Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity
Abstract
:1. Introduction
2. Results
2.1. Population Characteristics
2.2. HLA-DRB1 Is the Most Polymorphic Gene
2.3. HLA-A, -B, -C, -DPA1, -DPB1, -DQB1, -DRB1 Alleles Are Associated with COVID-19 Severity in a Biological Sex-Specific Manner
2.4. Single HLA-SNPs Are Associated with COVID-19 Severity
2.5. Age and Biological Sex Impact on the Significance of HLA-SNPs on COVID-19
2.6. “Super-Haplotypes” Are Shared Among Different HLA Alleles
- (1)
- the same haplotype was present in different HLA-alleles;
- (2)
- only a small number of haplotypes were found in the dictionary (see Supporting Information).
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Recruiting Centers
- Oxygen saturation (SaO2) < 94% on room air; <90% in presence of known chronic hypoxic conditions or receiving chronic supplemental oxygen;
- Respiratory rate > 24 breaths/min.
4.3. Molecular Methods
4.4. NGS Metrics
4.5. Sanger Sequencing
4.6. Bioinformatics and Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Zhu, Z.; Lian, X.; Su, X.; Wu, W.; Marraro, G.A.; Zeng, Y. From SARS and MERS to COVID-19: A brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir. Res. 2020, 21, 224. [Google Scholar] [CrossRef] [PubMed]
- Williamson, E.J.; Walker, A.J.; Bhaskaran, K.; Bacon, S.; Bates, C.; Morton, C.E.; Curtis, H.J.; Mehrkar, A.; Evans, D.; Inglesby, P.; et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020, 584, 430–436. [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] [PubMed]
- Pairo-Castineira, E.; Rawlik, K.; Bretherick, A.D.; Qi, T.; Wu, Y.; Nassiri, I.; McConkey, G.A.; Zechner, M.; Klaric, L.; Griffiths, F.; et al. GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19. Nature 2023, 619, E61. [Google Scholar] [CrossRef] [PubMed]
- Langton, D.J.; Bourke, S.C.; Lie, B.A.; Reiff, G.; Natu, S.; Darlay, R.; Burn, J.; Echevarria, C. The influence of HLA genotype on the severity of COVID-19 infection. HLA 2021, 98, 14–22. [Google Scholar] [CrossRef]
- Hoseinnezhad, T.; Soltani, N.; Ziarati, S.; Behboudi, E.; Mousavi, M.J. The Role of HLA Genetic Variants in COVID-19 Susceptibility, Severity, and Mortality: A Global Review. J. Clin. Lab. Anal. 2024, 38, e25005. [Google Scholar] [CrossRef]
- January, W., 3rd; Phillip, S.; Manuel, H.; Charlotte, T.; Müller, M.; Dimitri, P.; Claudia, Q.; Krüger, U.; Elisa, T.H.; Lena, L.; et al. HLA-C* 04:01 is a Genetic Risk Allele for Severe Course of COVID-19. MedRxiv 2020. [CrossRef]
