Genetic variation that determines TAPBP expression levels associates with the course of malaria in an HLA allotype-dependent manner.
Walker-Sperling V., Digitale JC., Viard M., Martin MP., Bashirova A., Yuki Y., Ramsuran V., Kulkarni S., Naranbhai V., Li H., Anderson SK., Yum L., Clifford R., Kibuuka H., Ake J., Thomas R., Rowland-Jones S., Rek J., Arinaitwe E., Kamya M., Rodriguez-Barraquer I., Feeney ME., Carrington M.
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 TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP 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 Plasmodium falciparum 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 TAPBP 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.