Significant association of KIR2DL3-HLA-C1 combination with cerebral malaria and implications for co-evolution of KIR and HLA.

Abstract

Cerebral malaria is a major, life-threatening complication of Plasmodium falciparum malaria, and has very high mortality rate. In murine malaria models, natural killer (NK) cell responses have been shown to play a crucial role in the pathogenesis of cerebral malaria. To investigate the role of NK cells in the developmental process of human cerebral malaria, we conducted a case-control study examining genotypes for killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands in 477 malaria patients. We found that the combination of KIR2DL3 and its cognate HLA-C1 ligand was significantly associated with the development of cerebral malaria when compared with non-cerebral malaria (odds ratio 3.14, 95% confidence interval 1.52-6.48, P = 0.00079, corrected P = 0.02). In contrast, no other KIR-HLA pairs showed a significant association with cerebral malaria, suggesting that the NK cell repertoire shaped by the KIR2DL3-HLA-C1 interaction shows certain functional responses that facilitate development of cerebral malaria. Furthermore, the frequency of the KIR2DL3-HLA-C1 combination was found to be significantly lower in malaria high-endemic populations. These results suggest that natural selection has reduced the frequency of the KIR2DL3-HLA-C1 combination in malaria high-endemic populations because of the propensity of interaction between KIR2DL3 and C1 to favor development of cerebral malaria. Our findings provide one possible explanation for KIR-HLA co-evolution driven by a microbial pathogen, and its effect on the global distribution of malaria, KIR and HLA.

• Authors: Kouyuki Hirayasu, Jun Ohashi, Koichi Kashiwase, Hathairad Hananantachai, Izumi Naka, Atsuko Ogawa, Minoko Takanashi, Masahiro Satake, Kazunori Nakajima, Peter Parham, Hisashi Arase, Katsushi Tokunaga, Jintana Patarapotikul, Toshio Yabe
• Journal: PLoS pathogens (PLoS Pathog) Vol. 8 Issue 3 Pg. e1002565 ( 2012) ISSN: 1553-7374 [Electronic] United States
• PMID: 22412373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes
• HLA-C Antigens
• KIR2DL3 protein, human
• Ligands
• Receptors, KIR
• Receptors, KIR2DL3

Topics

• Adult
• Alleles
• Case-Control Studies
• Endemic Diseases
• Epitopes
• Evolution, Molecular
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genetic Variation
• Genotype
• HLA-C Antigens (genetics)
• Humans
• Killer Cells, Natural (immunology)
• Ligands
• Malaria, Cerebral (genetics, immunology)
• Parasite Load
• Receptors, KIR (genetics)
• Receptors, KIR2DL3 (genetics)
• Selection, Genetic
• Young Adult