MULTIPLE SCLEROSIS AND DISEASE ASSOCIATION WITH HLA CLASS II GENES AND MICROSATELLITE MARKERS

Abstract

Genes of the human leukocyte antigen (HLA) region, the major histocompatibility complex (MHC) in humans, have been shown to be associated with a number of diseases, many of which are autoimmune in nature. Diseases often show association with multiple HLA loci due to strong linkage disequilibrium that exists between pairs of genes, making it difficult to identify the primary disease gene. Some diseases may have more than one HLA gene involved in disease susceptibility; others show multiple associations at the same locus. Multiple sclerosis (MS) is an autoimmune, chronic inflammatory disease of the central nervous system (CNS) that is characterized by T-cell mediated destruction of the myelin sheath surrounding axons, causing disruption of action potentials along nerves. The etiology of MS is not known, but studies suggest that both genetic and environmental factors are involved. Studies have shown that in Caucasian populations, MS is most commonly associated with DRB1*1501, DQB1*0602; class II genes of the HLA region. Microsatellites are short repetitive nucleotide repeats with unique flanking sequences. They are highly polymorphic and distributed randomly across the genome, making them useful as DNA markers in linkage studies. Microsatellites have been used to identify over forty autoimmune disease associated genes in human and animal models. To further evaluate the relationship between genes of the HLA region and multiple sclerosis, ten microsatellite loci, within or near the HLA region, were typed in a cohort of MS patients and appropriately matched controls. Samples were typed using a combination of the polymerase chain reaction (PCR) method to amplify the DNA and gel electrophoresis to identify the polymorphic alleles. Significant levels of association (p<0.04) were seen between MS and five microsatellite loci: DQCAR, G51152, MOGCA, D6S265, and RING3CA. Two loci, DQCAR and G51152, were even more significantly associated (p<0.0001). DQCAR and G51152 are located less than 150 bp from DRB1, a known MS disease associated locus. The association level of the other three microsatellite loci was most likely due to linkage disequilibrium, or alternatively, their contribution to disease susceptibility was relatively small. This data supports the use of microsatellite screening to identify susceptibility genes in disease studies in the HLA region and throughout the entire genome.