Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity

Atsushi Tanabe, Takahiro Yanagiya, Aritoshi Iida, Susumu Saito, Akihiro Sekine, Atsushi Takahashi, Takahiro Nakamura, Tatsuhiko Tsunoda, Seika Kamohara, Yoshio Nakata, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Kazuyuki Hamaguchi, Tatsuo ShimadaKiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Toshiie Sakata, Yuji Matsuzawa, Naoyuki Kamatani, Yusuke Nakamura, Kikuko Hotta

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Abstract

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; χ2 = 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.

Original languageEnglish
Pages (from-to)1145-1154
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number3
DOIs
Publication statusPublished - Mar 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Tanabe, A., Yanagiya, T., Iida, A., Saito, S., Sekine, A., Takahashi, A., Nakamura, T., Tsunoda, T., Kamohara, S., Nakata, Y., Kotani, K., Komatsu, R., Itoh, N., Mineo, I., Wada, J., Funahashi, T., Miyazaki, S., Tokunaga, K., Hamaguchi, K., ... Hotta, K. (2007). Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity. Journal of Clinical Endocrinology and Metabolism, 92(3), 1145-1154. https://doi.org/10.1210/jc.2006-1808