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

Objective To investigate whether lipid-related or body mass index (BMI)-related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS). Methods The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, "EDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting "EDSS. All analyses were conducted using linear regression. Results Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with "EDSS. The constructed lipid CGRS showed a significant, dose-dependent association with "EDSS (p trend =1.4×10-6), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in "EDSS. We also found significant interactions between the CGRS and lipid levels in modulating "EDSS, including high-density lipoprotein (HDL; p interaction =0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; p interaction =0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL. Interpretation In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression.