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Polymorphisms in CLOCK and ARNTL/BMAL-1 genes in multiple sclerosis: a systematic review and meta-analysis

Mobina Oladghaffari,Heliya Bandehagh,Fatemeh Malekinejad,Shahrzad Fakhkhari,Narges Koohi,Seyedehyasmin Moghaddamziabari,S. Hamzehzadeh,Elahe Mohammadian,M. Talebi,Hanieh Salehi‐pourmehr,A. Naseri

Published 2026 in European Journal of Medical Research

ABSTRACT

Multiple sclerosis (MS) is still under investigation for its pathogenesis. This study explores the relationship between the key circadian rhythm regulators’ genes, ARNTL/BMAL-1 and CLOCK, and MS pathogenesis. Following the PRISMA2020 statement, a systematic search was conducted in PubMed, Scopus, Embase, and Web of Science for studies published up to July 2024. Clinical studies concerning the role of circadian genes in MS pathogenesis were considered for inclusion. The risk of bias was assessed using the JBI critical appraisal tools, and Comprehensive Meta-Analysis (CMA4) was utilized for the quantitative synthesis. Out of 537 results of the database searches, four studies were included. The total sample size of the included studies was 4010 (2110 MS cases and 1900 controls). CT genotype in rs6811520 in the CLOCK gene is suggested as a risk factor for MS in the Iranian population; however, there was no noteworthy association with rs3789327 in the ARNTL/BMAL-1 gene in this population. In individuals of Slavic origin, the CC genotype in both rs3789327 in the ARNTL/BMAL-1 gene and rs6811520 in the CLOCK gene was reported as a genetic risk factor for MS. In contrast, there was no association between MS status and genotypes of rs3789327 in the ARNTL/BMAL-1 gene and rs6811520 in the CLOCK gene in Caucasians of Spanish origin. In the Egyptian population, a higher prevalence of the TT genotype in MS patients was found in rs6811520 in the CLOCK gene. In the quantitative synthesis, no significant statistical relationship was found between MS pathogenesis regarding rs6811520 in the CLOCK gene and rs3789327 in the ARNTL/BMAL-1 gene (p-values > 0.05). Based on the limited available evidence, there may be an ethnic-specific association between ARNTL/BMAL-1 and CLOCK gene and MS susceptibility; however, considering the limitations such as the small number of included studies and small sample sizes, future multiethnic studies are needed on this topic.

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