Genetic factors
HLA region of Chromosome 6. Changes in this area increase the probability of suffering MS.
MS is not considered a hereditary disease. However, a number of genetic variations have been shown to increase the risk of developing the disease. The risk of acquiring MS is higher in relatives of a person with the disease than in the general population, especially in the case of siblings, parents, and children. In the case of monozygotic twins, concordance occurs only in about 35% of cases, and half-siblings have a lower risk than full siblings, indicating a polygenic origin.
Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte antigen (HLA) system—a group of genes in chromosome 6 that serves as the major histocompatibility complex in humans—increase the probability of suffering MS. Two other genes have been shown to be linked to MS. These are the IL2RA and the IL7RA, subunits of the receptor for interleukin 2 and interleukin 7 respectively. The HLA complex is involved in antigen presentation, which is crucial to the functioning of the immune system, while mutations in the IL2 and IL7 receptor genes were already known to be associated with diabetes and other autoimmune conditions, supporting the notion that MS is an autoimmune disease. The gene encoding kinesin KIF1B is the first neuronal expressed gene demonstrated to enhance the risk for the disease. Other studies have linked genes in chromosome 5 with the disease.
Infectious cause
Genetic susceptibility can explain some of the geographic and epidemiological variations in MS incidence, like the high appearance of the disease among some families or the risk decline with genetic distance, but does not account for other phenomena, such as the changes in risk that occur with migration at an early age.
An explanation for this epidemiology finding could be that some kind of infection, produced by a widespread microbe rather than a rare pathogen, is the origin of the disease. Different hypotheses have elaborated on the mechanism by which this may occur. The hygiene hypothesis proposes that exposure to several infectious agents early in life is protective against MS. MS would be an autoimmune reaction triggered in susceptible individuals by multiple infective microorganisms, with risk increasing with age at infection. The prevalence hypothesis proposes that the disease is due to a pathogen more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic persistent infection. Only in a few cases, and after many years since the original infection, does it bring demyelination. The hygiene hypothesis has received more support than the prevalence hypothesis.
Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of most patients, the association of several viruses with human demyelinating encephalomyelitis, and induction of demyelination in animals through viral infection. Human herpesviruses are a candidate group of viruses linked to MS; Varicella zoster virus has been found at high levels in the cerebrospinal fluid of MS patients, but the most reproduced finding is the reduced risk of having the disease in those who have never been infected by the Epstein-Barr virus, together with the correlation of its markers with disease activity. This goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing. Other agents that have also been related with MS are human endogenous retroviruses and Chlamydia pneumoniae.
Non-infectious environmental risk factors
MS is more common in people who live farther from the equator. Decreased sunlight exposure has been linked with a higher risk of MS. Decreased vitamin D production and intake has been the main biological mechanism used to explain the higher risk among those less exposed to sun.
Severe stress may also be a risk factor although evidence is weak; parents who lost a child unexpectedly were more likely to develop MS than parents who had not. Smoking has also been shown to be an independent risk factor for developing MS. Association with occupational exposures and toxins—mainly solvents—has been evaluated, but no clear conclusions have been reached. Vaccinations were also considered as causal factors for the disease; however, most studies show no association between MS and vaccines. Gout occurs less than would statistically be expected in people with MS, and low levels of uric acid have been found in MS patients as compared to normal individuals. This led to the theory that uric acid, which can protect against oxidative stress from substances such as peroxynitrite, protects against MS, although its exact importance remains unknown. Several other possible risk factors, such as diet and hormone intake, have been investigated; however, more evidence is needed to confirm or refute their relation with the disease.
Although some of these risk factors, including infection, are partly modifiable, only further research—especially clinical trials—will reveal whether their elimination can help prevent MS
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