engleski

Association of circadian rhythm genes ARNTL and CLOCK with multiple sclerosis (MS).

Evidence from epidemiological studies indicates that, prevalence of MS varies with geographic latitude, increasing with distance from the equator on both hemispheres. Environmental parameters as a function of latitude vary dramatically (daily fluctuations in light intensity and seasonal changes). External circadian rhythms arise as a direct result of environmental stimuli. Interior circadian rhythms are regulated by circadian rhythm genes. Therefore we hypothesized that differences in epidemiology of MS, related to geographical latitude effect, might be associated with gene variability in circadian rhythms genes.The aim of this study was to examine whether there is an association between genetic variabilityand gene expression studies in the primary clock genes (ARNTL and CLOCK) in humans with multiple sclerosis.We performed a retrospective cross-sectional case-control study.A total of 900 Caucasian patients and 1024 healthy matched controls were included in the study. Altogether, 8 SNP were included in our study. Of these, four SNPs, rs3789327, rs1481892, rs4757144 and rs12363415, in the ARNTL gene and four SNPs, rs11932595, rs6811520, rs6850524, and rs13124436, in the CLOCK gene.For gene expression we analysed subgroup of the same patients - 50 patients and 40 controls. We found a statistically significant difference in the allelic distribution of ARNTL gene (rs3789327P =7.5·10-5)and confirmed our results by means of haplotypes distribution (CGG (P=0.004) and TGA (P=0.03)).In addition, we found a statistically significant association of the CLOCK gene with MS (rs6811520 P=0.021) and supported our results by means of haplotypes distribution in the CLOCK gene (TCAG (P= 0.001).We provide evidence that genetic variability in the key circadian rhythm genes might be associated with multiple sclerosis.

circadian rhythm genes; CLOCK and ARNTL (Bmal1) gene; multiple sclerosis

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