DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies

Area of Science:

• Genetics and Environmental Health
• Immunology
• Epidemiology

Background:

• Multiple sclerosis (MS) is a complex neurological disease with known genetic and environmental risk factors.
• The human leucocyte antigen (HLA) region, particularly HLA-DRB1*15:01, is a major genetic susceptibility locus for MS.
• Environmental factors such as smoking, Epstein-Barr virus (EBNA-1) antibody status, and adolescent Body Mass Index (BMI) have been implicated in MS etiology.

Purpose of the Study:

• To investigate the influence of environmental risk factors on MS development within varying genetic contexts.
• To examine if the interaction between environmental factors and HLA genes differs based on heterozygosity or homozygosity for HLA-DRB1*15:01.

Main Methods:

• Population-based case-control study including 6985 MS cases and 6569 controls.
• Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for MS risk.
• Interactions between HLA genotypes and environmental factors (smoking, EBNA-1 status, adolescent BMI) were assessed on an additive scale.

Main Results:

• Each HLA-DRB1*15:01 allele contributed additively to MS risk.
• The magnitude of interaction between HLA-DRB1*15:01 and environmental factors was consistent across different allele counts.
• A significant three-way interaction elevated MS risk dramatically in HLA-DRB1*15:01 homozygotes lacking the protective HLA-A*02:01 allele when exposed to any environmental factor (e.g., OR 44.3 for adolescent overweight/obesity).

Conclusions:

• High MS risk in HLA-DRB1*15:01 homozygotes exposed to environmental factors supports their role in immune-mediated mechanisms.
• These findings underscore the importance of preventive strategies, especially for individuals with genetic susceptibility to MS.
• Targeting environmental factors may mitigate MS risk in genetically predisposed populations.