An HLA allele frequency-based approach to resolving allelic and genotypic ambiguity in HLA typing data and its implementation in ImmPort (65.22)

Abstract

Abstract The classical human leukocyte antigen (HLA) loci are the most polymorphic loci in the human genome, with hundreds of new alleles reported yearly. HLA polymorphisms in exons 2 and 3 of class I loci and in exon 2 of class II loci distinguish the peptide binding regions of HLA proteins. Current HLA typing methodologies focus on identifying variant positions in these exons, and most do not detect allelic variation in other exons or non-coding regions of HLA genes. Because of the limitations in detecting polymorphic variants and the pace of new allele discovery, commonly used HLA typing methodologies cannot unambiguously identify all known HLA alleles or genotypes. Consequently, many HLA genotyping results are ambiguous in that both alleles of each HLA locus for a given subject may have multiple possible identities, and each subject may have multiple possible genotypes. Here, we describe an approach to allelic and genotypic ambiguity resolution that uses published HLA allele frequencies in 10 world regions to determine the most likely diploid alleles and genotype for each subject in an HLA typing study. This method has been implemented in an online tool at www.ImmPort.org, and is freely available for use by the immunology community. This ambiguity reduction tool will allow investigators studying autoimmune disease, adverse drug reactions, transplantation outcome and other HLA associated conditions to more accurately determine the contribution of specific HLA alleles to disease.