Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity.
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.
Tanabe
Atsushi
A
Laboratory for Obesity, SNP Research Center, RIKEN, 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Yanagiya
Takahiro
T
Iida
Aritoshi
A
Saito
Susumu
S
Sekine
Akihiro
A
Takahashi
Atsushi
A
Nakamura
Takahiro
T
Tsunoda
Tatsuhiko
T
Kamohara
Seika
S
Nakata
Yoshio
Y
Kotani
Kazuaki
K
Komatsu
Ryoya
R
Itoh
Naoto
N
Mineo
Ikuo
I
Wada
Jun
J
Funahashi
Tohru
T
Miyazaki
Shigeru
S
Tokunaga
Katsuto
K
Hamaguchi
Kazuyuki
K
Shimada
Tatsuo
T
Tanaka
Kiyoji
K
Yamada
Kentaro
K
Hanafusa
Toshiaki
T
Oikawa
Shinichi
S
Yoshimatsu
Hironobu
H
Sakata
Toshiie
T
Matsuzawa
Yuji
Y
Kamatani
Naoyuki
N
Nakamura
Yusuke
Y
Hotta
Kikuko
K
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*
D002864:Chromogranins; D009479:Neuropeptides; C506136:SCG3 protein, human