/L or hemoglobin A_1c of 6.5%, or both), hypercholesterolemia (serum total cholesterol of 5.72 mmol/L), and hyperuricemia (serum uric acid of 0.46 mmol/L for men or 0.33 mmol/L for women), but who had no history of CAD. Most of the subjects with hypertension and controls in the present study were included in the control group of our previous study.⁹ BP was measured with subjects in the seated position according to the guidelines of the American Heart Association.¹⁰ The study protocol was approved by the Committees on the Ethics of Human Research of Nagoya University Graduate School of Medicine, Gifu International Institute of Biotechnology, and Nagoya Daini Red Cross Hospital, and informed consent was obtained from each participant.

Selection of Candidate Gene Polymorphisms
With the use of public databases, including PubMed and Online Mendelian Inheritance in Man, we selected 27 candidate genes that have been characterized and were suggested to be associated with hypertension on the basis of a comprehensive overview of vascular biology, platelet and leukocyte biology, coagulation and fibrinolysis cascades, as well as lipid and glucose metabolism and other metabolic factors. We further selected 33 SNPs of these genes—most located in the promoter region, exons, or splice donor or acceptor sites in introns—that might be expected to affect the function or expression of the encoded protein (Table 1).⁹ We examined the relation of these SNPs to hypertension in the 1940 participants of the present study.

View this table: [in this window] [in a new window]   TABLE 1. Single Nucleotide Polymorphisms (SNPs) Examined for Association With Hypertension

Genotyping of SNPs
Venous blood (7 mL) was collected from each subject in tubes containing 50 mmol/L EDTA (disodium salt), and genomic DNA was isolated with a kit (Qiagen). Genotypes of SNPs were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system (Toyobo Gene Analysis) (Appendix 2) as previously described.⁹

Statistical Analysis
Quantitative clinical data were compared between patients with hypertension and controls by the unpaired Student t test or the Mann-Whitney U test. Qualitative data were compared by the ² test. Allele frequencies were estimated by the gene-counting method, and the ² test was used to identify significant departures from Hardy-Weinberg equilibrium. We performed multivariate logistic regression analysis to adjust risk factors, with hypertension as a dependent variable and independent variables including age, BMI, smoking status (0=nonsmoker, 1=smoker), metabolic variables (0=no history of diabetes mellitus, hypercholesterolemia, or hyperuricemia; 1=positive history), and genotype of each SNP. Each genotype was assessed according to dominant, recessive, and additive genetic models, and the P value, odds ratio, and 95% confidence interval were calculated. Unless indicated otherwise, a P value <0.05 was considered statistically significant.

	Results

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The characteristics of all 1940 participants (1107 men, 833 women) are shown in Table 2. For men, age, BMI, the prevalence of hyperuricemia, and the serum concentration of creatinine, as well as systolic and diastolic BP, were significantly greater, and the prevalence of smoking was significantly lower, in subjects with hypertension than in controls. For women, age, BMI, and the prevalence of hypercholesterolemia and hyperuricemia, as well as systolic and diastolic BP, were significantly greater in subjects with hypertension than in controls.

View this table: [in this window] [in a new window]   TABLE 2. Characteristics of the Study Subjects (n=1940)

Multivariate logistic regression analysis with adjustment for age, BMI, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that 2 different sets of 4 of the 33 SNPs examined were associated with hypertension in men and women on the basis of a probability value <0.05 in either a dominant, recessive, or additive genetic model. However, given the multiple comparisons of genotypes, we considered a probability value <0.01 to be statistically significant for such associations. On the basis of this criterion, the 825CT SNP of the G protein ß3 subunit gene and the 190GA SNP of the CC chemokine receptor 2 gene were significantly associated with hypertension in men, and the -238GA SNP of the tumor necrosis factor gene was significantly associated with hypertension in women (Table 3). The chromosomal loci of the corresponding genes are also shown in Table 3. The -850CT and -238GA SNPs of the tumor necrosis factor gene related to hypertension in women were not in linkage disequilibrium (pairwise linkage disequilibrium coefficient, D’[D/D_max], of -0.310 and standardized linkage disequilibrium coefficient, r=-0.020; P= 0.613, ² test). The genotype distributions of the various SNPs related to hypertension are shown in Table 4.

