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Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and Their Effect on Visceral Fat Area in the Japanese Population

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Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and Their Effect on Visceral Fat Area in the Japanese Population Journal of Human Genetics (2010) 55, 738–742 & 2010 The Japan Society of Human Genetics All rights reserved 1434-5161/10 $32.00 www.nature.com/jhg ORIGINAL ARTICLE Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population Kikuko Hotta1, Michihiro Nakamura1, Takahiro Nakamura2,3, Tomoaki Matsuo4, Yoshio Nakata4, Seika Kamohara5, Nobuyuki Miyatake6, Kazuaki Kotani7, Ryoya Komatsu8, Naoto Itoh9, Ikuo Mineo10, Jun Wada11, Masato Yoneda12, Atsushi Nakajima12, Tohru Funahashi7, Shigeru Miyazaki13, Katsuto Tokunaga14, Manabu Kawamoto15, Hiroaki Masuzaki16, Takato Ueno17, Kazuyuki Hamaguchi18, Kiyoji Tanaka4, Kentaro Yamada19, Toshiaki Hanafusa20, Shinichi Oikawa21, Hironobu Yoshimatsu22, Kazuwa Nakao23, Toshiie Sakata22, Yuji Matsuzawa7, Yusuke Nakamura24 and Naoyuki Kamatani3 The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist–hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist–hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2b (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P¼0.0039 and 0.0039, respectively), SFA (P¼0.0027 and 0.0023, respectively) and VFA (P¼0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects. Journal of Human Genetics (2010) 55, 738–742; doi:10.1038/jhg.2010.99; published online 12 August 2010 Keywords: fat mass and obesity associated (FTO); lysophospholipase-like 1 (LYPLAL1); melanocortin 4 receptor (MC4R); methionine sulfoxide reductase A (MSRA); neurexin 3 (NRXN3); subcutaneous fat area; transcription factor AP-2-b (TFAP2B); visceral fat area INTRODUCTION considerable interest because of increasing the number of patients. Metabolic syndrome is a common clinical phenotype that is mani- Although the pathogenesis of metabolic syndrome is not fully under- fested as concurrent metabolic abnormalities, including central obe- stood, the predominant underlying risk factor is considered to be sity, glucose intolerance, dyslipidemia and hypertension.1 Because visceral obesity due to an atherogenic diet and physical inactivity, in several other definitions also exist,2 the adequacy of this concept addition to certain genetic factors.1,2 Adipose tissue, especially the remains debatable. Recently, metabolic syndrome has attracted visceral fat, secretes various adipocytokines. An increase in the adipose 1Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Yokohama, Japan; 2Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Japan; 3Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Tokyo, Japan; 4Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan; 5Health Science University, Yamanashi, Japan; 6Okayama Southern Institute of Health, Okayama, Japan; 7Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan; 8Rinku General Medical Center, Osaka, Japan; 9Toyonaka Municipal Hospital, Osaka, Japan; 10Otemae Hospital, Osaka, Japan; 11Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; 12Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 13Tokyo Postal Services Agency Hospital, Tokyo, Japan; 14Itami City Hospital, Hyogo, Japan; 15Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan; 16Division of Endocrinology and Metabolism, Second Department of Internal Medicine, University of the Ryukyus Faculty of Medicine, Okinawa, Japan; 17Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan; 18Department of Community Health and Gerontological Nursing, Faculty of Medicine, Oita University, Oita, Japan; 19Division of Endocrinology and Metabolism, Department of Medicine, Kurume University, Kurume, Japan; 20First Department of Internal Medicine, Osaka Medical College, Osaka, Japan; 21Division of Endocrinology and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan; 22Department of Internal Medicine I, Faculty of Medicine, Oita University, Oita, Japan; 23Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan and 24Laboratory for Molecular Medicine, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo, Japan