Association of Human Leukocyte Antigen Alleles with COVID-19 Severity and Mortality in a Spanish Population
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Setting
2.2. Variables
- Sex: male or female.
- Age: at the moment of presentation in the ED.
- Hypertension: history of pharmacologically treated hypertension.
- Diabetes: history of type 1 or type 2 diabetes mellitus, under pharmacological treatment.
- Dementia: history of Alzheimer’s disease, Lewy bodies dementia, vascular dementia, frontotemporal dementia, or unspecified cognitive impairment with Global Disability Scale (GDS) score 4–7.
- Lung disease: history of asthma, chronic obstructive pulmonary disease, pulmonary hypertension, sleep apnea hypopnea syndrome, obesity hypoventilation syndrome, idiopathic pulmonary fibrosis or other types of chronic lung disease.
- Cardiovascular disease: history of congestive heart failure with preserved or reduced left ventricle ejection fraction, ischemic heart disease, moderate or severe mitral or aortic valve disease, miocardiopathy, periphery arterial disease or stroke. Atrial fibrillation with no other heart condition is not included.
- Kidney disease: history of chronic kidney disease from stage 3 to stage 5 (including hemodialysis and kidney transplant), chronic glomerular or tubular disease.
- Immunosuppression: history of primary or secondary immune deficiency. HIV infection with undetectable viral load and with active treatment when presenting at the ED is not considered as immunosuppression.
- Cancer: history of active cancer and/or under active treatment at the moment of presentation at the ED.
- Smoking history: either active, former, or no smoking history.
- Country: country of birth. Electronic clinical history does not record the patient’s race.
2.3. DNA Isolation and HLA Typing
2.4. Statistical Analyses
2.5. Ethical Aspects
3. Results
3.1. Univariable Analysis
3.2. Multivariable Analysis
4. Discussion and Limitations
4.1. Discussion
4.2. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Amoroso, A.; Magistroni, P.; Vespasiano, F.; Bella, A.; Bellino, S.; Puoti, F.; Alizzi, S.; Vaisitti, T.; Boros, S.; Grossi, P.A.; et al. HLA and AB0 Polymorphisms May Influence SARS-CoV-2 Infection and COVID-19 Severity. Transplantation 2021, 105, 193–200. [Google Scholar] [CrossRef] [PubMed]
- Pojero, F.; Candore, G.; Caruso, C.; Di Bona, D.; Groneberg, D.A.; Ligotti, M.E.; Accardi, G.; Aiello, A. The Role of Immunogenetics in COVID-19. Int. J. Mol. Sci. 2021, 22, 2636. [Google Scholar] [CrossRef]
- Deb, P.; Zannat, K.; Talukder, S.; Bhuiyan, A.H.; Jilani, S.A.; Saif-Ur-Rahman, K.M. Association of HLA gene polymorphism with susceptibility, severity, and mortality of COVID-19: A systematic review. HLA 2022, 99, 281–312. [Google Scholar] [CrossRef]
- Littera, R.; Campagna, M.; Deidda, S.; Angioni, G.; Cipri, S.; Melis, M. Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience. Front. Immunol. 2020, 11, 605688. [Google Scholar] [CrossRef] [PubMed]
- Instituto de Salud Carlos III. Informe nº 181: Situación de COVID-19 en España. 2023. Available online: https://www.isciii.es/QueHacemos/Servicios/VigilanciaSaludPublicaRENAVE/EnfermedadesTransmisibles/Documents/INFORMES/Informes%20COVID-19/INFORMES%20COVID-19%202023/Informe%20n%C2%BA%20181%20Situaci%C3%B3n%20actual%20de%20COVID-19%20en%20Espa%C3%B1a%20a%2030%20de%20junio%20de%202023.pdf (accessed on 10 January 2024).