- Correale, P.; Mutti, L.; Pentimalli, F.; Baglio, G.; Saladino, R.E.; Sileri, P.; Giordano, A. HLA-B*44 and C*01 Prevalence Correlates with Covid19 Spreading across Italy. Int. J. Mol. Sci. 2020, 21, 5205. [Google Scholar] [CrossRef]
- Barker, D.J.; Maccari, G.; Georgiou, X.; A Cooper, M.; Flicek, P.; Robinson, J.; E Marsh, S.G. The IPD-IMGT/HLA Database. Nucleic Acids Res. 2023, 51, D1053–D1060. [Google Scholar] [CrossRef]
- Excoffier, L.; Laval, G.; Schneider, S. Arlequin (version 3.0): An integrated software package for population genetics data analysis. Evol. Bioinform. 2007, 1, 117693430500100. [Google Scholar] [CrossRef]
- Markov, P.V.; Ghafari, M.; Beer, M.; Lythgoe, K.; Simmonds, P.; Stilianakis, N.I.; Katzourakis, A. The evolution of SARS-CoV-2. Nat. Rev. Microbiol. 2023, 21, 361–379. [Google Scholar] [CrossRef] [PubMed]
- Butler-Laporte, G.; Povysil, G.; Kosmicki, J.A.; Cirulli, E.T.; Drivas, T.; Furini, S.; Saad, C.; Schmidt, A.; Olszewski, P.; Korotko, U.; et al. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative. PLoS Genet. 2022, 18, e1010367. [Google Scholar] [CrossRef] [PubMed]
- Park, G.M.; Lee, S.; Park, B.; Kim, E.; Shin, J.; Cho, K.; Ahn, K. Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem. Biophys. Res. Commun. 2004, 313, 606–611. [Google Scholar] [CrossRef] [PubMed]
- Shimizu, M.; Kuroda, Y.; Uchida, M.; Takada, S.; Kamada, H.; Takahashi, D.; Nakajima, F.; Miyata, S.; Igarashi, S.; Satake, M. A new HLA-C allele with an alternative splice site in exon 3: HLA-C*03:23N. HLA 2020, 95, 555–560. [Google Scholar] [CrossRef] [PubMed]
- Cole, C.; Byrne, A.; Adams, M.; Volden, R.; Vollmers, C. Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing. Genome Res. 2020, 30, 589–601. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, F.; Suzuki, S.; Mizutani, A.; Shigenari, A.; Ito, S.; Kametani, Y.; Kato, S.; Fernandez-Viña, M.; Murata, M.; Morishima, S.; et al. Capturing Differential Allele-Level Expression and Genotypes of All Classical HLA Loci and Haplotypes by a New Capture RNA-Seq Method. Front. Immunol. 2020, 11, 941. [Google Scholar] [CrossRef]
- Johansson, T.; Koskela, S.; Yohannes, D.A.; Partanen, J.; Saavalainen, P. Targeted RNA-Based Oxford Nanopore Sequencing for Typing 12 Classical HLA Genes. Front. Genet. 2021, 12, 635601. [Google Scholar] [CrossRef]
- Klein, S.L.; Flanagan, K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016, 16, 626–638. [Google Scholar] [CrossRef]
- Lakshmikanth, T.; Consiglio, C.; Sardh, F.; Forlin, R.; Wang, J.; Tan, Z.; Barcenilla, H.; Rodriguez, L.; Sugrue, J.; Noori, P.; et al. Immune system adaptation during gender-affirming testosterone treatment. Nature 2024, 633, 155–164. [Google Scholar] [CrossRef]
