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Functional Single-Nucleotide Polymorphisms in the Secretogranin III (SCG3) Gene that Form Secretory Granules with Appetite-Related Neuropeptides Are Associated with Obesity

Laboratories for Obesity (A.Tan., T.Y., K.Ho.), Pharmacogenetics (A.I.), SNP Analysis (S.S.), SNP Genotyping (A.S.), Statistical Analysis (A.Tak., T.N., N.K.), and Medical Informatics (T.T.), SNP Research Center, RIKEN, Kanagawa 230-0045, Japan; Medicine and Health Science Institute (S.K.), Tokyo Medical University, Tokyo 101-0062, Japan; Institute of Health and Sport Sciences (Y.Nakat., K.T.), University of Tsukuba, Ibaraki 305-8574, Japan; Department of Internal Medicine and Molecular Science (K.K., T.F., Y.M.), Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Rinku General Medical Center (R.K.), Osaka 598-8577, Japan; Toyonaka Municipal Hospital (N.I.), Osaka 560-8565, Japan; Otemae Hospital (I.M.), Osaka 540-0008, Japan; Department of Medicine and Clinical Science (J.W.), Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan; Tokyo Postal Services Agency Hospital (S.M.), Tokyo 102-8798, Japan; Itami City Hospital (K.T.), Hyogo 664-8540, Japan; Department of Community Health and Gerontological Nursing (K.Ha.), Faculty of Medicine, Department of Health Sciences (T.S.), School of Nursing, and Department of Anatomy, Biology, and Medicine (H.Y., T.S.), Faculty of Medicine, Oita University, Oita 879-5593, Japan; Division of Endocrinology and Metabolism, Department of Medicine (K.Y.), Kurume University, Fukuoka 830-0011, Japan; First Department of Internal Medicine (T.H.), Osaka Medical College, Osaka 569-8686, Japan; Division of Endocrinology and Metabolism (S.O.), Department of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; and Laboratory for Molecular Medicine (Y.Nakam.), Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Address all correspondence and requests for reprints to: Kikuko Hotta, Laboratory for Obesity, SNP Research Center, RIKEN, 1-7-22, Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: kikuko{at}src.riken.jp.

Context: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear.

Objective: Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms (SNPs).

Design and Setting: We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied.

Patients: Obese subjects (body mass index 30 kg/m², n = 890) and control subjects (general population; n = 658, body mass index 25kg/m²; n = 711) were recruited for this study.

Results: Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity (odds ratio, 9.23; 95% confidence interval, 2.77–30.80; ² = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides.

Conclusions: Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.

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