title: Circadian gene variants and susceptibility to type 2 diabetes: a pilot study.
abstract: BACKGROUND
  Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants.
  
  
  RESULTS
  The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 × 10(-5)), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively).
  
  
  CONCLUSIONS
  None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility.
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. m.a.kelly@bham.ac.uk
authors.forename: M Ann
authors.initials: MA
authors.lastname: Kelly
authors.forename: Simon D
authors.initials: SD
authors.lastname: Rees
authors.forename: M Zafar I
authors.initials: MZ
authors.lastname: Hydrie
authors.forename: A Samad
authors.initials: AS
authors.lastname: Shera
authors.forename: Srikanth
authors.initials: S
authors.lastname: Bellary
authors.forename: J Paul
authors.initials: JP
authors.lastname: O'Hare
authors.forename: Sudhesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Shahrad
authors.initials: S
authors.lastname: Taheri
authors.forename: Abdul
authors.initials: A
authors.lastname: Basit
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Barnett
mesh_terms: D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D056925:Circadian Rhythm Signaling Peptides and Proteins