- Lin, A.; Yan, W.-H. The Emerging Roles of Human Leukocyte Antigen-F in Immune Modulation and Viral Infection. Front. Immunol. 2019, 10, 964. [Google Scholar] [CrossRef]
- Nagamatsu, T.; Fujii, T.; Matsumoto, J.; Yamashita, T.; Kōzuma, S.; Taketani, Y. Human Leukocyte Antigen F Protein is Expressed in the Extra-Villous Trophoblasts but Not on the Cell Surface of them. Am. J. Reprod. Immunol. 2006, 56, 172–177. [Google Scholar] [CrossRef] [PubMed]
- Taubenberger, J.K.; Morens, D.M. 1918 Influenza: The mother of all pandemics. Emerg. Infect. Dis. 2006, 12, 15–22. [Google Scholar] [CrossRef] [PubMed]
- Timpson, N.J.; Greenwood, C.M.T.; Soranzo, N.; Lawson, D.J.; Richards, J.B. Genetic architecture: The shape of the genetic contribution to human traits and disease. Nat. Rev. Genet. 2018, 19, 110–124. [Google Scholar] [CrossRef] [PubMed]
- Moltke, I.; Grarup, N.; Jørgensen, M.E.; Bjerregaard, P.; Treebak, J.T.; Fumagalli, M.; Korneliussen, T.S.; Andersen, M.A.; Nielsen, T.S.; Krarup, N.T.; et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 2014, 512, 190–193. [Google Scholar] [CrossRef] [PubMed]
- Purcell, S.; Cherny, S.S.; Sham, P.C. Genetic Power Calculator: Design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003, 19, 149–150. [Google Scholar] [CrossRef]
- Hong, E.P.; Park, J.W. Sample size and statistical power calculation in genetic association studies. Genom. Inform. 2012, 10, 117–122. [Google Scholar] [CrossRef]
- Abiusi, E.; Vaisfeld, A.; Fiori, S.; Novelli, A.; Spartano, S.; Faggiano, M.V.; Giovanniello, T.; Angeloni, A.; Vento, G.; Santoloci, R.; et al. Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: Towards specific guidelines and standard operating procedures for the molecular diagnosis. J. Med. Genet. 2023, 60, 697–705. [Google Scholar] [CrossRef]
- Li, H.; Handsaker, B.; Wysoker, A.; Fennell, T.; Ruan, J.; Homer, N.; Marth, G.; Abecasis, G.; Durbin, R.; 1000 Genome Project Data Processing Subgroup. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009, 25, 2078–2079. [Google Scholar] [CrossRef]
Inclusion Criteria | M # (%) | F # (%) | Total # (%) | Median Age Years (±IQR) | |
---|---|---|---|---|---|
Cases | Oxygen saturation: <94% on room air <90% with known chronic hypoxic conditions or Respiratory rate > 24/min | 333 (67.55) | 160 (32.45) | 493 (73) | 59.24 (11.45) |
Controls | Few or no signs/symptoms associated with COVID-19 or No relevant impairment in quality of life | 86 (42.47) | 100 (57.53) | 186 (27) | 52.55 (16.73) |
