The Association of Genetic Factors to Multiple Sclerosis Susceptibility

Dear Editor, Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of central nervous system (CNS) which is affecting more than 2 million individuals in the world. During the acute phase of the disease, neuroinflammation, the activation and invasion of immune cells to CNS and demyelination are prominent. However, in the chronic and progressive phase of the disease, the immunological aspects decline and demyelination and axonal degeneration leads to permanent disability of patients. Since introduced at 1868, the etiology of MS remains unclear. Two general hypotheses try to explain the etiology: outside-in and inside-out. The former which is more accepted, indicated that the disease starts with a malfunction in specific types of immune cells (outside of CNS) which can be explained by genetic factors. In the latter hypothesis, a signal from CNS -like exposure to myelin antigens or similar antigens from viruses/bacteriaelicit the harsh immune response. There are some evidences for each one but at present the most accepted opinion is to consider MS a heterogeneous disease in which genetic predisposition and many environmental factors are evaluated in the disease onset (1, 2). There are some strong evidences in favor of the influence of genetic factors in disease development. In monozygotic tweens, if one of them develop the disease, there is a risk of 20% 30% for the other one to be affected. The probability decreases by decreased degree of genetic sharing. For example, for dizygotic tweens the probability drops to 5% and it will be even less for half siblings (3, 4). Furthermore, the risk of MS in families with both affected parents is significantly higher than families with only one affected parent (5). Interestingly, the familial heritability of MS, not only determine the possibility of its incidence, but also the time course and the severity of the disease (6). In spite of this familial risk, there is no pattern of inheritance like Mendelian traits. Modern technologies like microarray open a pipeline for searching the genes which may have a role in MS susceptibility. Until now, near 200 loci are introduced that may contribute to MS susceptibility. However, no single gene is fully responsible for the disease and a MS-prone genotype may elicits from multiple independent DNA variants. Interestingly, near 90% of the introduced loci are located in noncoding part of the DNA. Logically, no protein is coded in the noncoding sequences of DNA, though they may play an important role in gene regulation. Many of the susceptibility genes, found to be associated to other autoimmune diseases which favors the outside-in hypothesize (7). As first described at 1972, there is a strong association with the loci in HLA/MHC region of chromosome 6 and MS susceptibility. HLA is a complex array of genes which in human code the MHC (major histocompatibility complex) peptides. These peptides are responsible for antigen presenting to T cells which can turn on a cascade of immune responses. Though HLA region may determine a MS-prone genotype, the exact mechanism of MHC peptides in MS is not known (7). In this region, A polymorphism loci named HLA-DRB1 has more than 400 allele and is strongly involved in MS susceptibility, as the HLA-DRB1*15:01 allele has the strongest association for MS (OR = 3.1). Interestingly in the promoter of HLA-DRB1 there is a functional binding site for vitamin D (VDRE or vitamin D response element). This observation, may explain the contribution of genetic and environmental factors together for MS development (8). There are some other important alleles in the region which have an association with MS susceptibility, including the risk alleles HLA-DRB1*03:01 (OR = 1.26), HLA-DRB1*13:03 (OR = 2.4) and protective class I HLA-A*02:01 allele (OR = 0.73).