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Meta-Analysis
. 2012;7(4):e32670.
doi: 10.1371/journal.pone.0032670. Epub 2012 Apr 2.

Circadian gene variants and susceptibility to type 2 diabetes: a pilot study

M Ann Kelly  1 , Simon D Rees, M Zafar I Hydrie, A Samad Shera, Srikanth Bellary, J Paul O'Hare, Sudhesh Kumar, Shahrad Taheri, Abdul Basit, Anthony H Barnett; DIAGRAM Consortium; SAT2D Consortium
Collaborators, Affiliations
Meta-Analysis

Circadian gene variants and susceptibility to type 2 diabetes: a pilot study

M Ann Kelly et al. PLoS One. 2012.

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.

Methodology/principal findings: 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/significance: 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.

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Conflict of interest statement

Competing Interests: We have read the journal’s policy and have the following conflicts. This study was partly funded by Eli Lilly. Professor Sudhesh Kumar has received lecture fees and research funding from Eli Lilly. Professor Anthony Barnett has received honoraria from Eli Lilly for lectures and advisory work, and has received research funding from Eli Lilly. Dr. Shahrad Taheri has received educational funding support from Eli Lilly. The United Kingdom Asian Diabetes Study was supported by Pfizer, Sanofi-Aventis, Servier Laboratories United Kingdom, Merck Sharp & Dohme/Schering-Plough, Takeda United Kingdom, Roche, Merck Pharma, Daiichi-Sankyo United Kingdom, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Bristol-Myers Squibb, Solvay Health Care and Assurance Medical Society UK. Professor Barnett has received research funding and honoraria for lecturing and advisory work from these sources. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Association of 13 circadian gene SNPs with type 2 diabetes.
Forest plot showing the association of 13 circadian gene SNPs with type 2 diabetes in South Asian (UKADS/DGP and SAT2D) and white European (DIAGRAM+) cohorts.
See this image and copyright information in PMC

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