Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity.

Background: Altering circadian rhythmicity results in pathophysiologic changes resembling metabolic syndrome and fat accumulation.

Objective: We investigated the role of gene variants and derived haplotypes of the CLOCK transcription factor in obesity and related quantitative metabolic traits.

Design: Lean (n = 715) and overweight or obese (n = 391) unrelated subjects aged 34.4 +/- 8.6 y were included in a population-based cross-sectional study. Six tag single-nucleotide polymorphisms (SNPs) with a minor (>10%) allele frequency (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G, and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r(2) > 0.8) were genotyped. Association was tested by PLINK and WHAP software, and multiple testing was controlled by permutation test.

Results: The genotype frequencies of 4 tag SNPs--rs1554483, rs6843722, rs6850524, and rs4864548--had significant (empiric P < 0.010, 0.021, 0.021, and 0.010, respectively) associations with overweight or obesity. Haplotype analysis showed that only paired haplotypes, including rs1554483 and rs4864548, had a significant effect on overweight or obesity. Combinations of these SNPs (haplotype block CG and GA) are responsible for the gene effect (GA frequencies: 47% in cases, 41% in controls; empiric P < 0.011). These findings were concurrently observed in a sample of persons from a hospital-based study, and the combined Mantel-Haenszel fixed effect was an odds ratio of 1.82 (95% CI: 1.31, 2.54; P < 0.001) for the paired haplotype, which included CG and GA for rs1554483 and rs4864548.

Conclusions: The present study suggests a putative role of the CLOCK polymorphism and related haplotypes in susceptibility to obesity. The haplotype of rs1554483G and rs4864548A was associated with a 1.8-fold risk of overweight or obesity.