Genetic predisposition to multiple sclerosis as a polygenic autoimmune disease

Unrelated patients with definite multiple sclerosis (MS) and healthy controls of Russian descent were genotyped at 16 polymorphic loci of the DRB1, TNF, LTa, TGFb1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. The association of allelic variants with MS (p<0,01) was studied using the case-control method with the PSampler algorithm recently developed by our group. The previously described DRB1*15(2) allele, the TNFa9 allele and the biallelic combination (CCR5d32,DRB1*04) were reidentified as MS-associated in Russians. We also identified previously unknown MS-associated tri-allelic combinations: (-509 TGFb1*C, DRB1*18(3),CTLA4*G) and (-238TNF*B1,-308TNF*A2,CTLA4*G). The biological properties of the MS-associated genes support the notion that autoimmune inflammatory processes play an important role in MS, whereas an existence of mainly non-overlapping subgroups of patients bearing different predisposing genetic factors is consistent with the MS genetic heterogeneity.