RT Journal Article
SR Electronic
T1 KIRCLE: An Analysis of Variations in KIR Genes in The Cancer Genome Atlas and UK Biobank
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.02.458787
DO 10.1101/2021.09.02.458787
A1 Galen F. Gao
A1 Dajiang Liu
A1 Xiaowei Zhan
A1 Bo Li
YR 2021
UL http://biorxiv.org/content/early/2021/09/04/2021.09.02.458787.abstract
AB Background Natural killer (NK) cells represent a critical component of the innate immune system’s response against cancer and viral infections, among other diseases. To distinguish healthy host cells from infected or tumor cells, killer immunoglobulin receptors (KIR) on NK cells bind and recognize Human Leukocyte Antigen (HLA) complexes on their target cells. Just like the HLAs they bind, these KIRs exhibit high allelic diversity in the human population.Results In order to better understand these immunoreceptors, we have developed KIRCLE, a novel method for genotyping individual KIR genes from whole exome sequencing data, and used it to analyze approximately 60,000 patient samples in The Cancer Genome Atlas and UK Biobank. We were able to assess population frequencies for different KIR alleles and demonstrate that, similar to HLA alleles, individuals’ KIR alleles correlate strongly with their ethnicities. In addition, we observed associations between different KIR alleles and HLA alleles, including HLA-B*53 with KIR3DL2*013 (Fisher’s Exact FDR = 7.64e-51). Finally, we showcased statistically significant associations between KIR alleles and various clinical correlates, including peptic ulcer disease (Fisher’s Exact FDR = 0.0429) and age of onset of atopy and various KIR alleles (Mann-Whitney-U FDR = 0.0751).Conclusions KIR polymorphism and NK cells play a critical role in many diseases, often through their interactions with HLA complexes. Peptic ulcer disease and atopy are just two diseases in which NK cells may play a role beyond their “classical” realm of anti-tumor and anti-viral responses.Competing Interest StatementThe authors have declared no competing interest.7 List of AbbreviationsNKNatural KillerKIRKiller Immunoglobulin ReceptorHLAHuman Leukocyte AntigenNGSNext Generation SequencingKIRCLEKIR CaLling by ExomesWESWhole Exome SequencingTCGAThe Cancer Genome AtlasNMDPNational Marrow Donor ProgramFDRFalse Discovery Ratet-SNEt-distributed Stochastic Neighbor EmbeddingICD10International Statistical Classification of Diseases 10PUDPeptic Ulcer Disease