- Dieter, C.; de Almeida Brondani, L.; Bauermann Leitão, C.; Gerchman, F.; Emerim Lemos, N.; Crispim, D. Genetic polymorphisms associated with susceptibility to COVID-19 disease and severity: A systematic review and metaanalysis. PLoS ONE 2022, 17, e0270627. [Google Scholar] [CrossRef]
- Lorente, L.; Martín, M.M.; Franco, A.; Barrio, Y.; Cáceres, J.J.; Solé-Violán, J.; Perez, A.; Marcos y Ramos, J.A.; Ramos-Gómez, L.; Ojeda, N.; et al. HLA genetic polymorphisms and prognosis of patients with COVID-19. Med. Intensiv. 2021, 45, 96–103. [Google Scholar] [CrossRef] [PubMed]
- Gutiérrez-Bautista, J.F.; Rodriguez-Nicolas, A.; Rosales-Castillo, A.; López-Ruiz, M.A.; Martín-Casares, A.M.; Fernández-Rubiales, A.; Anderson, P.; Garrido, F.; Ruiz-Cabello, F.; López-Nevot, M.A. Study of HLA-A, -B, -C, -DRB1 and -DQB1 polymorphisms in COVID-19 patients. J. Microbiol. Immunol. Infect. 2022, 55, 421–427. [Google Scholar] [CrossRef]
- Severe Covid-19 GWAS Group. Genomewide Association Study of Severe COVID-19 with Respiratory Failure. N. Engl. J. Med. 2020, 383, 1522–1534. [Google Scholar] [CrossRef]
- Weiner, J.; Suwalski, P.; Holtgrewe, M.; Rakitko, A.; Thibeault, C.; Müller, M.; Patriki, D.; Quedenau, C.; Krüger, U.; Ilinsky, V.; et al. Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01. EClinicalMedicine 2021, 40, 101099. [Google Scholar] [CrossRef]
- Tomita, Y.; Ikeda, T.; Sato, R.; Sakagami, T. Association between HLA gene polymorphisms and mortality of COVID-19: An in silico analysis. Immun. Inflamm. Dis. 2020, 8, 684–694. [Google Scholar] [CrossRef]
- Ishii, T. Human Leukocyte Antigen (HLA) Class I Susceptible Alleles Against COVID-19 Increase Both Infection and Severity Rate. Cureus 2020, 12, e12239. [Google Scholar] [CrossRef]
- Verlouw, J.A.M.; Clemens, E.; de Vries, J.H.; Zolk, O.; Verkerk, A.J.M.H.; Am Zehnhoff-Dinnesen, A.; Medina-Gomez, C.; Lanvers-Kaminsy, C.; Rivadeneira, F.; Langer, T.; et al. A comparison of genotyping arrays. Eur. J. Hum. Genet. 2021, 29, 1611–1624. [Google Scholar] [CrossRef] [PubMed]
- Dilthey, A.; Leslie, S.; Moutsianas, L.; Shen, J.; Cox, C.; Nelson, M.R.; McVean, G. Multi-Population Classical HLA Type Imputation. PLoS Comput. Biol. 2013, 9, e1002877. [Google Scholar] [CrossRef]
- Karnes, J.H.; Shaffer, C.M.; Bastarache, L.; Gaudieri, S.; Glazer, A.M.; Steiner, H.E.; Mosley, J.D.; Mallal, S.; Denny, J.C.; Phillips, E.J.; et al. Comparison of HLA allelic imputation programs. PLoS ONE 2017, 12, e0172444. [Google Scholar] [CrossRef] [PubMed]
- Gayán, J.; Galan, J.J.; González-Pérez, A.; Sáez, M.E.; Martínez-Larrad, M.T.; Zabena, C.; Rivero, M.C.; Salinas, A.; Ramírez-Lorca, R.; Morón, F.J.; et al. Genetic Structure of the Spanish Population. BMC Genom. 2010, 11, 326. [Google Scholar] [CrossRef] [PubMed]
- AxiomTM Analysis Suite (AxAS), v5.1; Thermo Fisher Scientific Inc.: Waltham, MA, USA, 2022.
