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To the Editor: Healy et al.1 join a series of case-control studies in the elucidation of human leukocyte antigen (HLA) Class I associations in multiple sclerosis (MS) susceptibility. They report that HLA-A*02 and HLA-B*44 are protective independent of the risk allele HLA-DRB1*15, whereas the effect of HLA-C*05 appears to be secondary due to LD with HLA-B*44. However, we do not believe this has been established.
The authors compared allele frequencies between cases and controls, which could be confounded by population stratification. Family-based analysis is more robust against population substructure, and therefore, confirmation using this approach in independent cohorts and other populations is needed. The authors' previous study included some family-based material2; however, only a fraction of the families were typed for HLA alleles, while the remaining genotype data were imputed from single nucleotide polymorphisms (SNPs). Given that HLA is a highly polymorphic locus with many functional alleles, direct typing could be more informative.3 By genotyping classic HLA alleles in a large cohort of MS families and utilizing TDT of HLA haplotypes,4 we found no protective effect of HLA-B*44 or any other Class I allelic associations independent of Class II.
Furthermore, as with previous studies of this type,1,2 the exclusion of HLA-DRB1*15 alone may not be sufficient because now nearly all HLA-DRB1 alleles have been implicated in MS susceptibility and those that have not are mostly infrequent alleles …
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