Association of HLA-DRB1*09:01 with tIgE levels among African ancestry individuals with asthma

Abstract Background Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970’s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (SNPs) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. Objective To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African ancestry individuals. Methods We collected high-density genomics data for the CAAPA participants (Consortium on Asthma among African-ancestry Populations in the Americas, N=4,993). Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE levels (tIgE) in subjects with and without asthma. Results Among the 1,607 individuals with asthma, 972 had available tIgE levels with a mean tIgE level of 198.7 IU.ml-1. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1*09:01 was associated with increased tIgE levels (P=8.5x10-4, weighted effect size 0.51 [0.15-0.87]). Conclusions We identified for the first time an HLA allele associated with tIgE levels in African ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.