- Shen, Y.; Khatril, B.; Rananaware, S.; Li, D.; Ostrov, D.A.; Jain, P.K.; Lessard, C.J.; Nguyen, C.Q. Ancestral origins are associated with SARSCoV-2 susceptibility and protection in a Florida patient population. PLoS ONE 2023, 18, e0276700. [Google Scholar] [CrossRef]
- Breno, M.; Noris, M.; Rubis, N.; Parvanova, A.I.; Martinetti, D.; Gamba, S.; Liguori, L.; Mele, C.; Piras, R.; Orisio, S.; et al. A GWAS in the pandemic epicenter highlights the severe COVID-19 risk locus introgressed by Neanderthals. iScience 2023, 26, 107629. [Google Scholar] [CrossRef]
- Chamnanphon, M.; Pongpanich, M.; Suttichet, T.B.; Jantarabenjakul, W.; Torvorapanit, P.; Putcharoen, O.; Sodsai, P.; Phokaew, C.; Hirankarn, N.; Chariyavilaskul, P.; et al. Host genetic factors of COVID-19 susceptibility and disease severity in a Thai population. J. Hum. Genet. 2022, 67, 295–301. [Google Scholar] [CrossRef]
- Gonzalez-Galarza, F.F.; McCabe, A.; Santos, E.J.; Jones, J.; Takeshita, L.Y.; Ortega-Rivera, N.D.; Del Cid-Pavon, G.M.; Ramsbottom, K.; Ghattaoraya, G.; Alfirevic, A.; et al. Allele frequency net database (AFND) 2020 update: Gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res. 2020, 8, D783–D788. [Google Scholar] [CrossRef]
- Poulton, K.; Wright, P.; Hughes, P.; Savic, S.; Welberry Smith, M.; Guiver, M.; Morton, M.; van Dellen, D.; Tholouli, E.; Wynn, R.; et al. A role for human leucocyte antigens in the susceptibility to SARS-Cov-2 infection observed in transplant patients. Int. J. Immunogenet. 2020, 47, 324–328. [Google Scholar] [CrossRef]
- Sakuraba, A.; Haider, H.; Sato, T. Population Difference in Allele Frequency of HLA-C*05 and Its Correlation with COVID-19 Mortality. Viruses 2020, 12, 1333. [Google Scholar] [CrossRef] [PubMed]
- Fricke-Galindo, I.; Falfán-Valencia, R. Genetics Insight for COVID-19 Susceptibility and Severity: A Review. Front. Immunol. 2021, 12, 622176. [Google Scholar] [CrossRef]
- Lerner, A.; Benzvi, C.; Vojdani, E. HLA-DQ2/8 and COVID-19 in Celiac Disease: Boon or Bane. Microorganisms 2023, 11, 2977. [Google Scholar] [CrossRef] [PubMed]
- Koutsakos, M.; McWilliam, H.E.G.; Aktepe, T.E.; Fritzlar, S.; Illing, P.; Mifsud, N.A.; Purcell, A.W.; Rockman, S.; Reading, P.C.; Vivian, J.P.; et al. Downregulation of MHC Class I Expression by Influenza A and B Viruses. Front. Immunol. 2019, 10, 1158. [Google Scholar] [CrossRef]
- Bonagura, V.R.; Vambutas, A.; DeVoti, J.A.; Rosenthal, D.W.; Steinberg, B.M.; Abramson, A.L.; Shikowitz, M.J.; Gjertson, D.W.; Reed, E.F. HLA Alleles, IFN-γ Responses to HPV-11 E6, and Disease Severity in Patients with Recurrent Respiratory Papillomatosis. Hum. Immunol. 2004, 65, 773–782. [Google Scholar] [CrossRef] [PubMed]
(A) Not Admitted in Hospital | (B) Admitted to COVID-19 Ward | (C) Admitted to ICU | (D) In-Hospital Death * | Total | p (A vs. B vs. C vs. D) | p (A vs. B + C + D) | p (A + B vs. C + D) | p (A + B + C vs. D) | |
---|---|---|---|---|---|---|---|---|---|
Gender, n (%) | |||||||||
Male | 9 (8.6) | 62 (59.6) | 14 (13.5) | 19 (18.3) | 104 | 0.44 | 0.151 | 0.553 | 0.241 |
Female | 12 (14) | 48 (55.8) | 15 (17.4) | 11 (12.8) | 86 | ||||
Age, median (IQR) | 52 (35–63) | 56 (45–71) | 57 (51–72) | 78 (72–88) | 60 (47–74) | <0.001 | 0.043 | <0.001 | <0.001 |
Hypertension, n (%) | |||||||||
Yes | 5 (23.8) | 37 (33.6) | 9 (31) | 20 (66.7) | 71 | <0.001 | 0.13 | 0.019 | <0.001 |
No | 16 (76.2) | 73 (66.4) | 20 (69) | 10 (33.3) | 119 | ||||
Diabetes, n (%) | |||||||||
Yes | 1 (4.8) | 13 (11.8) | 7 (24.1) | 13 (43.3) | 34 | <0.001 | 0.077 | <0.001 | <0.001 |
No | 20 (95.2) | 97 (88.2) | 22 (75.9) | 17 (56.7) | 156 | ||||
Dementia, n (%) | |||||||||
Yes | 0 (0) | 4 (3.6) | 0 (0) | 3 (10) | 7 | <0.001 | 0.434 | 0.376 | 0.08 |
No | 21 (100) | 106 (96.4) | 29 (100) | 27 (90) | 183 | ||||
Lung disease, n (%) | |||||||||
Yes | 4 (19) | 18 (16.4) | 2 (6.9) | 15 (50) | 39 | <0.001 | 0.561 | 0.046 | <0.001 |
No | 17 (81) | 92 (83.6) | 27 (93.1) | 15 (50) | 151 | ||||
Cardiovascular disease, n (%) | |||||||||
Yes | 2 (9.5) | 10 (9.1) | 0 (0) | 13 (43.3) | 25 | <0.001 | 0.456 | 0.016 | <0.001 |
No | 19 (90.5) | 100 (90.9) | 29 (100) | 17 (56.7) | 165 | ||||
Kidney disease, n (%) | |||||||||
Yes | 1 (4.8) | 4 (3.6) | 0 (0) | 8 (26.7) | 13 | <0.001 | 0.566 | 0.019 | <0.001 |
No | 20 (95.2) | 106 (96.4) | 29 (100) | 22 (73.3) | 177 | ||||
Immunosupression, n (%) | |||||||||
Yes | 0 (0) | 5 (4.5) | 1 (3.4) | 6 (20) | 12 | <0.001 | 0.234 | 0.041 | 0.004 |
No | 21 (100) | 105 (95.5) | 28 (96.6) | 24 (80) | 178 | ||||
Cancer, n (%) | |||||||||
Yes | 0 (0) | 4 (3.6) | 2 (6.9) | 8 (26.7) | 14 | <0.001 | 0.182 | 0.002 | <0.001 |
No | 21 (100) | 106 (96.4) | 27 (93.1) | 22 (73.3) | 176 | ||||
Smoker status, n (%) | |||||||||
Active | 2 (9.5) | 5 (4.5) | 2 (6.9) | 3 (10) | 12 | <0.001 | 0.637 | 0.156 | 0.001 |
Former | 7 (33.3) | 25 (22.7) | 5 (17.2) | 16 (53.3) | 53 | ||||
Never | 12 (57.1) | 80 (72.7) | 22 (75.9) | 11 (36.7) | 125 | ||||
Total (%) | 21 (11.1) | 110 (57.9) | 29 (15.3) | 30 (15.8) | 190 |
HLA Allele | Hospital Admission | ICU Admission/Death | Death | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Yes (B, C, D) n (%) | No (A) n (%) | p | Corrected * p | Yes (C, D) n (%) | No (A, B) n (%) | p | Corrected * p | Yes (D) n (%) | No (A, B, C) n (%) | p | Corrected * p | |
B*07:05 | 0/144 (0) | 2/19 (10.05) | 0.013 | 0.48 | 0/50 (0) | 2/113 (1.8) | 1 | ns | 0/26 (0) | 2/137 (1.5) | 1 | ns |
B*14:01 | 3/144 (2.1) | 0/19 (0) | 1 | ns | 3/50 (6) | 0/113 (0) | 0.028 | 1 | 2/26 (7.7) | 1/137 (0.7) | 0.067 | ns |
B*35:03 | 3/144 (2.1) | 0/19 (0) | 1 | ns | 3/50 (6) | 0/112 (0) | 0.028 | 1 | 3/26 (11.5) | 0/137 (0) | 0.004 | 0.15 |
C*05:01 | 13/167 (7.8) | 5/21 (23.8) | 0.035 | 0.70 | 5/58 (8.6) | 13/130 (10) | 1 | ns | 2/30 (6.7) | 16/158 (10.1) | 0.74 | ns |
DPA1*02:02 | 3/167 (1.8) | 0/21 (0) | 1 | ns | 3/59 (5.1) | 0/129 (0) | 0.030 | 0.15 | 2/30 (6.7) | 1/158 (0.6) | 0.067 | ns |
