Analysis of the SIM1 contribution to polygenic obesity in the French population.
SIM1 (single-minded 1) haploinsufficiency is responsible for obesity in both humans and mice, but the contribution of frequent DNA variation to polygenic obesity is unknown. Sequencing of all exons, exon/intron boundaries, 870 base pairs (bp) of the putative promoter, and 1,095 bp of the 3'UTR of SIM1 gene in 143 obese children and 24 control adults identified 13 common variants. After analysis of the linkage disequilibrium (LD) structure, association study of eight variants was performed in 1,275 obese children and severely obese adults, in 1,395 control subjects, and in 578 obesity-selected pedigrees. A nominal evidence of association was found for the nonsynonymous variant P352T C/A (rs3734354) (P = 0.01, OR = 0.81 (0.70-0.95)), the +2,004 TGA -/insT SNP (rs35180395) (P = 0.02, OR = 1.21 (1.02-1.43)), the +2,215A/G TGA SNP (rs9386126) (P = 0.002, OR = 0.81 (0.71-0.93)), and pooled childhood/adult obesity. Even though transmission disequilibrium test (TDT) further supported the association of P352T and +2,004 -/inst T with obesity, none of these nominal associations remained significant after a multiple testing Bonferroni correction. Therefore, our study excludes a major contribution of SIM1 common variants in exons, 5' and 3' UTR regions in polygenic obesity susceptibility in French Europeans.
Ghoussaini
Maya
M
Genomics and Molecular Physiology of Metabolic Diseases, CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Stutzmann
Fanny
F
Couturier
Cyril
C
Vatin
Vincent
V
Durand
Emmanuelle
E
Lecoeur
Cécile
C
Degraeve
Franck
F
Heude
Barbara
B
Tauber
Maithé
M
Hercberg
Serge
S
Levy-Marchal
Claire
C
Tounian
Patrick
P
Weill
Jacques
J
Traurig
Michael
M
Bogardus
Clifton
C
Baier
Leslie J
LJ
Michaud
Jacques L
JL
Froguel
Philippe
P
Meyre
David
D
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D005602:France; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C491094:SIM1 protein, human