Nature Genetics ( IF 31.7 ) Pub Date : 2024-08-05 , DOI: 10.1038/s41588-024-01844-1 Jack A Kosmicki 1 , Anthony Marcketta 1 , Deepika Sharma 1 , Silvio Alessandro Di Gioia 1 , Samantha Batista 1 , Xiao-Man Yang 1 , Gannie Tzoneva 1 , Hector Martinez 1 , Carlo Sidore 1 , Michael D Kessler 1 , Julie E Horowitz 1 , Genevieve H L Roberts 2 , Anne E Justice 3 , Nilanjana Banerjee 1 , Marie V Coignet 2 , Joseph B Leader 3 , Danny S Park 2 , Rouel Lanche 1 , Evan Maxwell 1 , Spencer C Knight 2 , Xiaodong Bai 1 , Harendra Guturu 2 , Asher Baltzell 2 , Ahna R Girshick 2 , Shannon R McCurdy 2 , Raghavendran Partha 2 , Adam J Mansfield 1 , David A Turissini 2 , Miao Zhang 2 , Joelle Mbatchou 1 , Kyoko Watanabe 1 , Anurag Verma 4 , Giorgio Sirugo 4 , , , , , Marylyn D Ritchie 4 , William J Salerno 1 , Alan R Shuldiner 1 , Daniel J Rader 4 , Tooraj Mirshahi 3 , Jonathan Marchini 1 , John D Overton 1 , David J Carey 3 , Lukas Habegger 1 , Jeffrey G Reid 1 , Aris Economides 1 , Christos Kyratsous 1 , Katia Karalis 1 , Alina Baum 1 , Michael N Cantor 1 , Kristin A Rand 2 , Eurie L Hong 2 , Catherine A Ball 2 , Katherine Siminovitch 1 , Aris Baras 1 , Goncalo R Abecasis 1 , Manuel A R Ferreira 1
Coronavirus disease 2019 (COVID-19) and influenza are respiratory illnesses caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses, respectively. Both diseases share symptoms and clinical risk factors1, but the extent to which these conditions have a common genetic etiology is unknown. This is partly because host genetic risk factors are well characterized for COVID-19 but not for influenza, with the largest published genome-wide association studies for these conditions including >2 million individuals2 and about 1,000 individuals3,4,5,6, respectively. Shared genetic risk factors could point to targets to prevent or treat both infections. Through a genetic study of 18,334 cases with a positive test for influenza and 276,295 controls, we show that published COVID-19 risk variants are not associated with influenza. Furthermore, we discovered and replicated an association between influenza infection and noncoding variants in B3GALT5 and ST6GAL1, neither of which was associated with COVID-19. In vitro small interfering RNA knockdown of ST6GAL1—an enzyme that adds sialic acid to the cell surface, which is used for viral entry—reduced influenza infectivity by 57%. These results mirror the observation that variants that downregulate ACE2, the SARS-CoV-2 receptor, protect against COVID-19 (ref. 7). Collectively, these findings highlight downregulation of key cell surface receptors used for viral entry as treatment opportunities to prevent COVID-19 and influenza.
中文翻译:
COVID-19 和流感的遗传风险因素在很大程度上是不同的
2019 冠状病毒病 (COVID-19) 和流感是分别由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 和流感病毒引起的呼吸道疾病。这两种疾病有共同的症状和临床危险因素1 ,但这些疾病在多大程度上具有共同的遗传病因尚不清楚。部分原因是宿主遗传风险因素对 COVID-19 具有很好的特征,但对流感却没有,已发表的针对这些疾病的最大的全基因组关联研究包括 >2 百万个体2和约 1,000 个体3,4,5,6 ,分别。共同的遗传风险因素可能会指明预防或治疗这两种感染的目标。通过对 18,334 例流感检测呈阳性的病例和 276,295 例对照者进行的基因研究表明,已发表的 COVID-19 风险变异与流感无关。此外,我们发现并复制了流感感染与B3GALT5和ST6GAL1中的非编码变异之间的关联,这两者均与 COVID-19 无关。 ST6GAL1(一种在细胞表面添加唾液酸的酶,用于病毒进入)的体外小干扰 RNA 敲除可将流感传染性降低 57%。这些结果反映了下调ACE2 (SARS-CoV-2 受体)的变体可以预防 COVID-19 的观察结果(参考文献7 )。总的来说,这些发现强调了用于病毒进入的关键细胞表面受体的下调是预防 COVID-19 和流感的治疗机会。