Asthma is an inflammatory condition involving the adaptive immune system. Human leukocyte antigen (HLA) genes play a central role in inflammatory responses and in the recognition of self and foreign antigens. This region has not been extensively studied in African Americans (AA). This analysis included 4,317 AA participants (3,444 with and 873 without an asthma diagnosis) from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) cohort. Whole genome sequence (WGS) were generated as part of the NHLBI TOPMed Program and the Asthma Translational Genomics Collaborative. RNA-seq data were also available for 408 asthma cases and 405 controls. Single nucleotide variations (SNV) within extended major histocompatibility complex (MHC) region (chr6:27~34Mb, hg38) were generated using the WGS data, and high resolution HLA alleles were derived from both the WGS and RNA-seq data. HLA gene expression abundance was estimated from RNA-seq data. Amino acids for each MHC protein were translated from 4-digit HLA alleles. We assessed for associations between asthma and variants defined by alleles, SNVs, and amino acids. We performed an expression quantitative trait locus (eQTL) analysis for those variants significantly associated with asthma. No SNV was found associated with asthma at genome-wide significance threshold. We examined two SNVs (rs9469220 and rs9273349) previously associated with IgE levels and asthma. Only rs9273349 was nominally associated (OR=1.13; P=0.05) with asthma in our data. But both two candidate SNPs were significant eQTL (FDR <1.0 x10-05) for HLA-DQ genes HLA-DQB1, HLA-DQA2 and HLA-DQB2. Top associations from HLA alleles and amino acids included HLA-DQB1*05 and a histidine at DQB1 residue 30 (P <0.001). HLA-DQB1 was also differentially expressed when comparing asthma cases and controls (FDR <0.05). In summary, this study replicated a previously described variant rs9273349 in the HLA region and verified that it was associated with HLA-DQ expression. We also identified an amino acid residue associated with asthma status in HLA-DQB1, a gene found to be differentially expressed by asthma status. These findings require additional validation in other cohorts, as well as studies to understand the functional consequence on amino acid substitutions at position 30 in HLA-DQB1.