Genetic and environmental mediators of multiple sclerosis susceptibility but not early severity run in families

BACKGROUND: Multiple sclerosis (MS) susceptibility and severity are mediated by different genetic and environmental risk factors. Familial aggregation in MS is partially explained by susceptibility determinants, yet impact on early disease course after clinically isolated syndrome (CIS) is uncertain. We investigated associations of reported familial MS with genetic and environmental risk factors, and with clinical presentation and disease course after CIS. METHODS: CIS participants were included in a prospective cohort within six months after symptom onset. Family history was assessed at baseline. We evaluated weighted genetic risk scores (wGRS) for MS susceptibility, 25-hydroxyvitamin D (25(OH)D) and body mass index (BMI), and determined HLA-DRB1*15:01 and MS severity SNP rs10191329 carriership. Anti-Epstein Barr virus Nuclear Antigen-1 (anti-EBNA1) IgG antibodies and 25(OH)D levels were measured. Disease course associations were estimated with Cox regression. RESULTS: Family members with MS were reported by 81/415 (19.5%) CIS participants. Familial MS was associated with higher MS susceptibility wGRS (7.54 (SD1.17) vs. 7.19 (SD1.22), p=0.04) and more frequent HLA-DRB1*15:01 carriership (first-degree 66.7%, other-degree 30.2%, no 38.4%, p=0.02). Anti-EBNA1 IgG and 25(OH)D levels did not differ, yet wGRS for lower 25(OH)D and higher adult BMI characterised MS participants with first-degree MS relatives. Baseline characteristics and disease severity measures were similar between participants with and without familial MS. CONCLUSION: Our results confirm that familial MS is associated with enrichment of genetic risk for MS susceptibility, low 25(OH)D and high BMI, but not with early disease course after CIS. These data support that MS susceptibility and disease course are driven by different pathophysiological processes.