BACKGROUND Mortality remains very high and unpredictable in COVID-19, with intense public protection strategies tailored to preceived risk. Males are at greater risk of severe COVID-19 complications. Genomic studies are in process to identify differences in host susceptibility to SARS-CoV-2 infection. METHODS Genomic structures were examined for the ACE2 gene that encodes angiotensin-converting enzyme 2, the obligate receptor for SARS-CoV-2. Variants in 213,158 exomes/genomes were integrated with ACE2 protein functional domains, and pathogenicity criteria from the American Society of Human Genetics and Genomics/Association for Molecular Pathology. RESULTS 483 variants were identified in the 19 exons of ACE2 on the X chromosome. All variants were rare, including nine loss-of-function (potentially SARS-CoV-2 protective) alleles present only in female heterozygotes. Unopposed variant alleles were more common in males (262/3596 [7.3%] nucleotides) than females (9/3596 [0.25%] nucleotides, p<0.0001). 37 missense variants substituted amino acids in SARS-CoV-2 interacting regions or critical domains for transmembrane ACE2 expression. Four upstream open reading frames with 31 associated variants were identified. Excepting loss-of-function alleles, variants would not meet minimum criteria for classification as Likely Pathogenic/beneficial if differential frequencies emerged in patients with COVID-19. CONCLUSIONS Males are more exposed to consequences from a single variant ACE2 allele. Common risk/beneficial alleles are unlikely in regions subject to evolutionary constraint. ACE2 upstream open reading frames may have implications for aminoglycoside use in SARS-CoV-2-infected patients. For this SARS-CoV-2-interacting protein with pre-identified functional domains, pre-emptive functional and computational studies are encouraged to accelerate interpretations of genomic variation for personalised and public health use.

中文翻译：

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COVID-19基因组易感性：根据ACMG / AMP指导，与SARS-CoV-2感染人类有关的ACE2变体的定义

背景技术在COVID-19中，死亡率仍然很高且无法预测，并且针对预期风险制定了严格的公共保护策略。男性患严重COVID-19并发症的风险更大。基因组研究正在进行中，以鉴定宿主对SARS-CoV-2感染的敏感性差异。方法检查基因组结构的ACE2基因，该基因编码SARS-CoV-2的专性受体血管紧张素转化酶2。213158个外显子组/基因组中的变体与ACE2蛋白功能域整合，并结合了美国人类遗传与基因组学/分子病理学协会的致病性标准。结果在X染色体的ACE2的19个外显子中鉴定到483个变异体。所有变体都很罕见，包括仅在女性杂合子中存在的9个功能丧失（可能是SARS-CoV-2保护性）等位基因。雄性（262/3596 [7.3％]核苷酸）的非对位变异等位基因比雌性（9/3596 [0.25％]核苷酸，p <0.0001）更常见。SARS-CoV-2相互作用区域或关键域中的37个错义变体取代了氨基酸，用于跨膜ACE2表达。鉴定了四个具有31个相关变体的上游开放阅读框。除功能丧失的等位基因外，如果COVID-19患者出现差异频率，则变体将不符合分类为“可能是致病性/有益”的最低标准。结论男性更容易受到单个ACE2等位基因变异的影响。受进化限制的地区不太可能出现常见风险/有益等位基因。ACE2上游开放阅读框可能对SARS-CoV-2感染患者使用氨基糖苷有影响。对于这种具有预先确定的功能域的SARS-CoV-2相互作用蛋白，鼓励进行先发制人的功能和计算研究，以加快对基因组变异的解释，以用于个性化和公共卫生用途。