Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study

Abstract

Background The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies. Methods Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (ΔEDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS). Results We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted ΔEDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: those having ≥5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with ≤2. The CGRS for ΔEDSS was also significant: those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with ≤2, and the CGRS model explained 32% of the variance in disability in this study cohort. Conclusions These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic.

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

“…On the other hand, our results are in disagreement with the only other study performed in Slavs which showed no individual association between rs1800693 and MS in the Russian population (Bashinskaya et al, 2015). Further analyses in subgroups stratified by sex or presence of the major MS risk allele consistent with most other studies performed in patients of predominantly European origin (Baranzini et al, 2009;Brynedal et al, 2010;Comabella et al, 2013;George et al, 2016;IMSGC et al, 2013IMSGC et al, , 2011IMSGC, 2011a;Lin et al, 2014;Ottoboni et al, 2013;Pan et al, 2016). However, possible effect of rs1800693 on disease course cannot be fully excluded yet, as suggested by a recent study in Russians which reported an association of C allele with moderate-to-severe MS (MSSS > 3) and unfavourable variants of MS manifestation, such as motor disorders, brainstem disorders, impaired coordination, pelvic disorders, mental disorders or polysymptomatic onset (Kulakova et al, 2016).…”

Lipid-related genetic polymorphisms significantly modulate the association between lipids and disability progression in multiple sclerosis

“…Bonferroni correction was used to adjust for multiple comparisons 18. To assess potential type I error, 50 000 permutation analyses were conducted as described previously19 by randomly reallocating the genotypes in the samples in proportion to that of the original sample’s genotype frequencies, and re-running the analyses. The proportion of the 50 000 simulated estimates that were significantly greater than that found in the as-measured analyses denoted the significance.…”

Subsets of activated monocytes and markers of inflammation in incipient and progressed multiple sclerosis

“…The cause of the neuro‐inflammatory and demyelinating disease multiple sclerosis (MS) is generally assumed a complex interaction between environmental factors and genetic susceptibility. Despite extensive research, a pathognomonic biomarker for the disease has never been identified . Initially, the disease course for patients with MS is characteristically either relapsing‐remitting (RRMS) or primary progressive (PPMS).…”