Genetic variation that determines <i>TAPBP</i> expression levels associates with the course of malaria in an HLA allotype-dependent manner.

Abstract

HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate <i>TAPBP</i> messenger RNA (mRNA) expression in Africans, <i>rs111686073</i> (<i>G</i>/<i>C</i>) and <i>rs59097151 (A</i>/<i>G)</i>, located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. <i>rs111686073G</i> and <i>rs59097151A</i> induced significantly higher <i>TAPBP</i> mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower <i>Plasmodium falciparum</i> parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed <i>TAPBP</i> mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.