Chromosome 19 Single-Locus and Multilocus Haplotype Associations With Multiple Sclerosis

Publisher Website
Google Scholar
Abstract
Context. —Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed. Objective. —To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOEAPOEon chromosome 19q13.2, andMBP(myelin basic protein) on chromosome 18q23. Design. —Case-control association testing. Subjects. —A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria. Main Outcome Measures. —ϰ2Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods. Results. —The HLA effect is due to the class II DR2 haplotype, DRB1*1501-DQA1*0102-DRB1*0602; contributions to MS susceptibility from additionalDRB1-DQB1alleles or other HLA region loci were not observed. Variation within theMBPlocus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, includingD19S178, D19S574, APOE, APOC2, andD19S219, differed between patient and control samples.D19S574showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). TheAPOEvariation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. Interaction effects between DR2 and chromosome 19q13.2 orMBPin MS susceptibility were not apparent. Conclusions. —The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS.