PMID- 35185875 OWN - NLM STAT- MEDLINE DCOM- 20220302 LR - 20231105 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity. PG - 769900 LID - 10.3389/fimmu.2022.769900 [doi] LID - 769900 AB - The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), P(bonf) <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), P(bonf) <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%). CI - Copyright (c) 2022 Hovhannisyan, Madelian, Avagyan, Nazaretyan, Hyussyan, Sirunyan, Arakelyan, Manukyan, Yepiskoposyan, Mayilyan and Jordan. FAU - Hovhannisyan, Anahit AU - Hovhannisyan A AD - Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia. AD - Russian-Armenian University, Yerevan, Armenia. FAU - Madelian, Vergine AU - Madelian V AD - Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia. FAU - Avagyan, Sevak AU - Avagyan S AD - Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia. FAU - Nazaretyan, Mihran AU - Nazaretyan M AD - Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia. FAU - Hyussyan, Armine AU - Hyussyan A AD - Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia. FAU - Sirunyan, Alina AU - Sirunyan A AD - Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia. FAU - Arakelyan, Rubina AU - Arakelyan R AD - ClinSoft Armenia, Yerevan, Armenia. FAU - Manukyan, Zorayr AU - Manukyan Z AD - ClinStat Group, Lexington, MA, United States. FAU - Yepiskoposyan, Levon AU - Yepiskoposyan L AD - Russian-Armenian University, Yerevan, Armenia. FAU - Mayilyan, Karine R AU - Mayilyan KR AD - Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia. FAU - Jordan, Frieda AU - Jordan F AD - Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220203 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (HLA-B51 Antigen) RN - 0 (HLA-C Antigens) RN - 0 (HLA-C*04 antigen) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Viral Proteins) SB - IM MH - Adult MH - Age Factors MH - Armenia MH - COVID-19/*pathology MH - Female MH - Gene Frequency/genetics MH - HLA-B51 Antigen/*genetics/immunology MH - HLA-C Antigens/*genetics/immunology MH - Heterozygote MH - Histocompatibility Antigens Class I/genetics MH - Humans MH - Male MH - Middle Aged MH - Pandemics MH - Risk MH - SARS-CoV-2/*immunology MH - *Severity of Illness Index MH - Sex Factors MH - Viral Proteins/immunology PMC - PMC8850920 OTO - NOTNLM OT - Armenian population OT - COVID-19 severity OT - HLA classical genes OT - HLA-B*51:01 OT - HLA-C*04:01 OT - HLA-I heterozygosity OT - affinity to SARS-CoV-2 OT - severity risk modelling COIS- RA and ZM declare that they work at the ClinSoft Armenia, Yerevan, Armenia, and ClinStat Group, Lexington, MA. The remaining 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. EDAT- 2022/02/22 06:00 MHDA- 2022/03/03 06:00 PMCR- 2022/02/03 CRDT- 2022/02/21 06:01 PHST- 2021/09/02 00:00 [received] PHST- 2022/01/13 00:00 [accepted] PHST- 2022/02/21 06:01 [entrez] PHST- 2022/02/22 06:00 [pubmed] PHST- 2022/03/03 06:00 [medline] PHST- 2022/02/03 00:00 [pmc-release] AID - 10.3389/fimmu.2022.769900 [doi] PST - epublish SO - Front Immunol. 2022 Feb 3;13:769900. doi: 10.3389/fimmu.2022.769900. eCollection 2022.