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Background  Despite the importance of the human leukocyte antigen (HLA) gene locus in research and clinical practice, direct HLA typing is laborious and expensive. Furthermore, the analysis requires specialized software and expertise which are unavailable in most developing country settings. Recently,  in silico  methods have been developed for predicting HLA alleles using single nucleotide polymorphisms (SNPs). However, the utility of these methods in African populations has not been systematically evaluated.    Methodology/Principal Findings  In the present study, we investigate prediction of HLA class II (HLA-DRB1 and HLA-DQB1) alleles using SNPs in the Wolaita population, southern Ethiopia. The subjects comprised 297 Ethiopians with genome-wide SNP data, of whom 188 had also been HLA typed and were used for training and testing the model. The 109 subjects with SNP data alone were used for empirical prediction using the multi-allelic gene prediction method. We evaluated accuracy of the prediction, agreement between predicted and HLA typed alleles, and discriminative ability of the prediction probability supplied by the model. We found that the model predicted intermediate (two-digit) resolution for HLA-DRB1 and HLA-DQB1 alleles at accuracy levels of 96% and 87%, respectively. All measures of performance showed high accuracy and reliability for prediction. The distribution of the majority of HLA alleles in the study was similar to that previously reported for the Oromo and Amhara ethnic groups from Ethiopia.    Conclusions/Significance  We demonstrate that HLA class II alleles can be predicted from SNP genotype data with a high level of accuracy at intermediate (two-digit) resolution in an African population. This finding offers new opportunities for HLA studies of disease epidemiology and population genetics in developing countries.

Prediction of HLA Class II Alleles Using SNPs in an African Population