Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis

Abstract

Genetic predisposition to multiple sclerosis (MS) only explains a fraction of the disease risk; lifestyle and environmental factors are key contributors to the risk of MS. Importantly, these nongenetic factors can influence pathogenetic pathways, and some of them can be modified. Besides established MS-associated risk factors - high latitude, female sex, smoking, low vitamin D levels caused by insufficient sun exposure and/or dietary intake, and Epstein-Barr virus (EBV) infection - strong evidence now supports obesity during adolescence as a factor increasing MS risk. Organic solvents and shift work have also been reported to confer increased risk of the disease, whereas factors such as use of nicotine or alcohol, cytomegalovirus infection and a high coffee consumption are associated with a reduced risk. Certain factors - smoking, EBV infection and obesity - interact with HLA risk genes, pointing at a pathogenetic pathway involving adaptive immunity. All of the described risk factors for MS can influence adaptive and/or innate immunity, which is thought to be the main pathway modulated by MS risk alleles. Unlike genetic risk factors, many environmental and lifestyle factors can be modified, with potential for prevention, particularly for people at the greatest risk, such as relatives of individuals with MS. Here, we review recent data on environmental and lifestyle factors, with a focus on gene-environment interactions.

Heterogeneity in association of remote herpesvirus infections and pediatric MS

“…Genetic and environmental risk factors and their interactions determine an individual's risk of developing multiple sclerosis (MS) 1. Approximately 200 common genetic variants that alter the risk of MS onset have been described in white adults2 and HLA‐DRB1*15:01 has the largest effect.…”

“…Approximately 200 common genetic variants that alter the risk of MS onset have been described in white adults2 and HLA‐DRB1*15:01 has the largest effect. Environmental risk factors consistently associated with MS susceptibility include prior infection with EBV, exposure to cigarette smoking, vitamin D deficiency and obesity 1. Exposures to commonly encountered viruses have also been linked to MS susceptibility.…”

“…The most well‐studied ones include Epstein–Barr virus (EBV), cytomegalovirus (CMV) and Herpes Simplex virus (HSV). While prior infection with EBV is reported in most patients with adult or pediatric‐onset MS,1 a few studies have suggested that remote CMV exposure might decrease the risk of having MS 3, 4…”

The Genetics of Multiple Sclerosis

“…In contrast, spouses and adoptees hold a risk comparable to that of the general population (or their original nuclear families), consistent with genetic sharing being the driver of familial aggregation (7). On the other hand, the fact that the relative risk does not reach 100% even in identical twins suggests that other factors beyond DNA sequence identity must concur to create the conditions that cause or allow the dysregulation of the immune response associated with MS. A broad range of determinants lie in this category; they include environmental exposures (e.g., smoking, viral infections, vitamin D intake, diet, and microbiome) as well as epigenetic signatures (e.g., DNA methylation patterns, histone modifications, and non-coding RNAs) (8).…”

Western lifestyle and immunopathology of multiple sclerosis

“…The industrial revolution and the contemporary age in Western countries gave rise to the fast‐food industry and widespread consumption of excessive salt, refined vegetable oils, and sugars and also led to reduced physical activity, exposure to artificial light at atypical biological times, and insufficient and poor‐quality sleep. The influence of other environmental factors, such as Epstein–Barr infection, vitamin D levels, smoking, obesity, and geographical location, has already been extensively reviewed 3, 4, 5. Here, we mainly focus on how Western diet and sleep‐circadian disruption may contribute to our understanding of MS etiology.…”