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

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

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 13, p. 15-pg., 2022-10-25.

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. (AU)

• FAPESP's process: 14/50931-3 - Aging and genetic disorders: genomics and metagenomics
• Grantee: Mayana Zatz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/09702-1 - Study of protective genetic variants in resilient nonagenarians and centenarians
• Grantee: Mateus Vidigal de Castro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/19223-0 - KIR2DL4, KIR3DL2, KIR3DL3, LILRB1 (ILT2) and LILRB2 (ILT4) variability and haplotypes in a Brazilian population sample from the São Paulo state
• Grantee: Erick da Cruz Castelli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/19998-8 - Development of pipeline for copy number variation (CNVs) analysis
• Grantee: Marília de Oliveira Scliar
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC