TY - JOUR
T1 - Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity
AU - Tanabe, Atsushi
AU - Yanagiya, Takahiro
AU - Iida, Aritoshi
AU - Saito, Susumu
AU - Sekine, Akihiro
AU - Takahashi, Atsushi
AU - Nakamura, Takahiro
AU - Tsunoda, Tatsuhiko
AU - Kamohara, Seika
AU - Nakata, Yoshio
AU - Kotani, Kazuaki
AU - Komatsu, Ryoya
AU - Itoh, Naoto
AU - Mineo, Ikuo
AU - Wada, Jun
AU - Funahashi, Tohru
AU - Miyazaki, Shigeru
AU - Tokunaga, Katsuto
AU - Hamaguchi, Kazuyuki
AU - Shimada, Tatsuo
AU - Tanaka, Kiyoji
AU - Yamada, Kentaro
AU - Hanafusa, Toshiaki
AU - Oikawa, Shinichi
AU - Yoshimatsu, Hironobu
AU - Sakata, Toshiie
AU - Matsuzawa, Yuji
AU - Kamatani, Naoyuki
AU - Nakamura, Yusuke
AU - Hotta, Kikuko
N1 - Funding Information:
This work was supported by a grant from the Japanese Millennium Project, Takeda Science Foundation (to K.Ho.), and Chiyoda Mutual Life Foundation (to K.Ho.).
PY - 2007/3
Y1 - 2007/3
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2006-1808
DO - 10.1210/jc.2006-1808
M3 - Article
C2 - 17200173
AN - SCOPUS:33947525459
SN - 0021-972X
VL - 92
SP - 1145
EP - 1154
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 3
ER -
