An insight about genomic susceptibility & multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) leading to various degrees of physical and cognitive disability1. The risk factors implicated in the development of MS are viral infections such as Epstein-Barr virus, human herpes virus-6, vitamin D3 deficiency and genomic susceptibility2. It is an immune-mediated disorder causing destruction to oligodendroglia, myelin sheath and secondary axonal damage3.

The disease has varied manifestations, the most common being remitting relapsing type, secondary progressive MS, primary progressive MS and acute fulminant MS4. The genomic vulnerability has been substantiated by many studies56. The incidence of MS is found to be more in monozygotic twins as compared to dizygotic twins6.

The immunopathogenesis is contributed by many immunological factors, which include CD4 cells, T helper type 1 (Th1) cells, antibodies, complement, CD8+ T-cells and innate immunity. These immunological factors have complex interplay, causing damage to CNS structures7.

Haile et al8 in 1980 reported that variability in human leucocyte antigen (HLA) region predisposed individuals to develop MS. The genetic vulnerability for MS has been ascertained by Class 2 risk alleles, while Class 1 alleles confer protective functions. In Class 2 risk alleles, HLA-DRB1*15.01 has been proven to be most important susceptible factor for MS, across the population throughout the world9.

The destruction of myelin sheaths surrounding axons of CNS has been caused by dysregulated immune processes. The most widely studied are the three polymorphisms within the proximal 1.3 kb (−1085 G/A, −819 C/T and −592 C/G) region of interleukin-10 (IL-10). These variations are mainly from three different haplotypes (GCC, ATA and ACC), which regulate expression levels of IL-10. The haplotype combination GCC/GCC is associated with high IL-10 expression, whereas GCC/ATA and GCC/ACC are associated with medium expression and ATA/ATA, ATA/ACC and ACC/ACC with low expression. Significant associations of these genotypes with MS have been reported in different population with causation as well as severity of disease10.

Genetic studies have shown implication of HLA DRB1*15, one among the three candidate risk genes of HLA-DR2 haplotype as the main susceptibility allele in MS11. Association of this allele is strongest in Northern Europeans genome-wide association study and identified almost in all population12.

Shahbazi et al13 in their study in this issue have evaluated the susceptibility of IL-10 (−1082 and −819) and HLA-DRB1*15 polymorphisms in relation to MS. The study was conducted in Iranian population in age-, sex-, ethnicity-matched MS patients and controls. IL-10 −1082 G/G and IL-10 −819 C/C genotypes were more frequent in MS patients than in healthy individuals. HLA DRB1*15 allele also showed an association with MS patients. Importantly, individuals having both G at −1082 position/C at −819 position with DR15 risk alleles showed risk for developing MS. Haplotypes [H2 (CA) and H4 (TG)] were suggested for their protective roles against MS13.

This study emphasizes on the association of IL-10 −1082 G/G and IL-10 −819 C/C genotypes and HLA DRB1*15 allele in MS patients. However, additional functional studies related to these polymorphisms will help further understand interplay between HLA DRB and IL-10 gene.

As ethnicity plays an important role in association studies, further larger studies in different ethnic population are needed. This may further provide evidence that both HLA DRB1*15 allele and HLA DRB1- regulated- Th-2-specific IL-10 cytokine polymorphisms may be important determinants of MS.

Future perspectives

The aetiology of MS is still not certain. MS is a complicated inflammatory neurodegenerative disease of the CNS, the aetiology and evolution both determined by environmental and genetic influences. The genetic studies have proved the role of genes regulating immunological factors. The genetic susceptibility studies have tried to establish the role of genetic polymorphisms in causation, progression, magnetic resonance imaging lesion loads, relapses and prognosis of MS. However, the results are conflicting in nature. The genetic studies are mainly related with genes governing immunopathological factors but not giving insights about natural course of the disease. Further research is required to know the genetic contribution to understand the causative factors in MS, their correlation with therapeutics and prognosis.