About 400,000 people carry an MS diagnosis in the United States (1 in 750), though this figure is a rough estimate, as no centralized reporting mechanism exists for MS. Globally, the figure is thought to be around 2.5 million. The incidence of MS has been increasing in recent years, not solely due to an improvement in diagnostic capability, for reasons that remain unclear [20]. As in other autoimmune conditions, women are more affected than men; the sex ratio is between 2:1 and 3:1 women-to-men and has been increasing over the last century [21]. This gender disparity may involve hormonal differences, as pediatric MS—though rarer—is diagnosed more equally in boys and girls. Indeed, endogenous hormones are not only implicated in MS susceptibility, but also in disease activity, most notably in the observation that various hormones rise dramatically during pregnancy, when MS activity is generally suppressed, and plunge in the immediate post-partum period, which is often marked by rebound disease activity. Like the overall increasing incidence of MS, the increasing rates of the disease in women compared to men are inadequately understood but probably involve changing environmental (nonheritable) risk factors. The demographics of PPMS differ somewhat from those of RRMS, in that PPMS generally presents at a later age and has a more equal male-to-female incidence ratio.

Many researchers have hoped that by learning about what predisposes certain people to developing MS, we can discover new avenues of treatment, or even prevention. Several decades of MS research have given rise to the theory that MS occurs in genetically susceptible individuals upon exposure to certain environmental triggers. Thus, this chapter will review the environmental risk factors before discussing the genetic ones.

Regarding the global MS distribution, the latitude gradient is probably the single most recognized feature: regions farther from the equator generally have higher rates of MS. Sunlight exposure and, by extension, vitamin D levels, which increase in relation to the duration and intensity of sunlight exposure, may be the primary driver of the latitude gradient. Evidence for the role of vitamin D deficiency in MS also comes from investigations of food consumption. In Scandinavia, for example, coastal fishing areas where diets are richer in vitamin D have a lower incidence of MS than inland regions [22]. It should be noted that many case-control trials that have found correlations between low vitamin D levels and MS are prone to biases, such as reverse causation and recall bias. For example, it may not be that low vitamin D levels cause MS, but rather that vitamin D levels (captured retrospectively after disease onset) are depressed in patients with MS because they choose to avoid sunlight. Munger et al. showed in a prospective nested case-control study that higher circulating levels of 25-hydroxy vitamin D were associated with a lower risk of MS [23]. A study drawing from two large prospective cohorts, the Nurses’ Health Study and the Nurses’ Health Study II, found a relative risk of developing MS of 0.67 when comparing those in the highest quintile of vitamin D intake to the lowest [24]. To be sure, not all studies have consistently shown an association between vitamin D deficiency and MS susceptibility. In fact, there may be differential effects of low vitamin D in different groups, the result of interactions with other environmental or genetic factors [25]. Vitamin D is known to have immunoregulatory and anti-inflammatory effects and can prevent the development of experimental autoimmune encephalomyelitis (EAE), the murine model of MS. Furthermore, fewer MRI lesions and relapses are observed in patients with MS and higher serum concentrations of vitamin D [26, 27]. Still, whether or not supplementation is an effective strategy to prevent MS, or even to reduce disease activity in patients with MS, has not been proven.

In addition to the increasing incidence of MS, another phenomenon that provides strong evidence for the influence of environmental factors is the presence of changing risk levels among migrants. When migrating from a low- to high-incidence region, individuals generally assume the risk level of the new region if migration occurs prior to age 15 [28]. Besides sunlight and vitamin D, population-based epidemiological studies have looked for associations with a variety of environmental risk factors, including various infections, vaccinations, trauma, surgeries, and toxin exposures. Of these, two of the risk factors that have emerged with the highest degree of confidence are cigarette smoking and Epstein-Barr virus (EBV) infection (e.g., infectious mononucleosis [IM]) [29]. In areas where early childhood exposure to EBV is universal, MS is rare. Where EBV exposure occurs later, the incidence of both IM and MS increases. People who have had IM have about a 2.17-fold increased risk of developing MS, according to one meta-analysis [30]. While EBV seropositivity in adults is nearly as high in healthy controls as it is in patients with MS, the difference is more pronounced among pediatric cases and controls [31]. Overall, the evidence of EBV involvement in MS pathogenesis rests on these epidemiological data; a direct mechanism has not been proved; although, interestingly, researchers have found B cell follicles within the meninges of MS brains with EBV-encoded RNA [32], a finding that has not yet been replicated.

The hygiene hypothesis posits that living in areas with greater exposure to infections protects from, rather than induces, autoimmune diseases such as MS. Over the past several decades, allergies and autoimmune conditions have been on the rise in the developed world, where improved sanitation and vaccination have prevented many childhood illnesses. As an example of this phenomenon, the prevalence of one common human pathogen, the parasite Trichuris trichiura, is inversely correlated with MS risk; in developing regions where the T. trichiura prevalence exceeds 10 %, MS rates drop sharply [33]. Though seemingly at odds with the theory of an infectious trigger of MS, the hygiene hypothesis could be viewed as complementary, in that exposure to, for example, EBV in developed countries is delayed and not outright prevented. If the immune system is not “educated” by a certain age through exposure to a pathogen such as EBV, according to this line of reasoning, then autoimmunity is more likely to develop.