View this table: [in this window] [in a new window]   TABLE 3. Multivariate Logistic Regression Analysis of SNPs Associated With Hypertension

View this table: [in this window] [in a new window]   TABLE 4. Genotype Distributions of SNPs Associated With Hypertension

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 References

 
We have examined the relation of hypertension to 33 SNPs of 27 candidate genes in a large-scale association study with 1940 individuals. We identified 3 different SNPs, 2 in men and 1 in women, that were significantly associated with hypertension.

Many association studies have previously examined the relations between gene polymorphisms and hypertension. The results of most of these studies, however, remain controversial, with no consensus on their implications, mainly because of the limited population size of the studies, the ethnic diversity of gene polymorphisms, and complicating environmental factors. Furthermore, even though associations have been detected, the relative risk (odds ratio) conferred by a single polymorphism has tended to be low in large populations. The regulation of BP involves both the integration of a variety of biological systems that control the structure and tone of the vasculature and the volume and composition of body fluid, as well as the adaptation of these systems to constantly changing physiological needs.¹¹ The 33 SNPs of the 27 genes examined in the present study were selected on the basis of a comprehensive overview of vascular biology, platelet and leukocyte biology, the fibrinolysis system, as well as lipid and glucose metabolism and other metabolic factors. Although these genes were studied in relation to myocardial infarction in our previous study,⁹ they are also candidates for susceptibility loci to hypertension. The genes now shown to be associated with hypertension may play important roles in vascular smooth muscle cell biology (G protein ß3 subunit), vascular inflammation (tumor necrosis factor ), and monocyte and lymphocyte biology (CC chemokine receptor 2). Given that 3 SNPs were located on different chromosomes, these SNPs were not in linkage disequilibrium.

For men, the 825CT SNP of the G protein ß3 subunit gene and the 190GA SNP of the CC chemokine receptor 2 gene were significantly associated with hypertension. Siffert et al⁷ previously showed that the 825CT SNP in exon 10 of the G protein ß3 subunit gene was associated with hypertension. The T allele was associated with the appearance of a splice variant lacking nucleotides 498 to 620 in exon 9 of the primary transcript, resulting in the loss of 41 amino acids (including one WD repeat domain) in the encoded protein. This splice variant may be responsible for the enhanced signal transduction via pertussis toxin–sensitive G proteins previously observed in lymphoblasts and fibroblasts from certain individuals with essential hypertension.^12,13 Our present results indicate that the T allele of the 825CT SNP is a risk factor for hypertension in men, consistent with the observation of Siffert et al.⁷ However, the allele frequency of this SNP in the Japanese population of the present study (C allele, 54%; T allele, 46%) is significantly different (P<0.0001, ² test) from that in the German population of the previous study⁷ (C allele, 75%; T allele, 25%), suggesting that the allele frequency differs among ethnic groups.

CC chemokine receptor 2 is a receptor for monocyte chemoattractant protein (MCP)-1 and closely related proteins including MCP-2, -3, -4, and -5. MCP-1 is chemotactic for monocytes and other leukocyte subsets. Both MCP-1 and CC chemokine receptor 2 have been implicated in the development of CAD.¹⁴ The A allele of the 190GA (Val64Ile) SNP of the CC chemokine receptor 2 gene was previously suggested to be associated with a reduced risk for severe CAD,¹⁵ whereas another study showed a lack of association between this SNP and the prevalence of myocardial infarction.¹⁶ CC chemokine receptor 2 has also been shown to contribute to the development of hypertension,¹⁷ although the 190GA SNP of the corresponding gene has not previously been associated with this condition. Our results suggest that the A allele of the 190GA SNP of this gene is a risk factor for predisposition to hypertension in men.

