The etiology of multiple sclerosis (MS) is not known; however, it is thought to be caused by a combination of genetic susceptibility and environmental factors. MS is a complex immune-mediated genetic disease that is characterized by “modest disease risk heritability and multifaceted gene–environment interactions”1,2.

Close relatives of an affected person have an increased risk of developing MS. The fact suggests that there might be a genetic component to the causality of disease. Lifetime risk of MS in the general population is about one in 1,000. The lifetime risk increases to about 2% in children with one parent who has MS and is even higher in children whose parents are both affected. Siblings of an affected person have about a 4% chance of developing the disease during the course of their lives. Lifetime risk of MS further increases to 5% in dizygotic twins and to 25% in monozygotic twins. These findings suggest that the greater the genetic sharing of an individual to a patient with MS, the higher the possibility of being affected by the disease1,2.

Plenty of potential culprit genes have been investigated in association with MS. Most likely, genetic susceptibility to MS is the product of many risk alleles throughout genome cumulatively. major histocompatibility complex (MHC) is the only genomic region that has consistently been shown to be associated with MS. In humans, MHC is also known as human leukocyte antigen (HLA) and is located on chromosome 6. Two alleles of the MHC called DR-15 and DQ-6 have been particularly shown to play a role in MS causality. Meanwhile, it is suggested that some other alleles of MHC might have a protective effect against developing MS. Studies suggest that MHC does not account for all genetic predispositions to MS; however, the genetic association of MS to other genomic regions is yet to be proven1,2.

The prevalence of MS increases in regions located farther from the equator, although some exceptions exist. Regions with a northern European population show a higher prevalence. MS is highly prevalent (more than 30 per 100,000) in northern Europe, northern USA, Canada, southern Australia, and New Zealand. Asia and Latin America, on the other hand, show low prevalence rates (less than five per 10,000). A variation in prevalence within each region can also be seen among different ethnic groups. Exposure to different environmental factors early in life is suggested as one of the explanations for the regional disease distribution that is supported by studies of younger immigrants who tend to adjust toward the risk of their new country after migration2,3.  

A wide range of environmental factors such as infections, diet, smoking, stress, occupational factors, sex hormones, and vaccines have been studied in association with MS. The linkage to MS for some of these factors is supported by multiple studies, but the evidence for others to support an association with the disease is weak3.

The idea of “hygiene hypothesis” and its role in the etiology of MS was first introduced decades ago. Based on this hypothesis, exposure to some microorganisms early in life might have a protective effect against some immune-mediated diseases including MS4. While this could explain—to some extent—several epidemiological aspects of the disease including the higher rates of MS prevalence in industrialized countries with better levels of sanitation, further investigations showed major limitations in the hypothesis. One argument against hygiene hypothesis arises from the studies of Epstein-Barr virus (EBV). Contrary to what hygiene hypothesis suggests, studies have overwhelmingly shown that MS is far more common in EBV-positive individuals than those who are seronegative for EBV. The incidence of MS is also significantly higher in people with a history of infectious mononucleosis—a common clinical manifestation of EBV infection in adolescents and young adults—than those without such medical history5,6. Despite all the evidence, the exact role of EBV in triggering MS remains unknown3

Many studies have been conducted in an attempt to identify other potential infectious causes of MS. Herpes simplex virus, varicella zoster virus, cytomegalovirus, measles, mumps, rubella, retroviruses, and chlamydia pneumoniae are among those that have been investigated for a possible link to MS. Most of these studies showed either no association or a weak association that could not be backed up by similar reports. Nevertheless, EBV infection alone cannot explain all the epidemiological features of MS, and the role of other infections in MS etiology cannot be excluded3,5. The causal relationship of vaccinations (for example hepatitis B vaccine) with MS has also been investigated, and no association could be established7,8.

It has been several decades since a link between vitamin D deficiency and MS was first speculated. The primary reason for this speculation was the latitudinal distribution of MS prevalence. UV light exposure, which is required for the production of vitamin D in humans, decreases as we move away from the equator. Therefore, a causal association with low levels of vitamin D and MS seems plausible. The hypothesis was further supported by the fact that migration from high-latitude to low-latitude regions results in a reduction in the risk of developing MS. In addition, it has been shown that most patients with MS have lower serum vitamin D levels when compared to the general population. Several prospective studies also reported that high levels of serum vitamin D as well as diets rich in vitamin D have a preventive role against MS. For example, a large longitudinal study of US military personnel showed that those with high levels of serum vitamin D (>99.2 nmol/L of 25-hydroxyvitamin D) had a significantly lower chance of developing MS than those with low levels of serum vitamin D (<63.3 nmol/L of 25-hydroxyvitamin D). Studies have also been conducted to explore the role of vitamin D in changing the disease course in patients with MS (for example to decrease the number of attacks or to improve long-term outcomes), but the available evidence is not enough to make a definitive conclusion6,9.

In several prospective studies, cigarette smoking was associated with an increased risk of developing MS. Other studies showed that smoking can also have an effect on the disease course by accelerating the conversion from relapsing-remitting to secondary progressive MS or shortening the time to develop disability in progressive MS. It is hypothesized that smoking is responsible for the recent increase of MS incidence in females compared to males. Overall, it can be concluded from available reports that cigarette smoking is an independent factor in developing MS6,9.

Plenty of other factors have also been assessed with MS. Diets high in saturated fat and low in unsaturated fat may increase the risk of MS. Diets rich in antioxidants may have a protective role. An association between the levels of estrogen and MS is also suggested. Studies have also tried to explore the potential role of occupational exposures, especially to organic solvents, in MS. Other studies suggested that increased levels of uric acid may decrease the risk for MS. The role of stress in causing MS has been the subject of multiple studies, but their results are not consistent. Overall, available evidence for these factors is not conclusive3,9.

From all the different environmental factors investigated, EBV infection, vitamin D, and cigarette smoking have a stronger body of evidence linking them to MS. It is also likely that these three factors (together with other unknown factors) interact with each other to trigger a patient’s genetic predisposition to the disease. Despite the established connection, the exact clinical implications of such associations are largely unknown. EBV infection cannot be avoided. On the other hand, vitamin D intake is clearly modifiable. Nevertheless, further studies are needed to provide a better idea of whether an active increase in vitamin D intake through diet or supplementation should be recommended, who needs vitamin D supplementation, at what age and at what dose. In a strict practical sense, it seems that there is no harm in recommending people to quit smoking even if the exact role of smoking in MS causality is not yet fully established. In all cases, an informed discussion between physicians and their MS patients to address these issues is warranted.