Human Molecular Genetics Advance Access originally published online on September 12, 2007
Human Molecular Genetics 2007 16(24):3017-3026; doi:10.1093/hmg/ddm260
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Association of single-nucleotide polymorphisms in MTMR9 gene with obesity
1 Laboratory for Obesity, 2 Laboratory for Genotyping, 3 Laboratory for Medical Informatics, SNP Research Center, RIKEN, Kanagawa 230-0045, Japan, 4 Laboratory for Pharmacogenetics, 5 Laboratory for Statistical Analysis, SNP Research Center, RIKEN, Tokyo 108-8639, Japan, 6 Medicine and Health Science Institute, Tokyo Medical University, Tokyo 163-1307, Japan, 7 Institute of Health and Sport Sciences, University of Tsukuba, Ibaraki 305-8574, Japan, 8 Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan, 9 Rinku General Medical Center, Osaka 598-0048, Japan, 10 Toyonaka Municipal Hospital, Osaka 560-8565, Japan, 11 Otemae Hospital, Osaka 540-0008, Japan, 12 Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan, 13 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan, 14 Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan, 15 Tokyo Postal Services Agency Hospital, Tokyo 102-8798, Japan, 16 Itami City Hospital, Hyogo 664-8540, Japan, 17 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, 18 Department of Community Health and Gerontological Nursing, 19 Department of Anatomy, Biology and Medicine, Faculty of Medicine, Oita University, Oita 879-5593, Japan, 20 Division of Endocrinology and Metabolism, Department of Medicine, Kurume University, Fukuoka 830-0011, Japan, 21 First Department of Internal Medicine, Osaka Medical College, Osaka 569-8686, Japan, 22 Division of Endocrinology and Metabolism, Department of Medicine, Nippon Medical School, Tokyo 113-8603, Japan, 23 SNP Research Center, RIKEN, Kanagawa 230-0045, Japan, 24 Laboratory for Molecular Medicine, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan and
* To whom correspondence should be addressed at: Laboratory for Obesity, SNP Research Center, RIKEN 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Tel: +81-45-503-9589; Fax: +81-45-503-9566; Email: kikuko{at}src.riken.jp
Received June 15, 2007; Accepted September 6, 2007
Genetic factors are clearly involved in the development of obesity, but the genetic background of obesity remains largely unclear. Starting from 62 663 gene-based single-nucleotide polymorphisms (SNPs) in three sequential case–control association studies, we identified a replicated association between the obesity phenotype (BMI 
30 kg/m2) and a SNP (rs2293855) located in the myotublarin-related protein 9 (MTMR9) gene in the chromosomal segment 8p23–p22. P-values (minor allele dominant model) of the first set (93 cases versus 649 controls) and the second set (564 cases versus 562 controls) were 0.008 and 0.0002, respectively. The association was replicated in the third set [394 cases versus 958 controls, P=0.005, odds ratio (95% CI) =1.40 (1.11–1.78)]. The global P-value was 0.0000005. A multiple regression analysis revealed that gender, age BMI and rs2293855 genotype (minor allele dominant model) were significantly associated with both systolic and diastolic blood pressures. MTMR9 was shown to be the only gene within the haplotype block that contained SNPs associated with obesity. Both the transcript and protein of MTMR9 were detected in the rodent lateral hypothalamic area as well as in the arcuate nucleus, and the protein co-existed with orexin, melanin concentrating hormone, neuropeptide Y and proopiomelanocortin. The levels of MTMR9 transcript in the murine hypothalamic region increased after fasting and were decreased by a high-fat diet. Our data suggested that genetic variations in MTMR9 may confer a predisposition towards obesity and hypertension through regulation of hypothalamic neuropeptides.