Kelly, M. Ann , Rees, Simon D., Hydrie, M. Zafar I., Shera, A. Samad, Bellary, Srikanth, O'Hare, J. Paul, Kumar, Sudhesh, Taheri, S., Basit, Abdul and Barnett, Anthony H. (2012) Circadian gene variants and susceptibility to type 2 diabetes : a pilot study. PLoS ONE, Vol.7 (No.4). e32670. doi:10.1371/journal.pone.0032670 ISSN 1932-6203.

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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.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Circadian rhythms, Non-insulin-dependent diabetes -- Susceptibility, Non-insulin-dependent diabetes -- Genetic aspects, Panjabis (South Asian people) -- Genetics
Journal or Publication Title:	PLoS ONE
Publisher:	PLOS
ISSN:	1932-6203
Official Date:	2 April 2012
Dates:	Date Event 2 April 2012 Published
Volume:	Vol.7
Number:	No.4
Page Range:	e32670
DOI:	10.1371/journal.pone.0032670
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	20 December 2015
Date of first compliant Open Access:	20 December 2015
Funder:	Diabetes UK, Pfizer Inc., Sanofi Aventis (Firm), Servier Laboratories UK, Merck Sharp & Dohme, Schering-Plough Corporation, Takeda UK (Firm), Roche, Merck Pharma, Daiichi-Sankyo UK, Boehringer Ingelheim Pharmaceuticals, Eli Lilly and Company, Novo Nordisk, Bristol-Meyers Squibb, Solvay Health Care, Assurance Medical Society UK
Grant number:	07/0003512 (DUK)

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