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

SOOKOIAN, SILVIA; GEMMA CAROLINA,; GIANOTTI TOMAS, FERNANDEZ; BURGUEÑO A,; PIROLA CJ

San Diego

Congreso; Annual Meeting American Society Human Genetics; 2007

Meeting American Society Human Genetics

Background: Altering circadian rhythmicity results in pathophysiological changes resembling metabolic syndrome and fat accumulation. Then we investigated the role of gene variants and derived haplotypes of the CLOCK transcription factor in obesity and related quantitative metabolic traits. Research Design and Methods: 715 lean and 391 overweight/obese unrelated subjects, aged 34.4±8.6, were included in a population-based cross sectional study. Six tag SNPs showing a minor allele frequency >10 % (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 (r2 >0.8) were genotyped. Association was tested by PLINK and WHAP software while multiple testing was controlled by permutation test. Results: the genotype frequencies of four tSNPs, rs1554483, rs6843722, rs6850524 and rs4864548, showed significant (empiric p= 0.009950, 0.01492, 0.01492 and 0.009950 respectively) association with overweight/obesity. Haplotype analysis showed that only paired haplotypes including rs1554483 and rs4864548 showed a significant effect on disease status. Combinations of these SNPs (haplotype block CG and GA) are responsible for the gene effect (GA frequencies cases: 0.47% vs. controls: 0.41%, empiric p=0.0102). These findings were replicated in an independent case-control hospital-based study and the combined Mantel-Haenszel’s fixed effect (MH) was OR 1.82, CI: 1.31-2.54, p=0.00034, for the paired haplotype which included CG and GA for the rs1554483 and rs4864548. Conclusions: our study suggests a putative role of the CLOCK polymorphism and related haplotypes in susceptibility to obesity. Carrying the diploid haplotype of rs1554483G and rs4864548A was associated with 1.8-fold increase for being overweight/obese.