DQA1*01:01 | 23/162 (14.2) | 7/20 (35) | 0.027 | 0.19 | 8/54 (14.8) | 22/128 (17.2) | 0.83 | ns | 5/28 (18.5) | 25/147 (16.1) | 0.78 | ns |
DQA1*05:01 | 41/162 (25.3) | 0/20 (0) | 0.008 | 0.056 | 19/54 (35.2) | 22/128 (17.2) | 0.011 | 0.077 | 7/28 (25.9) | 34/147 (21.9) | 0.62 | ns |
DQB1*02:02 | 1/155 (0.6) | 2/20 (10) | 0.035 | 0.49 | 0/53 (0) | 3/122 (2.5) | 0.55 | ns | 0/28 (0) | 3/147 (2) | 1 | ns |
DRB1*01:01 | 5/142 (3.5) | 1/18 (5.6) | 0.52 | ns | 3/48 (6.3) | 3/112 (2.7) | 0.37 | ns | 3/23 (13) | 3/137 (2.2) | 0.039 | 1 |
DRB1*15:01 | 12/142 (8.5) | 1/18 (5.6) | 1 | ns | 8/48 (16.7) | 5/112 (4.5) | 0.022 | 0.73 | 4/23 (17.4) | 9/137 (6.6) | 0.096 | ns |
DRB4*01:03 | 15/163 (9.2) | 5/20 (25) | 0.049 | 0.15 | 1/58 (1.7) | 19/125 (15.2) | 0.005 | 0.015 | 0/30 (0) | 20/153 (13.1) | 0.048 | 0.14 |
Hospital Admission (B, C and D vs. A) | |||
HLA Allele | p | ap | aOR (95%CI) |
B*07:05 | 0.013 | N/C | N/C |
C*05:01 | 0.035 | 0.015 | 0.2 (0.055–0.731) |
DQA1*01:01 | 0.027 | 0.121 | 0.408 (0.131–1.266) |
DQA1*05:01 | 0.008 | N/C | N/C |
DQB1*02:02 | 0.035 | 0.040 | 0.046 (0.002–0.871) |
DRB4*01:03 | 0.049 | 0.165 | 0.408 (0.115–1.446) |
ICU admission/Death (C and D vs. A and B) | |||
HLA allele | p | ap | aOR (95%CI) |
B*14:01 | 0.028 | N/C | N/C |
B*35:03 | 0.028 | N/C | N/C |
DPA1*02:02 | 0.03 | N/C | N/C |
DQA1*05:01 | 0.011 | 0.031 | 2.517 (1.086–5.833) |
DRB1*15:01 | 0.022 | 0.069 | 3.643 (0.905–14.662) |
DRB4*01:03 | 0.005 | 0.069 | 0.140 (0.017–1.164) |
Death (D vs. A, B and C) | |||
HLA allele | p | ap | aOR (95%CI) |
B*35:03 | 0.004 | N/C | N/C |
DRB1*01:01 | 0.039 | 0.110 | 197.275 (0.304–128221.91) |
DRB4*01:03 | 0.048 | N/C | N/C |
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Lobato-Martinez, E.; Muriel-Serrano, J.; García-Payá, E.; Gonzalez-de-la-Aleja, P.; Garcia-Sevila, R.; Navarro-de-Miguel, M.; Marco-de-la-Calle, F.; Ramos-Rincon, J.-M.; Sanchez-Martinez, R. Association of Human Leukocyte Antigen Alleles with COVID-19 Severity and Mortality in a Spanish Population. Medicina 2024, 60, 1392. https://doi.org/10.3390/medicina60091392
Lobato-Martinez E, Muriel-Serrano J, García-Payá E, Gonzalez-de-la-Aleja P, Garcia-Sevila R, Navarro-de-Miguel M, Marco-de-la-Calle F, Ramos-Rincon J-M, Sanchez-Martinez R. Association of Human Leukocyte Antigen Alleles with COVID-19 Severity and Mortality in a Spanish Population. Medicina. 2024; 60(9):1392. https://doi.org/10.3390/medicina60091392
Chicago/Turabian StyleLobato-Martinez, Ester, Javier Muriel-Serrano, Elena García-Payá, Pilar Gonzalez-de-la-Aleja, Raquel Garcia-Sevila, Mercedes Navarro-de-Miguel, Francisco Marco-de-la-Calle, Jose-Manuel Ramos-Rincon, and Rosario Sanchez-Martinez. 2024. "Association of Human Leukocyte Antigen Alleles with COVID-19 Severity and Mortality in a Spanish Population" Medicina 60, no. 9: 1392. https://doi.org/10.3390/medicina60091392