Abstract
BackgroundDisruption 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 FindingsThe 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/significanceNone 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.
Highlights
Accumulating evidence suggests that dysregulation of the circadian clock plays an important role in glucose homeostasis and the development of type 2 diabetes
A recent study in mice showed that mutations in the genes encoding the CLOCK and BMAL1 transcription factors resulted in impaired glucose tolerance, reduced insulin secretion and defects in islet development, while ablation of the endogenous pancreatic clock resulted in the development of diabetes [7]
Variants of circadian genes, such as MTNR1B, CRY2, PER3, PER2 and BMAL1, have recently been implicated as determinants of fasting glucose levels and/or diabetes risk in humans [8,9,10,11,12], while single nucleotide polymorphisms (SNPs) in the CLOCK and PER2 genes were reported to be associated with measures of obesity [13,14]
Summary
Accumulating evidence suggests that dysregulation of the circadian clock plays an important role in glucose homeostasis and the development of type 2 diabetes. Laboratory-imposed circadian desynchrony, resulting in misalignment between behavioural cycles (such as sleep/wake and fasting/feeding) and endogenous circadian rhythm, has been shown to result in increased postprandial glucose and insulin levels, increased mean arterial blood pressure and decreased leptin levels [3]. These metabolic disturbances could explain the increased risk of diabetes, obesity and cardiovascular disease observed in shift-workers [4,5]. 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
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