title: INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men.
abstract: BACKGROUND
  A common SNP upstream of the INSIG2 gene, rs7566605 (g.-10,1025G>C, Chr2:118,552,255, NT_022135.15), was reported to be associated with obesity (Body Mass Index, [BMI]) in a genome-wide association scan using the Framingham Heart Study but has not been reproduced in other cohorts. As BMI is a relatively insensitive measure of adiposity that is subject to many confounding variables, we sought to determine the relationship between the INSIG2 SNP and subcutaneous fat volumes measured by MRI in a young adult population.
  
  
  METHODS
  We genotyped the INSIG2 SNP rs7566605 in college-aged population enrolled in a controlled resistance-training program, (the Functional Polymorphism Associated with Human Muscle Size and Strength, FAMuSS cohort, n = 752 volunteers 18-40 yrs). In this longitudinal study, we examined the effect of the INSIG2 polymorphism on subcutaneous fat and muscle volumes of the upper arm measured by magnetic resonance imaging (MRI) before and after 12 wks of resistance training. Gene/phenotype associations were tested using an analysis of covariance model with age and weight as covariates. Further, the % variation in each phenotype attributable to genotype was determined using hierarchical models and tested with a likelihood ratio test.
  
  
  RESULTS
  Women with a copy of the C allele had higher levels of baseline subcutaneous fat (GG: n = 139; 243473 +/- 5713 mm3 vs. GC/CC: n = 181; 268521 +/- 5003 mm3; p = 0.0011); but men did not show any such association. Men homozygous for the G ancestral allele showed a loss of subcutaneous fat, while those with one or two copies of the C allele gained a greater percentage of subcutaneous fat with resistance training (GG: n = 103; 1.02% +/- 1.74% vs. GC/CC: n = 93; 6.39% +/- 1.82%; p = 0.035).
  
  
  CONCLUSIONS
  Our results show that the INSIG2 rs7566605 polymorphism underlies variation in subcutaneous adiposity in young adult women and suppresses the positive effects of resistance training on men. This supports and extends the original finding that there is an association between measures of obesity and INSIG2 rs7566605 and further implicates this polymorphism in fat regulation.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA. fsuer@cnmcresearch.org
authors.forename: Funda E
authors.initials: FE
authors.lastname: Orkunoglu-Suer
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Priscilla M
authors.initials: PM
authors.lastname: Clarkson
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Angelopoulos
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gordon
authors.forename: Niall M
authors.initials: NM
authors.lastname: Moyna
authors.forename: Linda S
authors.initials: LS
authors.lastname: Pescatello
authors.forename: Paul S
authors.initials: PS
authors.lastname: Visich
authors.forename: Robert F
authors.initials: RF
authors.lastname: Zoeller
authors.forename: Brennan
authors.initials: B
authors.lastname: Harmon
authors.forename: Richard L
authors.initials: RL
authors.lastname: Seip
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Devaney
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000328:Adult; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055070:Resistance Training; D012737:Sex Factors; D050151:Subcutaneous Fat / Q000473:pathology; D055815:Young Adult
chemical_list: C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins