title: 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.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. hirayasu@ifrec.osaka-u.ac.jp
authors.forename: Kouyuki
authors.initials: K
authors.lastname: Hirayasu
authors.forename: Jun
authors.initials: J
authors.lastname: Ohashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Hathairad
authors.initials: H
authors.lastname: Hananantachai
authors.forename: Izumi
authors.initials: I
authors.lastname: Naka
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ogawa
authors.forename: Minoko
authors.initials: M
authors.lastname: Takanashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satake
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakajima
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.forename: Hisashi
authors.initials: H
authors.lastname: Arase
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Jintana
authors.initials: J
authors.lastname: Patarapotikul
authors.forename: Toshio
authors.initials: T
authors.lastname: Yabe
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D019353:Endemic Diseases; D000939:Epitopes; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D016779:Malaria, Cerebral / Q000235:genetics* / Q000276:immunology; D059208:Parasite Load; D054340:Receptors, KIR / Q000235:genetics*; D054344:Receptors, KIR2DL3 / Q000235:genetics*; D012641:Selection, Genetic; D055815:Young Adult
chemical_list: D000939:Epitopes; D015236:HLA-C Antigens; C515078:KIR2DL3 protein, human; D008024:Ligands; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3