Correspondence: Dr K Hotta, Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, 1-7-22, Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: [email protected] Received 14 June 2010; revised and accepted 21 July 2010; published online 12 August 2010 Gene polymorphisms and body fat distribution KHottaet al 739 Table 1 Clinical characteristics of the subjects database. Two SNPs (rs1558902 and rs1421085) in FTO were sig- nificantly associated with BMI in women (Table 2). The association of Men (n¼518) Women (n¼710) Total (n¼1228) rs489693 and rs17700144 in MC4R with BMI has been reported in the Caucasian population;7,8 however, such association was not observed Age (years) 49.7±11.9 52.1±11.3 51.1±11.6 BMI (kg À2)30.3±6.2 28.2±5.3 29.1±5.8 in our study. The SNPs in TFAP2B, MSRA and LYPLAL1 were not VFA (cm2)160.9±66.8 102.5±54.5 127.1±66.5 associated with BMI, which is a finding consistent with that of 7 SFA (cm2)213.0±110.8 246.4±98.6 232.3±105.2 Lindgren et al. No SNPs in the five genes were associated with VFA in either men or women (Table 3). Although rs489693 was marginally Abbreviations: BMI, body mass index; SFA, subcutaneous fat area; VFA, visceral fat area. Data are shown as the mean ± s.d. associated with VFA in men, the risk allele was different from that reported in the Caucasian population.7 Two SNPs (rs1558902 and tissue mass leads to an alteration in the plasma adipocytokine level, rs1421085) in FTO were significantly associated with SFA both in men resulting in dyslipidemia, hypertension and insulin resistance.3,4 Intra- (P¼0.034 and 0.040, respectively) and women (P¼0.010 and 0.0083, abdominal fat accumulation (central adiposity) is determined in terms respectively) (Table 4). SNPs in other genes were not significantly of the waist circumference and waist–hip ratio measurements and associated with SFA. All SNPs were found to exhibit Hardy–Weinberg visceral fat area (VFA) that is measured by computed tomo- equilibrium (P40.10). graphy (CT).1,5,6 Recently, two genome-wide association studies had Next, we attempted to perform multiple linear regression analysis been conducted to identify the loci that were linked with waist by using BMI, VFA and SFA as the dependent variables, and with age, circumference or waist–hip ratio.7,8 gender or genotype as an explanatory variable. We transformed In this study, we investigated the association of single-nucleotide genotypes to 0, 1 or 2 depending on the number of copies of the polymorphisms (SNPs) in neurexin 3 (NRXN3), transcription factor risk alleles. The A-allele of rs1558902 and the C-allele of rs1421085 in AP-2b (TFAP2B), methionine sulfoxide reductase A (MSRA), lyso- FTO were significantly associated with increases in BMI (P¼0.0039 phospholipase-like-1 (LYPLAL1), fat mass and obesity associated and 0.0039, respectively), VFA (P¼0.045 and 0.040, respectively) and (FTO) and melanocortin 4 receptor (MC4R) genes with VFA and SFA (P¼0.0027 and 0.0023, respectively) even after age and gender subcutaneous fat area (SFA) that were determined by CT. were included in the model (Supplementary Tables 1, 2, and 3). Multiple linear regression analysis showed that the SNPs of other MATERIALS AND METHODS genes were not significantly associated with BMI, VFA and SFA. Study subjects We also conducted power analysis of linear regression (additive We recruited 1228 Japanese subjects from outpatient clinics after they agreed to model) with a significance level of 0.05, considering the effect size of undergo CT examinations (supine position) that were performed to determine the parameters. For rs1558902, the estimated effect sizes per allele the VFA and SFA values at the level of the umbilicus (L4–L5). Both VFA and (regression coefficients) for VFA and SFA were 5.8 and 14.4 cm2, SFA were calculated using the FatScan software program (N2system, Osaka, respectively (Supplementary Tables 2 and 3). The power of our 9 Japan). The clinical characteristics of the patients are summarized in Table 1. statistical test was calculated on the basis of these estimated effect All subjects provided their informed written consent, and the protocol was sizes and
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