CHROMOSOME-19 SINGLE-LOCUS AND MULTILOCUS HAPLOTYPE ASSOCIATIONS WITHMULTIPLE-SCLEROSIS - EVIDENCE OF A NEW SUSCEPTIBILITY LOCUS IN CAUCASIAN AND CHINESE PATIENTS

Context.-Susceptibility to multiple sclerosis (MS) involves a genetica lly complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed. Obje ctive.-To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups usin g both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE on chromosome 19q13.2, and MBP (myelin basi c protein) on chromosome 18q23. Design.-Case-control association testi ng. Subjects.-A total of 120 Caucasian patients with MS and 107 unrela ted control individuals from California, and 32 patients and 32 unrela ted control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to publishe d criteria. Main Outcome Measures.-chi(2) Testing of loci and individu al alleles and haplotypes. Haplotype frequencies were estimated with s tandard maximum likelihood methods. Results.-The HLA effect is due to the class II DR2 haplotype, DRB11501-DQA1*0102-DRB1*0602; contributio ns to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chro mosome 18q23 showed no effect in MS. The distribution of haplotypes fr om 5 loci within the chromosome 19q13.2 region, including D19S178, D19 S574, APOE, APOC2, and D19S219, differed between patient and control s amples. D19S574 showed a significant effect (P=.015) in Caucasian pati ents with MS due to the increased frequency of a single allele (P=.002 ). The APOE variation, prominent in other neurological diseases, showe d no influence on MS susceptibility, despite its location within the c hromosome 19q13.2 region. interaction effects between DR2 and chromoso me 19q13.2 or MBP in MS susceptibility were not apparent. Conclusions. -The significant chromosome 19q13.2 single-locus and multilocus haplot ype associations with MS in Caucasian and Chinese patient samples indi cate an effect from a nearby disease susceptibility locus. These initi al observations are an encouraging step toward the description of non- HLA genetic susceptibility to MS.