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

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

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

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.

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.

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.