MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil.
MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil.
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DOI：
10.3389/fimmu.2022.975918
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管衰老与 Covid-19 的预后较差相关，但全球范围内仍有未接种疫苗的高龄个体出现轻微或无症状的报道。大多数报道的导致疾病易感性增加的遗传变异与免疫反应有关，涉及 I 型干扰素免疫和调节； HLA簇基因；炎症小体激活；白介素基因；和趋化因子受体。另一方面，人们对 SARS-CoV-2 感染的抵抗机制知之甚少。在这里，我们探讨了与具有严重后果的年轻患者相比，超级老年复原力患者的 MHC 区域多态性与 Covid-19 结局相关。通过RT-PCR检测证实SARS-CoV-2感染。为了确定与宿主抵抗力相关的候选基因，我们调查了 87 名从 Covid-19 中康复但症状轻微或在 SARS-CoV-2 检测呈阳性后仍无症状的 90 岁以上个体，与 55 名患有严重疾病或因 Covid-19 死亡的 60 岁以下个体以及同一城市的一般老年人群进行比较。对 MHC 区域进行了全外显子组测序和深入分析。所有样本均于 2020 年初、当地疫苗接种计划开始之前收集。我们发现，与严重的Covid-19组和一般老年人对照人群相比，有弹性的超级老年人组在MUC22基因（粘蛋白家族的成员）中表现出更高频率的某些错义变异，这是MHC区域最强的信号之一。例如，MUC22 处的错义变异 rs62399430 在有弹性的超级老年人中出现的频率是其两倍（p = 0.00002，OR = 2.24）。由于老年人的促炎基础状态可能会增加对严重Covid-19的易感性，因此我们假设MUC22可能通过减少老年人群中过度活跃的免疫反应，对严重Covid-19发挥重要的保护作用。
Although aging correlates with a worse prognosis for Covid-19, super elderly still unvaccinated individuals presenting mild or no symptoms have been reported worldwide. Most of the reported genetic variants responsible for increased disease susceptibility are associated with immune response, involving type I IFN immunity and modulation; HLA cluster genes; inflammasome activation; genes of interleukins; and chemokines receptors. On the other hand, little is known about the resistance mechanisms against SARS-CoV-2 infection. Here, we addressed polymorphisms in the MHC region associated with Covid-19 outcome in super elderly resilient patients as compared to younger patients with a severe outcome. SARS-CoV-2 infection was confirmed by RT-PCR test. Aiming to identify candidate genes associated with host resistance, we investigated 87 individuals older than 90 years who recovered from Covid-19 with mild symptoms or who remained asymptomatic following positive test for SARS-CoV-2 as compared to 55 individuals younger than 60 years who had a severe disease or died due to Covid-19, as well as to the general elderly population from the same city. Whole-exome sequencing and an in-depth analysis of the MHC region was performed. All samples were collected in early 2020 and before the local vaccination programs started. We found that the resilient super elderly group displayed a higher frequency of some missense variants in the MUC22 gene (a member of the mucins’ family) as one of the strongest signals in the MHC region as compared to the severe Covid-19 group and the general elderly control population. For example, the missense variant rs62399430 at MUC22 is two times more frequent among the resilient super elderly (p = 0.00002, OR = 2.24). Since the pro-inflammatory basal state in the elderly may enhance the susceptibility to severe Covid-19, we hypothesized that MUC22 might play an important protective role against severe Covid-19, by reducing overactive immune responses in the senior population.
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