Abstract:
Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10-10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10-15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.
摘要:
尽管对严重COVID-19的遗传易感性进行了广泛的全球研究,但关于罕见宿主遗传变异的作用及其与其他风险因素的关系的知识仍然有限。这里,对来自西班牙/意大利的1,772例严重COVID-19病例和5,347例基于人群的对照中的52个具有先前病因证据的基因进行了测序。罕见的有害TLR7变异出现在2.4%的年轻(<60岁)病例中,没有报告的临床危险因素(n=378)。与对照组的0.24%相比(比值比(OR)=12.3,p=1.27x10-10)。功能测定或蛋白质建模的结果的并入导致效应大小的显著增加(ORmax=46.5,p=1.74x10-15)。在仅女性亚组中也检测到X染色体TLR7的关联信号,表明在男性中存在X连锁隐性遗传以外的其他机制。此外,先前涉及的基因IFNAR2,IFIH1和TBK1对严重COVID-19的贡献得到了支持证据。我们的研究结果完善了罕见的TLR7变异体对严重COVID-19的遗传贡献,并加强了干扰素信号通路中基因的病因学相关性的证据。