Gene | Allele # | Whole Population | Males | Females | M vs. F | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
# of Alleles | OR | CI | p | # of Alleles | OR | CI | p | # of Alleles | OR | CI | p | p | ||||||||
Cases (n = 970) | Ctrls (n = 284) | Low | Up | Cases (n = 654) | Ctrls (n = 172) | Low | Up | Cases (n = 316) | Ctrls (n = 198) | Low | Up | |||||||||
A | *24 | 151 | 42 | 1.44 | 1 | 2.07 | 0.05 | 104 | 15 | 1.98 | 3.5 | 1.12 | 0.02 | 47 | 27 | 1.11 | 1.84 | 0.66 | 0.8 | 1.00 |
B | *14 | 35 | 26 | 0.5 | 0.29 | 0.83 | 0.01 | 19 | 16 | 0.29 | 0.58 | 0.15 | 5*10-4 | 16 | 10 | 1 | 2.26 | 0.66 | 1 | 0.48 |
B | *55 | 17 | 14 | 0.45 | 0.22 | 0.93 | 0.03 | 10 | 6 | 0.43 | 1.2 | 0.15 | 0.18 | 7 | 8 | 0.54 | 1.51 | 0.19 | 0.35 | 0.25 |
C | *08 | 22 | 17 | 0.47 | 0.25 | 0.9 | 0.02 | 11 | 12 | 0.23 | 0.53 | 0.1 | 5*10-4 | 11 | 5 | 1.39 | 4.07 | 0.66 | 0.73 | 0.73 |
C | *12 | 120 | 51 | 0.87 | 0.61 | 1.23 | 0.43 | 92 | 21 | 1.18 | 1.95 | 0.71 | 0.61 | 28 | 30 | 0.54 | 0.94 | 0.66 | 0.04 | 0.20 |
C | *15 | 15 | 11 | 0.5 | 0.23 | 1.11 | 0.08 | 6 | 6 | 0.26 | 0.8 | 0.08 | 0.03 | 9 | 5 | 1.13 | 3.43 | 0.66 | 1 | 0.10 |
DPA1 | *01 | 636 | 221 | 1.28 | 1 | 1.64 | 0.05 | 423 | 108 | 1.09 | 1.54 | 0.77 | 0.71 | 213 | 113 | 1.56 | 2.24 | 0.66 | 0.02 | 0.75 |
DPA1 | *02 | 318 | 141 | 0.79 | 0.62 | 1.02 | 0.07 | 219 | 60 | 0.94 | 1.34 | 0.66 | 0.8 | 99 | 81 | 0.66 | 0.95 | 0.66 | 0.03 | 0.64 |
DPB1 | *17 | 23 | 13 | 0.67 | 0.33 | 1.33 | 0.25 | 18 | 3 | 1.59 | 5.48 | 0.46 | 0.63 | 5 | 10 | 0.3 | 0.9 | 0.66 | 0.05 | 0.68 |
DPB1 | *416 | 4 | 4 | 0.38 | 0.09 | 1.52 | 0.16 | 1 | 3 | 0.09 | 0.83 | 0.01 | 0.04 | 3 | 1 | 1.89 | 18.28 | 0.66 | 0.97 | 0.5 |
DQB1 | *05 | 229 | 108 | 0.75 | 0.57 | 0.98 | 0.04 | 148 | 51 | 0.69 | 1.01 | 0.48 | 0.07 | 81 | 57 | 0.85 | 1.27 | 0.57 | 0.49 | 0.26 |
DRB1 | *10 | 21 | 11 | 1.91 | 0.22 | 16.42 | 0.55 | 11 | 8 | 0.35 | 0.89 | 0.14 | 0.04 | 10 | 3 | 2.12 | 7.82 | 0.66 | 0.38 | 0.79 |
Gene | gDNA (chr6:) | dbSNP ID | cDNA | a.a. Change | Exon | Effect | OR | CI | p | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Low | Up | ||||||||||
Class I | |||||||||||
HLA-B | 31324086G>C | rs709054 | c.477C>G | p.Ala159= | 3 | R | 1.02 | 0.47 | 2.23 | 0.04 | |
31324145A>C | rs9266150 | c.418T>G | p.Tyr140Asp | 4 | R | 1.86 | 1.11 | 3.11 | 0.01 | ||
31324523T>C | rs1131214 | c.285A>G | p.Ala95= | 2 | P | 0.44 | 0.24 | 0.82 | 0.01 | ||
31324526CTG>GGA | n.a. | c.280CAG>TCC | p.Gln94Ser | 2 | P | 0.48 | 0.27 | 0.85 | 0.01 | ||
31324535GTA>CAT | n.a | c.271TAC>ATG | p.Tyr91Met | 2 | P | 0.5 | 0.29 | 0.88 | 0.02 | ||
