Genetic Variants Of Clock Transcription Factor Are Associated With Susceptibility To Obesity And Hypertension In Individuals With Metabolic Syndrome

SOOKOIAN S; FERNANDEZ GIANOTTI T; BURGUEÑO A; PIROLA CJ

Miami, FL, USA

Congreso; XVII meetting of the InterAmerican Society of Hypertension; 2007

InterAmerican Society of Hypertension

Background: Emerging studies showed that altering circadian rhythmicity results in pathophysiological changes resembling metabolic syndrome. Objective: to investigate the association of Clock transcription factor gene SNPs and their haplotypes with metabolic syndrome and related quantitative metabolic traits in a population-based study. Patients & Methods: 1106 men of self-reported European ancestry, aged 34.4±8.6 years, were included in a cross sectional study, in which 715 lean individuals were compared with 391 overweight/obese subjects having features of metabolic syndrome. 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 the Clock gene (117 kb in chromosome 4) and representing 115 polymorphic sites (r2 >0.8) were genotyped. Association was tested by PLINK and WHAP software while controlling for multiple testing by permutation tests. Results: In univariate analysis,we found that there was no significant association between the tSNPs and most of metabolic traits. However, the genotype frequencies of the 6 tSNPs (rs1554483, rs6843722, rs6850524 and rs4864548)(p value <0.009, 0.014, 0.014 and 0.009 respectively) showed significant association with overweight/obesity. Besides, rs1554483, rs6850524 and rs6843722 were significantly associated with arterial hypertension (p value < 0.01, 0.033 and 0.01 respectively) and systolic arterial blood pressure (rs1554483 p<0.03 and rs4864548 p<0.03). Consistent with the analysis of significantly associated individual markers, we observed that global frequencies of Clock gene variant haplotypes in overweight/obese individuals significantly differed from that in lean subjects (OR: 1.50, CI: 1.04-2.19, p<0.033) independently of age and HOMA index. In the same way, Clock haplotype frequencies in hypertensive subjects significantly differed from normotensive individuals (OR: 1.76, CI: 1.13-2.76, p<0.012). Findings regarding obesity were replicated in another independent obesity/overweight case-control (n: 200) hospital-based study. The combined Mantel-Haenszel’s fixed effect was: OR 1.82, CI: 1.31-2.54, p<0.0003). Conclusions: our study is the first to suggest a potential role of the Clock polymorphisms and related haplotypes in increased susceptibility to obesity and hypertension in subjects with metabolic syndrome. Carrying the diploid haplotype of rs1554483-G and rs4864548-A was associated with a 1.50-fold increase in overweight/obesity risk and 1.76 fold in hypertension risk.