title: Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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 < or = 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.
  
  
  METHODS
  Obese subjects (body mass index > or = 30 kg/m(2), n = 890) and control subjects (general population; n = 658, body mass index < or = 25 kg/m(2); 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; chi(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.
authors.affiliation: Laboratory for Obesity, SNP Research Center, RIKEN, 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanabe
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yanagiya
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Seika
authors.initials: S
authors.lastname: Kamohara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakata
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kotani
authors.forename: Ryoya
authors.initials: R
authors.lastname: Komatsu
authors.forename: Naoto
authors.initials: N
authors.lastname: Itoh
authors.forename: Ikuo
authors.initials: I
authors.lastname: Mineo
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hamaguchi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimada
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oikawa
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yoshimatsu
authors.forename: Toshiie
authors.initials: T
authors.lastname: Sakata
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuzawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kikuko
authors.initials: K
authors.lastname: Hotta
mesh_terms: D000328:Adult; D000368:Aged; D001069:Appetite Regulation / Q000502:physiology; D016022:Case-Control Studies; D002864:Chromogranins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D002864:Chromogranins; D009479:Neuropeptides; C506136:SCG3 protein, human