31324539A>T | rs1131202 | c.269T>A | p.Ile90Thr | 2 | P | 0.44 | 0.24 | 0.82 | 0.01 | ||
31324542T>C | rs1131201 | c.266A>G | p.Gln89Arg | 2 | P | 0.42 | 0.23 | 0.77 | 0.01 | ||
HLA-C | 31237124T>C | rs1130838 | c.1087T>C | p.Thr363Ser | 7 | R | 3.62 | 1.05 | 1.77 | 0.02 | |
31237162C>G | rs35708511 | c.1049C>G | p.Cys350Ser | 7 | R | 1.36 | 1.03 | 1.76 | 0.03 | ||
31237773T>C | rs1130947 | c.985T>C | p.Thr329Ala | 5 | R | 1.85 | 1.44 | 2.37 | <10−4 | ||
31237774T>G | rs41540512 | c.984T>G | p.Val328= | 5 | R | 1.85 | 1.44 | 2.37 | <10−4 | ||
31237779C>T | rs146911342 | c.979C>T | p.Val327Leu | 5 | R | 1.85 | 1.52 | 1.1 | 0.02 | ||
31237858T>C | rs34794906 | c.900T>C | p.Pro300= | 5 | R | 1.41 | 1.06 | 1.9 | 0.02 | ||
31237987C>T | rs41556321 | c.895C>T | p.Glu299Ter | 4 | R | 1.48 | 1.05 | 2.09 | 0.02 | ||
31238009TT>CG | rs1131014 | c.872TT>CG | p.Gln291Pro | 4 | R | 1.31 | 1.03 | 1.66 | 0.02 | ||
31238027C>A | rs41540117 | c.855C>A | p.Met285Ile | 4 | R | 1.47 | 1.06 | 2.04 | 0.01 | ||
31238029T>C | rs2308622 | c.853T>C | p.Met285Leu | 4 | R | 1.28 | 1.01 | 1.62 | 0.04 | ||
31238138C>T | rs1050320 | c.744C>T | p.Gln248His | 4 | R | 1.34 | 1.01 | 1.77 | 0.03 | ||
31239449C>G | rs28626310 | c.270C>G | p.Lys90Asn | 2 | P | 0.62 | 0.47 | 0.82 | <10−4 | ||
31239501G>T | rs1050409 | c.218G>T | p.Ala73Glu | 2 | R | 1.34 | 1.00 | 1.81 | 0.05 | ||
HLA-F | 29694777G>A | rs17875384 | c.1153G>A | p.Arg385Gln | 7 | R | 3.62 | 1.28 | 10.25 | 0.01 | |
Class II | |||||||||||
HLA-DQA1 | 32609806C>T | rs707952 | c.388C>T | p.Thr130Ile | 3 | P | 0.72 | 0.52 | 0.99 | 0.04 | |
32609952T>C | rs707949 | c.534T>C | p.Phe179Leu | 3 | P | 0.69 | 0.49 | 0.96 | 0.02 | ||
32609969T>G | rs707963 | c.551T>G | p.Asp184Glu | 3 | P | 0.68 | 0.49 | 0.95 | 0.02 | ||
32609974T>G | rs707962 | c.556T>G | p.Ile186Ser | 3 | P | 0.66 | 0.47 | 0.92 | 0.01 | ||
HLA-DRB1 | 32551939GG>AT | rs16822512 | c.317CC>AT | p. Thr106Asn | 2 | P | 0.77 | 0.61 | 0.97 | 0.02 | |
32552092A>T | rs1059569 | c.174T>A | p.Phe55Tyr | 2 | R | 1.52 | 1.52 | 1.08 | 0.03 | ||
HLA-DRB5 | 32487256G>A | rs112401921 | c.543C>T | p.Asp181= | 3 | P | 0.48 | 0.25 | 0.94 | 0.03 |
Gene | gDNA Coordinates (dbSNP rsID) | Log Additive Model | Genotypic Frequencies | Allelic Frequencies | M vs. F | |||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Global | Males | Females | Global | Males | Females | |||||||||||||||||||||||||
OR | Low | Up | p | OR | Low | Up | p | OR | Low | Up | p | OR | Low | Up | P | OR | Low | Up | p | OR | Low | Up | p | OR | Lower | Upper | p | p | ||
