Background: coronavirus disease 2019 (COVID-19) causes severe illness including cytokine storms, but mortality among countries differs largely. In the present study, we investigated the association between human leukocyte antigen (HLA) class I, which plays a major role in susceptibility to viral infections, and the mortality of COVID-19. Methods: data of allele frequencies of HLA-A, -B and -C and COVID-19 mortality were obtained for 74 countries from the Allele Frequency Net Database and worldometer.info. Association between allele frequency of each HLA and mortality was assessed by linear regression followed by multivariable regression. Subsequently, association of HLA-C*05 to its receptor KIR2DS4fl, expressed on natural killer (NK) cells, and differential mortality to historic pandemics were analyzed. Results: HLA-A*01, -B*07, -B*08, -B*44 and -C*05 were significantly associated with the risk of deaths (adjusted p = 0.040, 0.00081, 0.047, 0.0022, 0.00032, respectively), but only HLA-C*05 remained statistically significant (p = 0.000027) after multivariable regression. A 1% increase in the allele frequency of HLA-C*05 was associated with an increase of 44 deaths/million. Countries with different mortality could be categorized by the distribution of HLA-C*05 and its receptor KIR2DS4fl, which in combination cause NK cell-induced hyperactive immune response. Countries with similar ethnic and/or geographic background responded in a similar pattern to each pandemic. Conclusions: we demonstrated that allele frequency of HLA-C*05 and the distribution pattern with its receptor KIR2DS4fl strongly correlated with COVID-19 mortality. Host genetic variance of innate immunity may contribute to the difference in mortality among various countries and further investigation using patient samples is warranted.

中文翻译：

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HLA-C * 05等位基因频率的群体差异及其与COVID-19死亡率的关系

背景：2019年冠状病毒病（COVID-19）导致包括细胞因子风暴在内的严重疾病，但各国之间的死亡率差异很大。在本研究中，我们调查了人类白细胞抗原（HLA）I类（其对病毒感染的易感性起主要作用）与COVID-19的死亡率之间的关联。方法：从等位基因频率网数据库和worldometer.info获得74个国家的HLA-A，-B和-C等位基因频率数据以及COVID-19死亡率。每个HLA的等位基因频率与死亡率之间的关联通过线性回归，然后进行多元回归评估。随后，将HLA-C * 05与其受体KIR2DS4fl结合分析了在自然杀伤（NK）细胞上表达的，以及与历史性大流行病不同的死亡率。结果：HLA-A * 01，-B * 07，-B * 08，-B * 44和-C * 05与死亡风险显着相关（分别调整后的p = 0.040、0.00081、0.047、0.0022、0.00032 ），但在多变量回归之后，只有HLA-C * 05仍然具有统计学意义（p = 0.000027）。HLA-C * 05等位基因频率增加1％与每百万人死亡44例增加有关。可以通过HLA-C * 05及其受体KIR2DS4fl的分布对死亡率不同的国家进行分类，它们共同导致NK细胞诱导的过度活跃的免疫反应。具有相似种族和/或地理背景的国家对每种大流行的反应方式也相似。结论：我们证明HLA-C * 05的等位基因频率及其受体KIR2DS4f1的分布模式与COVID-19死亡率密切相关。固有免疫的宿主遗传差异可能会导致不同国家之间的死亡率差异，因此有必要使用患者样本进行进一步调查。