Common Single Nucleotide Polymorphisms in Japanese Patients with Essential Hypertension: Aldehyde Dehydrogenase 2 Gene as a Risk Factor Independent of Alcohol Consumption

585 Hypertens Res Vol.30 (2007) No.7 p.585-592 Original Article Common Single Nucleotide Polymorphisms in Japanese Patients with Essential Hypertension: Aldehyde Dehydrogenase 2 Gene as a Risk Factor Independent of Alcohol Consumption Peng HUI1),2), Tomohiro NAKAYAMA1), Akihiko MORITA3), Naoyuki SATO1), Mikano HISHIKI1), Kosuke SAITO1),4), Yukie YOSHIKAWA1),4), Masaaki TAMURA5), Ichiro SATO5), Teruyuki TAKAHASHI6), Masayoshi SOMA7), Yoichi IZUMI7), Yukio OZAWA8), and Zuheng CHENG2) Essential hypertension (EH) is a multifactorial disorder determined by the interaction of environmental and genetic factors. EH patients’ responses to these factors may vary, depending on differences in their genes that determine the physiological systems that mediate the response. The purpose of this investigation was to clarify the contributions of genetic background and lifestyle to EH through an association study using some common single nucleotide polymorphisms (SNPs) that should have functional effects on EH phenotypes. We studied the associations between common SNPs of some causal genes related to EH and lifestyle in a Japanese population. The variants of the causal genes were selected based on their functions, including: obesity (adrenergic, β-3-, receptor: ADRB3), alcohol consumption (aldehyde dehydrogenase 2: ALDH2), water-electrolyte metabolism (guanine nucleotide binding protein [G protein], β polypeptide 3: GNB3), glycometabolism (peroxisome proliferator–activated receptor γ: PPARG), lipometabolism (cholesteryl ester transfer protein, plasma: CETP), atherosclerosis (5,10-methylenetetrahydrofolate reductase [NADPH]: MTHFR), and cellular behavior (gap junction protein, α 4, 37 kD: GJA4). Case-control association analysis showed a significant association between EH and both the ALDH2 (Lys487Glu) and GNB3 (C825T) variants. Logistic regression analysis indicated that body mass index (BMI) is an important risk factor for EH, and that the GG (Glu/Glu) genotype of ALDH2 was an independent risk factor for EH overall and especially for EH in males. There was no interaction between the ALDH2 genotype and alcohol consumption overall or in male subjects. Our results suggest that the ALDH2 genotype is associated with EH independently of alcohol consumption. (Hypertens Res 2007; 30: 585–592) Key Words: single nucleotide polymorphisms, essential hypertension, gene-environment interaction, common variants From the 1)Division of Molecular Diagnostics, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan; 2)Department of Internal Medicine, First Affiliated Hospital, Xinjiang Medical University, Urumqi, P.R. China; 3)Division of Neurology, 7)Division of Nephrology and Endocrinology, and 8)Division of Cardiovascular Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; 4)Department of Biotechnology and Applied Chemistry, Toyo University Graduate School of Engineering, Kawagoe, Japan; 5)Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan; and 6)Department of Neurology, Graduate School of Medicine, Nihon University, Tokyo, Japan. This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (High-Tech Research Center, Nihon University). Address for Reprints: Tomohiro Nakayama, M.D., Division of Molecular Diagnostics, Advanced Medical Research Center, Nihon University School of Medicine, Ooyaguchi-kamimachi, 30–1 Itabashi-ku, Tokyo 173–8610, Japan. E-mail: Received November 1, 2006; Accepted in revised form February 7, 2007. 586 Hypertens Res Vol. 30, No. 7 (2007) Introduction Hypertension affects 1 billion people worldwide and is implicated in 7.1 million deaths each year due to ischemic heart disease and stroke (www.who.int/en/index.html). Essential hypertension (EH) is a multifactorial disorder caused by the interaction of environmental and genetic factors. It is most likely that there are several causal genes, which together account for 30% to 50% of the blood pressure variation found among individuals (1). It is clear from familial and epidemiological studies that hypertension occurs as a result of a complex interplay between genetic and environmental lifestyle exposures (2). EH subjects happen to have inherited an aggregate of genes related to hypertension and/or have been exposed to exogenous factors that predispose them to hypertension. It is quite remarkable that obesity and salt intake have consistently been shown to be risk factors for hypertension worldwide. Some of the other well-recognized risk factors are alcohol intake, inactivity, and psychosocial stress (3). Lifestyle factors have long been recognized as playing an important role in the pathogenesis of EH. Individuals may vary in their responses to these factors depending on differences in their genes that determine the way their physiological systems mediate responses. During the last several years, many genetic susceptibility variants have been reported to be associated with multifactorial diseases. A few causal variants have been proven to have a functional effect on gene expression or protein structure, resulting in phenotypic differences. Furthermore, among the variants mentioned above, very few are considered common variants. To the best of our knowledge, the human aldehyde dehydrogenase 2 (ALDH2) gene (4) is the most famous variant proven to have a relationship between a genetic variant and alcohol consumption as a phenotype. No reports have examined the relationship between multiple common variants and EH. The purpose of this investigation was to clarify the contributions of genetic background and lifestyle to EH through an association study using common variants that are known to have functional effects in the phenotypes of multifactorial disorders. In particular, we studied the associations between common variants of some causal genes related to lifestyle and EH in a Japanese population. The candidate genes were selected based on their functions, and included: alcohol consumption (aldehyde dehydrogenase 2: ALDH2) (4), obesity (adrenergic, β-3-, receptor: ADRB3) (5), atherosclerosis (5,10-methylenetetrahydrofolate reductase [NADPH]: MTHFR) (6), glycometabolism (peroxisome proliferator– activated receptor γ: PPARG) (7), water-electrolyte metabolism (guanine nucleotide binding protein [G protein], β polypeptide 3: GNB3) (8), lipometabolism (cholesteryl ester transfer protein, plasma: CETP) (9), and cellular behavior (gap junction protein, α 4, 37 kD: GJA4) (10). Based on their effects on gene expression or protein structure (Table 1), we chose seven common variants of these causal genes. Methods Subjects The EH group consisted of 261 EH patients diagnosed according to the following criteria: sitting systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg on three occasions within 2 months after the first blood pressure reading. 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