HLA-B | 31324086G>C (rs709054) | 1 | 0.5 | 2.23 | 0.05 | 1.09 | 0.78 | 1.52 | 0.67 | 1.11 | 0.69 | 1.77 | 0.14 | 1.15 | 0.7 | 1.88 | 0.61 | 1.12 | 0.87 | 1.46 | 0.39 | 1.63 | 0.76 | 1.53 | 0.71 | 1.1 | 7.41 | 1.63 | 0.68 | 0.23 |
31324145A>C (rs9266150) | 1.9 | 1.1 | 3.11 | 0.01 | 1.8 | 1 | 3.1 | 0.04 | 2.2 | 1 | 4.8 | 0.05 | 1.5 | 0.59 | 3.82 | 0.48 | 2 | 1.6 | 3.41 | 0.01 | 1.84 | 0.93 | 3.67 | 0.10 | 1.68 | 0.68 | 4.13 | 0.29 | 0.07 | |
31324523T>C (rs1131214) | 0.4 | 0.2 | 0.82 | 0.01 | 0.5 | 0.2 | 0.9 | 0.02 | 0.62 | 0.26 | 1.47 | 0.22 | 0.2 | 0.1 | 0.73 | 0.01 | 0.4 | 0.2 | 0.8 | 0.01 | 0.56 | 0.25 | 1.26 | 0.16 | 0.2 | 0.1 | 0.75 | 0.01 | 0.73 | |
31324526CTG>GGA (n.a.) | 0.5 | 0.3 | 0.85 | 0.02 | 0.79 | 0.51 | 1.23 | 0.29 | 0.67 | 0.3 | 1.52 | 0.36 | 0.3 | 0.1 | 0.7 | 0.01 | 0.5 | 0.3 | 0.85 | 0.02 | 0.61 | 0.29 | 1.32 | 0.19 | 0.3 | 0.1 | 0.8 | 0.01 | 0.88 | |
31324535GTA>CAT (n.a) | 0.5 | 0.3 | 0.88 | 0.03 | 0.5 | 0.3 | 0.9 | 0.03 | 0.71 | 0.32 | 1.58 | 0.38 | 0.2 | 0.1 | 0.78 | 0.01 | 0.5 | 0.3 | 0.88 | 0.02 | 0.63 | 0.3 | 1.37 | 0.28 | 0.3 | 0.1 | 0.8 | 0.01 | 0.8 | |
31324539A>T (rs1131202) | 0.4 | 0.2 | 0.82 | 0.01 | 0.5 | 0.2 | 0.9 | 0.02 | 0.69 | 0.26 | 1.47 | 0.32 | 0.2 | 0.7 | 0.73 | 0.01 | 0.4 | 0.2 | 0.81 | 0.01 | 0.56 | 0.25 | 1.26 | 0.16 | 0.2 | 0.1 | 0.75 | 0.01 | 0.73 | |
31324542T>C (rs1131201) | 0.4 | 0.2 | 0.77 | 0.01 | 0.4 | 0.2 | 0.8 | 0.01 | 0.54 | 0.24 | 1.25 | 0.15 | 0.2 | 0.7 | 0.73 | 0.01 | 0.4 | 0.2 | 0.77 | 10-3 | 0.5 | 0.23 | 1.1 | 0.10 | 0.2 | 0.1 | 0.75 | 0.01 | 0.65 | |
HLA-C | 31237124T>C (rs1130838) | 1.4 | 1.1 | 1.77 | 0.02 | 2.9 | 1.6 | 5.3 | 10−3 | 2.9 | 1.3 | 6.3 | 0.01 | 2.23 | 0.82 | 6.05 | 0.12 | 1.4 | 1.1 | 1.79 | 0.02 | 1.6 | 1.2 | 2.3 | 6*10-3 | 1.1 | 0.75 | 1.63 | 0.69 | 0.43 |
31237162C>G (rs35708511) | 1.3 | 1 | 1.76 | 0.03 | 2.9 | 1.5 | 5.1 | 3*10-3 | 2.8 | 1.1 | 6.8 | 0.03 | 1.98 | 0.71 | 5.5 | 0.19 | 1.3 | 1 | 1.73 | 0.03 | 1.6 | 1.1 | 2.3 | 7*10-3 | 1.01 | 0.69 | 1.49 | 1 | 0.17 | |
31237773T>C (rs1130947) | 1.9 | 1.4 | 2.37 | <10−4 | 1.28 | 0.86 | 1.92 | 0.24 | 1.54 | 1 | 3.02 | 0.06 | 0.96 | 0.54 | 1.17 | 1 | 1.3 | 1 | 1.3 | 0.03 | 1.6 | 1.1 | 2.2 | 0.01 | 0.97 | 0.68 | 1.38 | 0.85 | 0.11 | |
31237774T>G (rs41540512) | 1.9 | 1.4 | 2.37 | <10−4 | 1.28 | 0.86 | 1.92 | 0.24 | 1.54 | 1 | 3.02 | 0.06 | 0.96 | 0.54 | 1.17 | 1 | 1.3 | 1 | 1.3 | 0.03 | 1.6 | 1.1 | 2.2 | 0.01 | 0.97 | 0.68 | 1.38 | 0.85 | 0.11 | |
31237779C>T (rs146911342) | 1.5 | 1.1 | 2.1 | 0.01 | 1.5 | 1.1 | 2.2 | 0.02 | 2.2 | 1.3 | 3.8 | 4*10-3 | 1.32 | 0.77 | 2.28 | 0.34 | 1.5 | 1.1 | 2.1 | 0.01 | 2 | 1.3 | 3.3 | 4*10-3 | 1.14 | 0.72 | 1.82 | 0.63 | 0.56 | |
