MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil

Abstract

BackgroundAlthough 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.MethodsSARS-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.ResultsWe 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).ConclusionSince 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.

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

“…In couples discordant for COVID-19, HLA-A variants associated with symptomatic versus asymptomatic SARS-CoV-2 infection in highly exposed individuals ( 22 ). Moreover, the number of missense variants in the MUC22 gene was higher in resilient super elders (people over 90 years old who were infected but had mild or no symptoms) ( 23 ).…”

The Influence of SARS-CoV-2 Pandemic on the Diagnosis of Celiac Disease and Clinical Practice in Pediatric Gastroenterology

“…Despite the fact that exposure to SARS-CoV-2 may initiate gastrointestinal inflammation supports the hypothesis that SARS-CoV-2 may trigger autoimmune mechanisms in genetically predisposed subjects [ 39 , 40 , 41 ], a protective effect of SARS-CoV-2 infection on the occurrence of CD cannot be excluded a priori. Some human leukocyte antigens are implicated in the autoimmune reactivity triggered by the viruses [ 42 , 43 , 44 ], other than the resulting protective effect against some viral diseases such as HIV and dengue [ 45 , 46 ]. Furthermore, during the lockdown, the reduction in environmental pollution and the changes in diet and lifestyles may have positively influenced the complex homeostasis between the microbiome and the immune system and, therefore, may have had a protective effect on the onset of autoimmune diseases, including CD.…”

Optimal HLA imputation of admixed population with dimension reduction

“…Genome-wide association studies (GWASs) have now become a strong ally in the understanding of the underlying mechanisms of diseases susceptibility and outcomes, with historical associations such as rs2395029 in HIV (Limou and Zagury 2013;Fellay et al 2007), or the identification of 233 genomic regions linked to multiple sclerosis susceptibility (International Multiple Sclerosis Genetics Consortium 2019). GWASs have also been performed as first lines of research at the beginning of the SARS-CoV-2 outbreak to evaluate how host genetics can influence COVID-19 outcomes (Pairo-Castineira et al 2021;COVID-19 Host Genetics Initiative 2021;Douillard et al 2021b;Castelli et al 2022). Starting from the first GWAS with hundreds of individuals in the 2000s (Klein et al 2005;Duerr et al 2006), multiple initiatives emerged in the last decade seeking to systematically gather clinical and genetic information, such as the UK Biobank (Bycroft et al 2018), Japanese BioBank (Hirata et al 2017), or TOPMed (Taliun et al 2021), which count hundreds of thousands of samples.…”