PMID- 32804949
OWN - NLM
STAT- MEDLINE
DCOM- 20200923
LR  - 20200923
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 16
IP  - 8
DP  - 2020 Aug
TI  - Epistatic interactions between killer immunoglobulin-like receptors and human 
      leukocyte antigen ligands are associated with ankylosing spondylitis.
PG  - e1008906
LID - 10.1371/journal.pgen.1008906 [doi]
LID - e1008906
AB  - The killer immunoglobulin-like receptors (KIRs), found predominantly on the 
      surface of natural killer (NK) cells and some T-cells, are a collection of highly 
      polymorphic activating and inhibitory receptors with variable specificity for 
      class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in 
      haplotypes of diverse gene content across the human population, and the 
      repertoire of independently inherited KIR and HLA alleles is known to alter risk 
      for immune-mediated and infectious disease by shifting the threshold of 
      lymphocyte activation. We have conducted the largest disease-association study of 
      KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele 
      dosages from genotype data for 12,214 healthy controls and 8,107 individuals with 
      the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). 
      We identified epistatic interactions between KIR genes and their ligands (at both 
      HLA subtype and allele resolution) that increase risk of disease, replicating 
      analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We 
      further confirmed that the strong AS-association with a pathogenic variant in the 
      endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 
      presented peptidome, is not modified by carriage of the canonical HLA-B receptor 
      KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement 
      of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which 
      collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to 
      contribute to disease immunopathogenesis.
FAU - Hanson, Aimee L
AU  - Hanson AL
AUID- ORCID: 0000-0002-0231-8771
AD  - University of Queensland Diamantina Institute, University of Queensland, 
      Brisbane, Queensland, Australia.
CN  - International Genetics of Ankylosing Spondylitis Consortium
FAU - Vukcevic, Damjan
AU  - Vukcevic D
AUID- ORCID: 0000-0001-7780-9586
AD  - Melbourne Integrative Genomics, School of Mathematics and Statistics, University 
      of Melbourne, Parkville, Victoria, Australia.
AD  - Data Science, Murdoch Children's Research Institute, Parkville, Victoria, 
      Australia.
FAU - Leslie, Stephen
AU  - Leslie S
AUID- ORCID: 0000-0003-3511-3470
AD  - Melbourne Integrative Genomics, School of Mathematics and Statistics, University 
      of Melbourne, Parkville, Victoria, Australia.
AD  - Data Science, Murdoch Children's Research Institute, Parkville, Victoria, 
      Australia.
AD  - School of Biosciences, University of Melbourne, Parkville, Victoria Australia.
FAU - Harris, Jessica
AU  - Harris J
AD  - Institute of Health and Biomedical Innovation, Queensland University of 
      Technology, Brisbane, Queensland, Australia.
AD  - Translational Research Institute, Princess Alexandra Hospital, Brisbane, 
      Queensland, Australia.
FAU - Le Cao, Kim-Anh
AU  - Le Cao KA
AUID- ORCID: 0000-0003-3923-1116
AD  - Melbourne Integrative Genomics, School of Mathematics and Statistics, University 
      of Melbourne, Parkville, Victoria, Australia.
FAU - Kenna, Tony J
AU  - Kenna TJ
AUID- ORCID: 0000-0001-6844-3463
AD  - Institute of Health and Biomedical Innovation, Queensland University of 
      Technology, Brisbane, Queensland, Australia.
AD  - Translational Research Institute, Princess Alexandra Hospital, Brisbane, 
      Queensland, Australia.
FAU - Brown, Matthew A
AU  - Brown MA
AD  - Institute of Health and Biomedical Innovation, Queensland University of 
      Technology, Brisbane, Queensland, Australia.
AD  - Translational Research Institute, Princess Alexandra Hospital, Brisbane, 
      Queensland, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200817
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (HLA Antigens)
RN  - 0 (Minor Histocompatibility Antigens)
RN  - 0 (Receptors, KIR)
RN  - EC 3.4.11.- (Aminopeptidases)
RN  - EC 3.4.11.- (ERAP1 protein, human)
SB  - IM
MH  - Alleles
MH  - Aminopeptidases/genetics
MH  - *Epistasis, Genetic
MH  - HLA Antigens/*genetics
MH  - Humans
MH  - Minor Histocompatibility Antigens/genetics
MH  - Polymorphism, Single Nucleotide
MH  - Receptors, KIR/*genetics
MH  - Spondylitis, Ankylosing/*genetics
PMC - PMC7451988
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/08/18 06:00
MHDA- 2020/09/24 06:00
PMCR- 2020/08/17
CRDT- 2020/08/18 06:00
PHST- 2020/01/06 00:00 [received]
PHST- 2020/06/03 00:00 [accepted]
PHST- 2020/08/27 00:00 [revised]
PHST- 2020/08/18 06:00 [pubmed]
PHST- 2020/09/24 06:00 [medline]
PHST- 2020/08/18 06:00 [entrez]
PHST- 2020/08/17 00:00 [pmc-release]
AID - PGENETICS-D-20-00016 [pii]
AID - 10.1371/journal.pgen.1008906 [doi]
PST - epublish
SO  - PLoS Genet. 2020 Aug 17;16(8):e1008906. doi: 10.1371/journal.pgen.1008906. 
      eCollection 2020 Aug.