P069UTR SNPS rs111686073 and rs73410010 independently modify expression of tapasin in blacks

Abstract

Aim The transmembrane glycoprotein tapasin (TAPBP) mediates the binding of MHC-I and TAP1/2 of the peptide loading complex in the endoplasmic reticulum and aids in optimal peptide loading. TAPBP absence in mice alters both MHC-I expression and T cell development, and virally mediated inhibition of TAPBP gene transcription impairs antigen presentation in CMV infection. Owing to its importance in antigen presentation, we hypothesized that TAPBP expression may also affect HIV pathogenesis, and gene variants indicating TAPBP expression could then serve as markers for HIV outcome. We sought to identify single nucleotide polymorphisms (SNPs) affecting TAPBP expression and ascertain the mechanism. Methods A scan of the TAPBP gene identified two variants, rs111686073 (G/C) and rs73410010 (A/G), found only in blacks that significantly and independently correlated with TAPBP expression via qPCR in three South African cohorts (FRESH, SK and CAPRISA002). Luciferase expression constructs containing the UTRs of TAPBP were generated and examined in HeLa cells. For rs111686073, electrophoretic mobility shift assays (EMSAs) were performed to determine if the transcription factors predicted to bind by Alibaba2 mediated the change in TAPBP expression. Results Both rs111686073 (p = 0.0003–0.0006) and rs73410010 (p Conclusions The SNPs rs111686073 and rs73410010 are independently and significantly associated with TAPBP expression, and rs111686073G results in increased expression over the C variant, likely due to binding affinity of AP-2a. The lower expression of TAPBP may alter TAPBP-dependent HLA-B expression and antigen presentation, and affect CD8+ T cell development. Tapasin expression and tapasin-dependence of HLA-I alleles will be considered in future studies of HIV pathogenesis.