Abstract
Introduction: Genetic susceptibility to multiple sclerosis (MS) is predominantly determined by polymorphism at the HLA-DRB1 gene locus. The HLA-DRB1 *1501 allele is found in over half of MS cases in Caucasians. Western Australia (WA) is a geographically isolated State with a reasonably uniform and stable Caucasian population, providing a unique opportunity for genotype-phenotype studies.
Methods: The Perth demyelinating disease database (PDDD) recruited over 1000 patients representing approximately two-thirds of the MS population in WA. HLA-DRB1 genotyping was performed using a high-resolution DNA sequencing technique on a cohort of ∼500 well-characterized MS patients from the PDDD and genotype-phenotype correlations were examined. Among the study participants, 465 had clinically definite or probable MS (MS), comprising 41 cases of primary progressive MS (PPMS) and 425 cases of relapsing remitting/ secondary progressive MS (RR/SPMS). A cohort of 189 Caucasian individuals from a rural WA Community comprised the control group.
Results: A total of 34 DRB1 allele variants were detected in the study cohort. A significantly increased frequency of DRB1*1501 was observed in the RR/SPMS (54.1%, p < 10−6 OR = 4.8) and PPMS (58.5%, p < 10−6) groups compared with the control group (19.5%). Frequencies of four other DRB1 alleles (DRB1*0101, *0701, *0901 and *1101) were significantly decreased in the MS group. No association was found between the presence of DRB1*1501 and gender, age of onset, disease duration or frequency, of brain or spinal MRI or visual evoked potential abnormalities. DRB1*1501 carriers had higher positive rate of oligoclonal bands (67%) compared with non-DRB1*1501 carriers (49.4%, p = 0.027). Frequency of DRB1*1501 homozygosity was not increased in the MS cohort. However, a gene-dose effect was found for level of disability (median EDSS: DRB1*1501 homozygote 4.0, heterozygote 3.0, and DRB1*1501 negative group 2.5, p = 0.009). A correlation was also observed between DRB1*0301 gene-dose and spinal cord MRI abnormalities (100% in homozygotes, 94.1% in heterozygotes and 85.6% in DRB1*0301 negative cases, p = 0.026).
Conclusion: This is the largest Caucasian MS cohort studied to date in the Southern Hemisphere. Our results demonstrate the important role of HLA-DRB1 alleles in determining risk of MS and clinical outcomes in this population.