title: Insulin receptor variants and obesity-related cancers in the Framingham Heart Study.
abstract: OBJECTIVE
  The insulin-signaling pathway plays a pivotal role in cancer biology; however, evidence of genetic alterations in human studies is limited. This case-control study nested within the Framingham Heart Study (FHS) examined the association between inherited genetic variation in the insulin receptor (INSR) gene and obesity-related cancer risk.
  
  
  METHODS
  The study sample consisted of 1,475 controls and 396 cases from the second familial generation of the FHS. Participants who provided consent were genotyped. Nineteen single-nucleotide polymorphisms (SNPs) in the INSR gene were investigated in relation to risk of obesity-related cancers combined and breast, prostate and colorectal cancers. Generalized estimation equation models controlling for familial correlations and include age, sex, smoking and body mass index as covariates, assuming additive models, were used.
  
  
  RESULTS
  Three SNPs, rs2059807, s8109559 and rs919275, were significantly associated with obesity-related cancers (p value < 0.02) with the most significantly associated SNP being rs2059807 (p value = 0.008). Carriers of two copies of SNP rs2059807 risk allele T were significantly less prevalent among subjects with obesity-related cancers [f(TT)cases = 14 vs. f(TT)controls = 18 %; OR 1.23]. In exploratory analyses evaluating site-specific cancers, the INSR rs2059807 association with these cancers was consistent with that observed for the main outcome (ORs colorectal cancer = 1.5, breast cancer = 1.29, prostate = 1.06). There was no statistically significant interaction between the INSR-SNP and blood glucose in relation to obesity-related cancer.
  
  
  CONCLUSIONS
  The INSR gene is implicated in obesity-related cancer risk, as 3 of 19 SNPs were nominally associated, after false discovery rate (FDR) correction, with the main outcome. Risk allele homozygotes (rs2059807) were less prevalent among subjects with obesity-related cancer. These results should be replicated in other populations to confirm the findings.
authors.affiliation: Department of Nutrition, Food Studies and Public Health, Steinhardt School, New York University, 411 Lafayette Street, 5th Floor, Room 542, New York, NY, 10003, USA, niyati.parekh@nyu.edu.
authors.forename: Niyati
authors.initials: N
authors.lastname: Parekh
authors.forename: Guia
authors.initials: G
authors.lastname: Guffanti
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Heather M
authors.initials: HM
authors.lastname: Ochs-Balcom
authors.forename: Nour
authors.initials: N
authors.lastname: Makarem
authors.forename: Richard
authors.initials: R
authors.lastname: Hayes
mesh_terms: D000328:Adult; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D009765:Obesity / Q000097:blood / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011972:Receptor, Insulin / Q000235:genetics*; D012306:Risk; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D001786:Blood Glucose; C435941:INSR protein, human; D011972:Receptor, Insulin