title: Replication and extension of association between common genetic variants in SIM1 and human adiposity.
abstract: Haplo-insufficiency of the bHLH (basic helix-loop-helix) transcription factor single-minded 1 (SIM1) causes severe obesity in mice and humans. We hypothesized that common genetic variations in/near SIM1 could exert more subtle effects on its function and associate with human adiposity. First, SIM1 coding regions were sequenced in severely obese subjects, and two common nonsynonymous single-nucleotide polymorphisms (nsSNPs) in complete linkage disequilibrium (LD) were identified: Pro352Thr (rs3734354) and Ala371Val (rs3734355). We next carried out a SNP association study of five adiposity traits (BMI, % body fat, abdominal visceral and subcutaneous fat, and leptin concentrations) in 1,699 whites and 1,173 blacks. TagSNPs covering SIM1 and nearby conserved regions, and the only common nsSNP in SIM1's binding partner aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) (Gly679Ser/rs4072568), were investigated. The effects of rs3734355/4 on SIM1 activity were tested using an in vitro reporter assay. We replicated previous observations that homozygosity for the 371Val allele was associated with higher BMI in white males (P = 0.003). Together with previous findings in white males (combined n = 3,479), BMI was increased by 1.10 kg/m(2) in 371Val homozygotes (95% confidence interval (CI): 0.25-1.95 kg/m(2), P = 0.01). In vitro, the 352Thr-371Val haplotype impaired SIM1 transcriptional activity by 22% (P < 0.0001). TagSNP analysis of SIM1 revealed two SNPs in the 3' region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity- and sex-specific manners after multiple testing correction. In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 × 10(-4)) and % body fat (P = 0.001). Our findings implicate heritable defects of the SIM1-ARNT2 axis in the predisposition to human obesity.
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Swarbrick
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Valle
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Favre
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Shi-Hsuan
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Omer T
authors.initials: OT
authors.lastname: Njajou
authors.affiliation: Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Zmuda
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Iva
authors.initials: I
authors.lastname: Miljkovic
authors.affiliation: Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California, USA.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Vaisse
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsueh
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000273:Adipose Tissue; D050154:Adiposity; D000483:Alleles; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D044383:Black People / Q000235:genetics; D001823:Body Composition / Q000235:genetics*; D015992:Body Mass Index; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057895:Haploinsufficiency; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007438:Introns; D020738:Leptin / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D009765:Obesity / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D012737:Sex Factors; D014158:Transcription, Genetic; D044465:White People / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D020738:Leptin; D012097:Repressor Proteins; C491094:SIM1 protein, human