Association of single-nucleotide polymorphisms in MTMR9 gene with obesity.
Genetic factors are clearly involved in the development of obesity, but the genetic background of obesity remains largely unclear. Starting from 62 663 gene-based single-nucleotide polymorphisms (SNPs) in three sequential case-control association studies, we identified a replicated association between the obesity phenotype (BMI > or =30 kg/m(2)) and a SNP (rs2293855) located in the myotublarin-related protein 9 (MTMR9) gene in the chromosomal segment 8p23-p22. P-values (minor allele dominant model) of the first set (93 cases versus 649 controls) and the second set (564 cases versus 562 controls) were 0.008 and 0.0002, respectively. The association was replicated in the third set [394 cases versus 958 controls, P = 0.005, odds ratio (95% CI) =1.40 (1.11-1.78)]. The global P-value was 0.0000005. A multiple regression analysis revealed that gender, age BMI and rs2293855 genotype (minor allele dominant model) were significantly associated with both systolic and diastolic blood pressures. MTMR9 was shown to be the only gene within the haplotype block that contained SNPs associated with obesity. Both the transcript and protein of MTMR9 were detected in the rodent lateral hypothalamic area as well as in the arcuate nucleus, and the protein co-existed with orexin, melanin concentrating hormone, neuropeptide Y and proopiomelanocortin. The levels of MTMR9 transcript in the murine hypothalamic region increased after fasting and were decreased by a high-fat diet. Our data suggested that genetic variations in MTMR9 may confer a predisposition towards obesity and hypertension through regulation of hypothalamic neuropeptides.
Yanagiya
Takahiro
T
Laboratory for Obesity, SNP Research Center, RIKEN, Kanagawa 230-0045, Japan.
Tanabe
Atsushi
A
Iida
Aritoshi
A
Saito
Susumu
S
Sekine
Akihiro
A
Takahashi
Atsushi
A
Tsunoda
Tatsuhiko
T
Kamohara
Seika
S
Nakata
Yoshio
Y
Kotani
Kazuaki
K
Komatsu
Ryoya
R
Itoh
Naoto
N
Mineo
Ikuo
I
Wada
Jun
J
Masuzaki
Hiroaki
H
Yoneda
Masato
M
Nakajima
Atsushi
A
Miyazaki
Shigeru
S
Tokunaga
Katsuto
K
Kawamoto
Manabu
M
Funahashi
Tohru
T
Hamaguchi
Kazuyuki
K
Tanaka
Kiyoji
K
Yamada
Kentaro
K
Hanafusa
Toshiaki
T
Oikawa
Shinichi
S
Yoshimatsu
Hironobu
H
Nakao
Kazuwa
K
Sakata
Toshiie
T
Matsuzawa
Yuji
Y
Kamatani
Naoyuki
N
Nakamura
Yusuke
Y
Hotta
Kikuko
K
D000818:Animals; D016022:Case-Control Studies; D004036:Diet, Atherogenic; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C435691:MTMR9 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor