Department of Paediatrics, University of Oxford, Oxford, UK.
MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Nat Commun. 2022 Jul 14;13(1):4073. doi: 10.1038/s41467-022-31626-4.
Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.
自然杀伤细胞是先天淋巴细胞，在免疫监视中起核心作用，并与自身免疫发病机制有关。调节变体对自然杀伤细胞基因表达的影响程度还知之甚少。在这里，我们对来自健康欧洲人群（n=245）的负选择自然杀伤细胞进行了表达数量性状基因座作图。我们发现了一个显著的基因子集，这些基因具有自然杀伤细胞特有的表达数量性状基因座，这些基因高度提示人类疾病，特别是自身免疫性疾病。对五种常见自身免疫性疾病的自然杀伤细胞全转录组关联研究，在 27 个基因中确定了进一步的新关联。除了这些顺式观察结果外，我们还发现了新的主调控区域，这些区域包括 19q13.4、杀伤细胞免疫球蛋白样受体区域、GNLY、MC1R 和 UVSSA，影响着跨基因网络的表达。我们的研究结果为自然杀伤细胞的独特生物学提供了新的见解，表明与其他免疫细胞相比，其表达数量性状基因座明显不同，这对疾病机制具有重要意义。
