Polymorphisms in ARNTL/BMAL1 and CLOCK Are Not Associated with Multiple Sclerosis in Spanish Population

SIMPLE SUMMARY: Autoimmune diseases such as multiple sclerosis develop from an undefined mixture of environmental factors interacting with dozens to hundreds of genetic variations that confer risk. In the particular case of multiple sclerosis, shift work at a young age has been related to a higher risk of developing the disease. Shift work may alter the circadian rhythm, a series of complex molecular signals that inform our body of the day–night cycles. Circadian rhythm could be altered by external signals (longer days or nights, jet lag), but it is also genetically regulated through two master genes: CLOCKand ARNTL/BMAL1. A previous study in a population of Slavic origin found two genetic associations with multiple sclerosis risk in these genes. However, these genetic association studies require replication in independent populations to verify the true nature and magnitude of the effects on disease development. We replicated the study in an independent population and found no association of the two polymorphisms with multiple sclerosis. ABSTRACT: Disrupted circadian cycle has been reported in multiple sclerosis (MS). Previous genome-wide association studies (GWAS) singled out over 230 variants associated with MS. A study performed in a Slavic population identified two new single nucleotide polymorphisms (SNPs), rs6811520 (CLOCK) and rs3789327 (ARNTL/BMAL1), associated with MS risk. However, these regions that codify the capital regulators of circadian rhythm had not been linked to the disease before, so replication in independent populations is warranted to ascertain possible geographical differences. Our aim was to replicate the associations reported in the ARNTL/BMAL1 and CLOCK genes in a Spanish cohort with a maximum of 974 MS patients and 626 controls. In this study, 956 MS patients and 612 controls were successfully genotyped for rs6811520 and 943 MS patients and 598 controls for rs3789327.Clinical variables (age at disease onset, EDSS, or relapses) were collected in a maximum of 549 patients. No statistically significant differences were found between cases and controls for the analyzed SNPs, even after stratifications by sex, clinical form, or HLA-DRB1*15:01 status. No influence of the SNPs was found on age at disease onset, EDSS, or annual relapse rate at 5 years after onset. In conclusion, our study does not replicate the associations observed in the previously investigated Slavic population.