학술논문
Genetic variation that determines TAPBP expression levels associates with the course of malaria in an HLA allotype-dependent manner
Document Type
article
Author
Walker-Sperling, Victoria; Digitale, Jean C; Viard, Mathias; Martin, Maureen P; Bashirova, Arman; Yuki, Yuko; Ramsuran, Veron; Kulkarni, Smita; Naranbhai, Vivek; Li, Hongchuan; Anderson, Stephen K; Yum, Lauren; Clifford, Robert; Kibuuka, Hannah; Ake, Julie; Thomas, Rasmi; Rowland-Jones, Sarah; Rek, John; Arinaitwe, Emmanuel; Kamya, Moses; Rodriguez-Barraquer, Isabel; Feeney, Margaret E; Carrington, Mary
Source
Proceedings of the National Academy of Sciences of the United States of America. 119(29)
Subject
Language
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 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.