Association between CHI3L1 and CRTH2 genetic variants, clinical phenotype, and neurological disability in multiple...

Multiple sclerosis (MS) is a neuroinflammatory disease, and reliable genetic markers associated with disease course and disability remain limited. CHI3L1 (YKL-40) and CRTH2 (PTGDR2) are involved in inflammatory and glial processes, but the contribution of their genetic variants to MS remains incompletely understood.

We aimed to investigate whether selected CHI3L1 and CRTH2 single-nucleotide polymorphisms (SNPs) are associated with MS susceptibility, clinical phenotype, and neurological disability.

We included 123 MS patients and 117 healthy controls. MS diagnosis was based on the 2017 McDonald criteria, and patients were classified as RRMS, SPMS, or PPMS. For subgroup analyses, SPMS and PPMS were combined into a Progressive MS group because of the limited number of PPMS patients. Neurological disability was evaluated cross-sectionally using the Expanded Disability Status Scale (EDSS; <4 vs. ≥ 4). We genotyped CHI3L1 rs10399805 and rs871799, and CRTH2 rs533116 and rs11571288 using RT-PCR or PCR-RFLP. Associations were tested using chi-square or Fisher's exact tests under different genetic models, and odds ratios (ORs) with 95% confidence intervals were calculated. In silico analyses were also performed to explore the potential functional effects of the variants.

CHI3L1 rs871799 showed a significant association with MS under the dominant model, with the CG + GG genotypes being more frequent in patients than in controls. In direct comparisons between RRMS and Progressive MS patients, rs871799 genotype and allele distributions differed significantly, with the G allele and GG genotype being more frequent in Progressive MS. The rs871799 variant was also associated with cross-sectional neurological disability (EDSS ≥ 4) under multiple genetic models. For CRTH2 rs11571288, no significant association was observed between the overall MS group and healthy controls; however, the GG genotype was more frequent in RRMS patients than in healthy controls under the recessive model. No significant associations were observed for rs10399805 or rs533116 in the overall analysis or in the clinical subgroup comparisons.

CHI3L1 rs871799 may be associated with MS susceptibility under the dominant model, clinical phenotype, and cross-sectional neurological disability. CRTH2 rs11571288 was not associated with overall MS susceptibility but may be associated with the RRMS phenotype under the recessive model. These findings are exploratory and should be interpreted cautiously, particularly given the limited number of PPMS patients, the combined analysis of SPMS and PPMS, and the cross-sectional assessment of disability. Further studies in larger independent cohorts with longitudinal follow-up are warranted.