A Case-control Study On The Associations Between Sleep,Genetic Polymorphisms In Circadian Genes And Risk Of Obesity

ObjectiveObesity is a complex and multifactorial metabolic disorder, and promoted by interplay of genetic and environmental factors. Accumulated studies have focused on the associations between sleep duration, circadian rhythm, and risk of obesity. The epidemiological and laboratory evidences have demonstrated that short sleep duration was associated with weight gain and risk of obesity, type II diabetes, and metabolic syndrome. Circadian clock are composed of a series genes that generate self-sustained transcriptional positive and negative feedback loops with a period of24h. Clock is the key component of the positive feedback loops in circadian clock. Studies showed that genetic polymorphisms of Clock were associated with energy metabolism, weight gain, obesity and metabolic syndrome. Cry is one component of the negative feedback loops, and it has been highlighted that the polymorphism of Cry2rs11605924is associated with the plasma glucose in a genome-wide association study.A population-based case-control study was conducted to describe the association between lifestyle factors, sleep duration and risk of obesity, identify the risk factors of obesity, and explore the associations on genetic variants of Clock and Cry with risk of obesity, with the aim of providing the fundamental evidence for the future study.MethodsA total number of326and260cases for obesity and abdominal obesity were selected, respectively, following the criterion for obesity and abdominal obesity recommended by the Working Group on Obesity in China. The corresponding controls were individually matched with cases by gender,3-years categories and residence. All participants were recruited from Jiashan County, China. Magnetic beads method was used for extracting and purifying genomic DNA. Genotyping for all SNPs was performed using MassARRAY technique. Paired t tests and Person X2tests were used to evaluate the distribution of the continuous and the categorical variables between cases and controls, respectively. Hardy-Weinberg equilibrium(HWE) for all SNPs was tested by goodness-of-fit test chi-square analysis. Associations between genetic polymorphisms in Clock, Cry and risk of obesity and abdominal obesity was estimated by calculating the adjusted odds ratios and corresponding95%confidence intervals (95%CIs) with multivariate logistic regression. Haploview software was used to identify the linkage disequilibrium among controls. Construction of haplotype in Clock, Cry was conducted using R window for2.13.0software. Potential gene-gene interaction was explored by generalized multifactor dimensionality reduction (GMDR).ResultsThe significant difference between cases and controls was observed in the distribution of education. However, there are no significant differences in the distribution of socio-demographic characteristics between two groups. No associations were found between lifestyle factors and risk of obesity or abdominal obesity.Sleep duration, bedtime, waking time and nap were not associated with risk of obesity or abdominal obesity. There were no significant association between genetic polymorphisms of Clock、 Cry and obesity (BMI>24kg/m2), after adjusting for age, gender, profession, marriage and other variables. However, Clock rs10002541T/C, rs6850524G/C, Cryl rsl0861688C/T were significantly associated with risk of abdominal obesity (Men: waist circumference≥85cm, Women:waist circumference≥80cm). Compared with the wild-type TT, mutant homozygous carrier had protective effects on abdominal obesity (rs10002541:OR=0.41,95%CI:0.21-0.80; rs6850524: OR=0.44,95%CI:0.22-0.89; rs10861688:OR=0.50,95%CI:0.25-0.97)Haplotype analyses also demonstrated that specific haplotypes in Clock and Cryl were not associated with risk of obesity and abdominal obesity. However, GCCCG haplotype in Cry2was associated with abdominal obesity, but not with overweight or obesity.Potential gene-gene interaction was evaluated by the generalized multifactor dimensionality reduction(GMDR). The results showed that the best2-locus gene-gene interaction model of the possible SNP combinations was rs12368868in Cryl and rs3824872in Cryl, which might have influence on obesity. Moreover, the interaction between Clock rs10002541and Cryl rsl056560are associated with risk of abdominal obesity.Based on cross-over analysis and multiplicative model, it showed that smoking had interaction with Clock (rs10002541/rs6850524), respectively.ConclusionOur study have been focused on the associations between sleep, genetic polymorphisms of circadian gene Clock. Cry and risk of obesity as well as abdominal obesity. The findings of our study are as follows:(1) Socio-demographic characteristics and lifestyle factors were not associated with risk of obesity and abdominal obesity. (2) No association were found between sleep and risk of obesity as well as the abdominal obesity.(3) Associations were detected between Clock rs10002541CC, rs6850524CC and Cryl rs10861688TT and risk of abdominal obesity. Specific haplotype in Cry2(GCCCG) was associated with risk of abdominal obesity.(4) Gene-gene interaction was also detected between Clock、Cryland Cry2.(5) Gene-environment interaction was observed in smoking and Clock.