For women, the -238GA SNP of the tumor necrosis factor gene was significantly associated with the prevalence of hypertension. The tumor necrosis factor gene locus was previously shown to be associated with obesity-related hypertension in French Canadians.¹⁸ A -308AG SNP of the tumor necrosis factor gene also previously showed a tendency to associate with essential hypertension, although statistical significance was not achieved.¹⁹ The serum concentration of this cytokine was associated with systolic BP and insulin resistance in a native Canadian population.²⁰ Tumor necrosis factor stimulates the production of the potent vasoconstrictor endothelin-1 by cultured vascular endothelial cells,²¹ and the serum concentrations of these 2 agents were positively correlated in subjects with android-type obesity.²² These previous observations, as well as our present results, suggest that the tumor necrosis factor gene is a candidate locus for susceptibility to hypertension and that the A allele of the -238GA SNP of this gene protects against the development of hypertension, although the frequency of the A allele was low in women (G and A alleles, 96.8% and 3.2%, respectively, in controls, and 98.6% and 1.4%, respectively, in subjects with hypertension).

The 33 SNPs examined in the present study likely represent only a small proportion of polymorphisms potentially associated with hypertension. Thus, it remains possible that further investigations will identify other polymorphisms that are associated with this condition. It is also possible that one or more of the SNPs associated with hypertension in our study are in linkage disequilibrium with polymorphisms of other nearby genes that are actually responsible for the development of hypertension. Our present results suggest, however, that the genes encoding the G protein ß3 subunit and CC chemokine receptor 2 are susceptibility loci for hypertension in Japanese men and that the tumor necrosis factor gene constitutes such a locus in Japanese women. Genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension and thereby may contribute to the primary prevention of hypertension and of cardiovascular, cerebral, or renal diseases induced by this condition.

Perspectives
We have examined the relation of hypertension to 33 SNPs of 27 candidate genes in a large-scale association study with 1940 individuals and identified 2 SNPs (825CT in the G protein ß3 subunit gene and 190GA in the CC chemokine receptor 2 gene) in men and 1 SNP (-238GA in the tumor necrosis factor gene) in women that were significantly associated with hypertension. These results suggest that 2 and 1 genes may be susceptibility loci for hypertension in Japanese men and women, respectively. Genotyping of these SNPs may prove informative for prediction of the genetic risk for hypertension.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 References

 
The following physicians and institutions participated in this study: H. Horibe, M. Watarai, K. Takemoto, S. Shimizu, and F. Takatsu (Kosei Hospital); A. Hirashiki, Y. Murase, and H. Ishihara (Okazaki City Hospital); N. Tsuboi and T. Itoh (Nagoya Daini Red Cross Hospital); S. Ichihara, and R. Ishiki (Nagoya University Hospital); K. Takagi and T. Sone (Ogaki Municipal Hospital); C. Takanaka (Hamamatsu Medical Center); M. Maeda and Y. Nishinaka (Chita City Hospital); T. Fukumitsu (Hekinann City Hospital); H. Kanda (Nagoya East City Hospital); T. Watanabe (Nagoya National Hospital); S. Ishikawa and F. Saito (Showa Hospital); H. Inagaki and S. Kamihara (Toyota Memorial Hospital); S. Ogawa and T. Fujimura (Tokai Central Hospital); J. Goto (National Chubu Hospital); and S. Kato (Marine Clinic).

	Appendix 2

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 References

 
Table 5 presents the primers, probes, and other conditions for genotyping.

View this table: [in this window] [in a new window]   TABLE 5. Primers, Probes, and Other Conditions for Genotyping

	Acknowledgments

 
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (to M.Y.), a grant from Gifu Life Science Research Foundation (to Y.Y.), a grant from Japan Cardiovascular Research Foundation (to Y.Y.), a grant from Takeda Science Foundation (to Y.Y.), and a grant from Mitsui Life Social Welfare Foundation (to M.Y.).

Received December 18, 2002; first decision January 15, 2003; accepted February 27, 2003.

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This Article Abstract Full Text (PDF) All Versions of this Article: 41/5/1035    most recent 01.HYP.0000065618.56368.24v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Izawa, H. Articles by Yokota, M. Search for Related Content PubMed PubMed Citation Articles by Izawa, H. Articles by Yokota, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information High Blood Pressure Related Collections Genetics of cardiovascular disease