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. 2022 Oct 25:13:975918.
doi: 10.3389/fimmu.2022.975918. eCollection 2022.

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

Erick C Castelli  1   2 , Mateus V de Castro  3 , Michel S Naslavsky  3   4 , Marilia O Scliar  3 , Nayane S B Silva  2 , Raphaela N Pereira  2 , Viviane A O Ciriaco  2 , Camila F B Castro  2   5 , Celso T Mendes-Junior  6 , Etiele de S Silveira  7 , Iuri M de Oliveira  7 , Eduardo C Antonio  7 , Gustavo F Vieira  7   8 , Diogo Meyer  4 , Kelly Nunes  4 , Larissa R B Matos  3 , Monize V R Silva  3 , Jaqueline Y T Wang  3 , Joyce Esposito  3 , Vivian R Cória  3 , Jhosiene Y Magawa  9   10   11 , Keity S Santos  9   10   11 , Edecio Cunha-Neto  9   10   11 , Jorge Kalil  9   10   11 , Raul H Bortolin  12 , Mário Hiroyuki Hirata  12 , Luiz P Dell'Aquila  13 , Alvaro Razuk-Filho  13 , Pedro B Batista-Júnior  13 , Amaro N Duarte-Neto  14 , Marisa Dolhnikoff  14 , Paulo H N Saldiva  14 , Maria Rita Passos-Bueno  3   4 , Mayana Zatz  3   4
Affiliations

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

Erick C Castelli et al. Front Immunol. .

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: COVID-19; HLA; MUC22; SARS-CoV-2; human leukocyte antigens; immune response; major histocompatibility complex (MCH); resistant genetic variants.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Distribution of Brazilian individuals with SARS-CoV-2 infection according to Covid-19 severity, and the definition of the larger groups MILD and SEVERE Covid-19.
Figure 2
Figure 2
Manhattan plot illustrating differences among patients with MILD and SEVERE Covid-19, and the general elderly population from the same city. The general elderly population consists of whole-genomes (WGS) of 1,170 elders from São Paulo city, with unknown status regarding Covid-19. We considered only variants with a minor allele frequency of 1% in at least one of the groups, with no more than 5% of missing alleles in both groups, and with a ratio between read depth for each allele in heterozygous sites ranging from 0.3 to 0.5 for Exomes (the MILD and SEVERE groups). The red line marks the threshold for detecting a variant associated with the phenotype by calculating the number of segregation blocks observed in our data. The blue line marks the suggestive threshold for a candidate variant, p < 0.005. Most MUC22 variants are in Linkage Disequilibrium (r2 > 0.8).
Figure 3
Figure 3
Manhattan plot illustrating differences between Brazilian centenarians (>90 y) recovered from Covid-19 and the general elderly population. The general population consists of whole-genomes (WGS) of 1,170 elders from São Paulo city (> 65 y), with unknown status regarding Covid-19. The centenarian group includes exomes of 87 patients more than 90 years old that presented mild Covid-19 symptoms. We considered only variants with a minor allele frequency of 1% in at least one of the groups, with no more than 5% of missing alleles in both groups, and with a ratio between read depth for each allele in heterozygous sites ranging from 0.3 to 0.5 for Exomes. The red line marks the threshold for detecting a variant associated with the phenotype by calculating the number of segregation blocks observed in our data. The blue line marks the suggestive threshold for a candidate variant, p < 0.005. Most MUC22 variants are in Linkage Disequilibrium (r2 > 0.8).
Figure 4
Figure 4
Top view of HLA-A molecules and hierarchical clusterization of HLA-A alleles. In (A) there is a MHC structure in both the ribbon and surface visualizations from the region that interacts with the TCR, respectively. The area in orange represents the zone proximal about the residues 62 and 63. In (B) we can see the cluster dendrogram of the analyzed MHCs. Under each allele name, there is the surface image that was generated for electrostatic potential distribution. In the right branch, we can see the cluster of alleles carrying rs199474424 (please refer to Figure 2), HLA-A*33:01, A*33:03, A*68:01, and A*68:02, with their respective shared molecular fingerprint.
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