Cigarette smoking is a risk factor that has been consistently found to have an impact both on MS susceptibility, increasing the risk by about 50 % [34], and on disease course. A 3-year study of patients with CIS, abnormal brain MRI, and oligoclonal bands unique to the CSF (both indicative of a high risk for the conversion from CIS to MS) found that 75 % of smokers had converted to MS, compared to 51 % of nonsmokers [35]. In addition, smokers are more likely to be diagnosed with PPMS or transition from RRMS to SPMS [36–38].

In the search for modifiable risk factors, investigations have also pointed to a link between adolescent obesity and MS. In the developed world, the rates of obesity, including in children and adolescents, have been climbing in recent years, a trend that could in part explain the rising MS incidence. Langer-Gould et al. found an association between childhood obesity and MS in adolescent girls, but not in boys, and demonstrated an escalating risk level at higher weights, which were measured prior to disease onset [39]. Others have shown a correlation with juvenile obesity in both sexes [40, 41]. Another feature of the Western diet that has changed over the past century, salt intake, has garnered attention as a possible MS risk factor, with studies demonstrating the deleterious effects of salt on the immune system. In vivo experiments in mice and in humans showed that high salt conditions boost the induction of inflammatory T_H17 lymphocytes, which are pathogenic in MS and other autoimmune diseases [42]. As with other putative risk factors, high sodium consumption not only seems to affect the development of MS but also is associated with more active disease [43]. Despite their growing popularity among patients with MS, little is known about the impact of fad diets on MS susceptibility or disease course.

In parallel with environmental risk factors, scientists have investigated human genetics to better answer the question of “who gets MS?” Epidemiological observations about higher prevalence of the disease in certain ethnic groups have strongly suggested a genetic component. In the United States and Europe, Caucasians, especially those of Northern European background, have the highest risk of MS, while other groups, such as those of African and Southeast Asian descent, have a lower risk. African-Americans, whose ancestry is largely a mix of Caucasian and African, have an intermediate risk of MS, but those who develop MS tend to have a more aggressive course [44, 45]. Sardinia, a semi-autonomous Mediterranean island, has a particularly high risk of MS in relation to its neighbors, owing to the disproportionate genetic burden found in its population [46, 47].

In addition to varying rates of MS in different ethnic groups, the recognition of MS as a disease with a strong genetic underpinning is demonstrated by the clustering of MS and other autoimmune diseases within families. Siblings and children of patients with MS have an increased risk of developing MS: the risk of MS in those with affected first-degree relatives is about 2–3 %, similar to the 2–5 % seen in dizygotic twins [48], while the concordance rate in monozygotic twins is roughly 25 % [49]. Mendelian (e.g., autosomal dominant or recessive) forms of MS have not been identified. Rather, it appears that numerous genetic variants common in the general population all individually contribute a small increase in risk to render a person genetically susceptible (rarer undiscovered variants with larger effect sizes may also increase risk in some people).

Though much of what is known about the genetic architecture of MS has been revealed in recent years, early linkage and candidate gene studies established correlations between genetic variants in the major histocompatibility complex (MHC) and MS risk. The MHC, encoded by a large gene family on chromosome 6, is a set of cell surface markers that display fragments of peptides broken down by the cell, allowing the body’s immune cells to distinguish self from non-self. Different populations are very heterogeneous with respect to the distribution of MHC alleles. The degree of polymorphism and linkage disequilibrium (the tendency of different alleles to distribute together) within the MHC had previously made it difficult to identify the specific allele driving the association, though recent studies have demonstrated that the allele with the largest strength of association and effect size is HLA–DRB1*1501 [50, 51]. Not all genetic variants confer risk; HLA–A*0201 exerts a protective effect.

Improvements in genotyping technology and the creation of large international consortia have facilitated the identification of 110 unique variants outside the MHC that are associated with MS susceptibility [51]. The vehicle for the discovery of these risk alleles was the Genome-Wide Association Study (GWAS), a case-control design in which hundreds of thousands of single nucleotide polymorphisms (SNPs) were genotyped in every subject. Large numbers of cases and controls are required to generate the statistical power needed for so many concurrent tests. Most risk alleles were found to be in regulatory, as opposed to coding, regions of the DNA, and likely influence gene expression on a tissue-specific level. While most of the loci are in or near genes associated with immune function, and several alleles have been linked to other autoimmune conditions, the functional consequences of most of them have yet to be worked out.

Through multiple GWASs as well as prior studies, we have learned that each risk allele exerts a very modest effect size: the odds ratio (OR) associated with possessing one copy of the HLA–DRB1*1501 allele is roughly 3, while all other risk alleles outside of the MHC have ORs below 1.5. This underscores the difference between a risk allele and a genetic variant associated with a monogenic disorder, like cystic fibrosis, where possessing one or two copies determines that the phenotype will be expressed. In MS, possessing all the known genetic risk alleles does not guarantee development of the disease, though the creation of predictive models in healthy individuals is a focus of ongoing research.