[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.

[Polymorphism of length of tetranucleotide repeat from the 5'-side from the myelin basic protein gene in multiple sclerosis in Russians]. / Polimorphizm dliny tetranukleotidnogo povtora s 5'-storny ot gena osnovnogo belka mielina pri rasseiannom skleroze u Russkikh.

The myelin basic protein gene (MBP) can confer the susceptibility to multiple sclerosis, because its protein product is the main protein component of myelin of the central nervous system and a potential autoimmune antigen in the disease. A possible association of multiple sclerosis with alleles and genotypes of a microsatellite repeat (TGGA)n, located to the 5' side from the first exon of MBP in ethnic Russians (126 patients with reliable multiple sclerosis and 142 healthy controls from Central Russia) was analyzed using the case-control method. Upon separation of the tetranucleotide repeat site amplification products in 1.5% agarose gel, one can see two distinct bands that can be analyzed as two allele groups (A and B). The distribution of allele A and B group frequencies as well as frequency of allele group B and genotype A/A reliably differs in multiple sclerosis patients and healthy controls. Alleles A and the A/A genotype are associated with the development of multiple sclerosis. We also analyzed the association of multiple sclerosis with combined bearing of alleles and genotypes A and B of MBP and groups of alleles of the DRB1 gene of the major histocompatibility complex that correspond to serospecificities DR1-DR18. The comparison of subgroups of multiple sclerosis patients and healthy individuals, formed on the basis of the DRB1 phenotype, has shown a reliable increase in the frequency of allele B in healthy individuals and the genotype A/A frequency in patients, only among DR4- and DR5-positive individuals. No reliable difference was found in the MBP allele and genotype distribution between multiple sclerosis patients and healthy individuals in combined groups of (DR4,DR5)-negative individuals, i.e., no carriers of any phenotype except DR4 and DR5 were revealed. Thus, MBP or some other nearby gene is involved in the multiple sclerosis development in Russians, predominantly (or exclusively) among DR4 and DR5 carriers. In this case, without stratification of analyzed individuals by the MBP alleles, multiple sclerosis is reliably associated only with DR2(15), but not of DR4 and DR5 alleles of DRB1. The results obtained are in favor of the genetic heterogeneity of multiple sclerosis, and suggest the possibility of epistatic interactions between the MBP and DRB1 genes.

[Polymorphism A/G in position +49 of CTLA4 exon 1 in multiple sclerosis in Russians]. / Polimorfizm A/G v polozhenii +49 pervogo ékzona CTLA4 pri rasseiannom skleroze u russkikh.

The association of multiple sclerosis (MS) with alleles A and G of the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, a candidate gene for autoimmune disorders, was studied. The allele polymorphism results from single nucleotide substitution (A/G) in position +49 of exon 1 and leads to substitution Thr-->Ala in the leader peptide. The case-control study involved two groups of ethnic Russians: 168 MS patients and 209 healthy subjects from central Russia. Genotype frequencies were in agreement with the Hardy-Weinberg equilibrium in both groups (P > 0.05). The controls significantly differed in CTLA4 allele and genotype frequencies from Mongoloids but not from other Caucasians. No association was observed between MS and CTLA4. In addition, the combined association with MS was analyzed for both the CTLA4 alleles and allele groups of HLA DRB1. The results showed that the CTLA4 dimorphism does not affect susceptibility to MS in ethnic Russians, be these stratified or not with regard to DRB1 alleles corresponding to serologic specificities DR1 to DR16.