| Title: | Analysis of KIR gene variants in The Cancer Genome Atlas and UK Biobank using KIRCLE |
| Journal: | BMC Biology |
| Published: | 24 Aug 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36002830/ |
| DOI: | https://doi.org/10.1186/s12915-022-01392-2 |
| URL: | https://bmcbiol.biomedcentral.com/counter/pdf/10.1186/s12915-022-01392-2 |
Publication 10454
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Abstract
BackgroundNatural 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. However, NK cells exhibit great diversity in their mechanism of activation, and the outcomes of their activation are not yet understood fully. Just like the HLAs they bind, KIR receptors exhibit high allelic diversity in the human population. Here we provide a method to identify KIR allele variants from whole exome sequencing data and uncover novel associations between these variants and various molecular and clinical correlates.ResultsIn order to better understand KIRs, we have developed KIRCLE, a novel method for genotyping individual KIR genes from whole exome sequencing data, and used it to analyze approximately sixty-thousand patient samples in The Cancer Genome Atlas (TCGA) 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 (Mann-Whitney U FDR = 0.0751).ConclusionsWe show that KIRCLE is able to infer KIR variants accurately and consistently, and we demonstrate its utility using data from approximately sixty-thousand individuals from TCGA and UK Biobank to discover novel molecular and clinical correlations with KIR germline variants. 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. This tool may be used both as a benchmark for future KIR-variant-inference algorithms, and to better understand the immunogenomics of and disease processes involving KIRs.</p>
4 Authors
- Galen F. Gao
- Dajiang Liu
- Xiaowei Zhan
- Bo Li
1 Application
| Application ID | Title |
|---|---|
| 21237 | Elucidate the causal roles of smoking on human diseases using large genetic datasets linked with health records |
Enabling scientific discoveries that improve human health