31237858T>C (rs34794906) | 1.4 | 1.1 | 1.9 | 0.02 | 1.7 | 1.2 | 2.3 | 5*10-3 | 1.45 | 0.9 | 2.34 | 0.12 | 1.66 | 0.99 | 2.8 | 0.06 | 1.4 | 1.1 | 1.91 | 0.01 | 1.5 | 1 | 2.3 | 0.05 | 1.31 | 0.85 | 2.02 | 0.23 | 0.28 | |
31237987C>T (rs41556321) | 1.5 | 1.1 | 2.09 | 0.02 | 1.8 | 1.2 | 2.6 | 3*10-3 | 1.9 | 1.1 | 3.3 | 0.01 | 1.42 | 0.86 | 2.46 | 0.27 | 1.5 | 1.1 | 2.05 | 0.02 | 1.7 | 1.1 | 2.8 | 0.03 | 1.21 | 0.74 | 1.97 | 0.46 | 0.47 | |
31238009TT>CG (rs1131014) | 1.3 | 1 | 1.66 | 0.02 | 1.7 | 1.2 | 2.4 | 2*10-3 | 1.56 | 0.98 | 2.47 | 0.07 | 1.48 | 0.9 | 2.44 | 0.13 | 1.4 | 1.1 | 1.8 | 0.01 | 1.5 | 1.1 | 2.2 | 0.02 | 1.16 | 0.79 | 1.7 | 0.49 | 0.06 | |
31238027C>A (rs41540117) | 1.5 | 1.1 | 2.04 | 0.02 | 1.8 | 1.2 | 2.6 | 3*10-3 | 1.8 | 1.1 | 3.1 | 0.03 | 1.54 | 0.87 | 2.67 | 0.16 | 1.5 | 1.1 | 2.12 | 0.01 | 1.8 | 1.1 | 2.9 | 0.02 | 1.27 | 0.78 | 2.06 | 0.39 | 0.49 | |
31238029T>C (rs2308622) | 1.3 | 1 | 1.62 | 0.04 | 1.6 | 1.1 | 2.4 | 0.02 | 1.72 | 1 | 2.97 | 0.07 | 1.07 | 0.6 | 1.93 | 0.88 | 1.3 | 1 | 1.66 | 0.02 | 1.6 | 1.1 | 2.2 | 0.01 | 1.05 | 0.74 | 1.5 | 0.78 | 0.36 | |
31238138C>T (rs1050320) | 1.3 | 1 | 1.77 | 0.04 | 1.8 | 0.1 | 2.5 | 2*10-3 | 2.2 | 1.4 | 3.6 | 2*10-3 | 1.06 | 0.63 | 1.78 | 0.89 | 1.22 | 0.96 | 1.56 | 0.11 | 1.4 | 1 | 1.97 | 0.05 | 0.98 | 0.69 | 1.42 | 1 | 0.18 | |
31239449C>G (rs28626310) | 0.6 | 0.5 | 0.82 | <10−4 | 0.5 | 0.4 | 0.7 | <10−4 | 0.5 | 0.3 | 0.7 | 3*10-3 | 0.8 | 0.48 | 1.32 | 0.43 | 0.1 | 0.4 | 0.8 | 10-3 | 0.5 | 0.3 | 0.7 | <10−4 | 0.87 | 0.57 | 1.32 | 0.52 | 0.39 | |
HLA-F | 29694777G>A (rs17875384) | 3.6 | 1.3 | 10.3 | 0.01 | 1.88 | 0.81 | 4.33 | 0.14 | 2.81 | 0.64 | 12.28 | 0.18 | 5.1 | 1.1 | 23 | 0.02 | 3.6 | 1.3 | 10.2 | 0.01 | 2.9 | 0.67 | 12.53 | 0.19 | 4.9 | 1.1 | 21.9 | 0.02 | 0.62 |
HLA-DQA1 | 32609806C>T (rs707952) | 0.7 | 0.5 | 0.99 | 0.05 | 0.66 | 0.4 | 1.08 | 0.10 | 0.73 | 0.36 | 1.49 | 0.44 | 0.64 | 0.3 | 1.38 | 0.32 | 0.6 | 0.4 | 9.43 | 0.02 | 0.67 | 0.38 | 1.2 | 0.20 | 0.59 | 0.32 | 1.1 | 0.10 | 0.47 |
32609952T>C (rs707949) | 0.7 | 0.5 | 0.96 | 0.03 | 0.74 | 0.53 | 1.04 | 0.09 | 0.7 | 0.44 | 1.11 | 0.14 | 0.67 | 0.4 | 1.13 | 0.14 | 0.76 | 0.57 | 1.02 | 0.07 | 0.76 | 0.51 | 1.14 | 0.20 | 0.71 | 0.43 | 1.12 | 0.15 | 0.58 | |
32609969T>G (rs707963) | 0.7 | 0.5 | 0.95 | 0.02 | 0.74 | 0.52 | 1.03 | 0.08 | 0.74 | 0.46 | 1.18 | 0.22 | 0.62 | 0.37 | 1.04 | 0.08 | 0.76 | 0.56 | 1.01 | 0.06 | 0.8 | 0.53 | 1.19 | 0.28 | 0.67 | 0.43 | 1.06 | 0.10 | 0.71 | |
32609974T>G (rs707962) | 0.7 | 0.5 | 0.92 | 0.01 | 0.71 | 0.5 | 0.99 | 0.05 | 0.72 | 0.45 | 1.15 | 0.18 | 0.6 | 0.4 | 0.98 | 0.05 | 0.7 | 0.6 | 0.98 | 0.04 | 0.78 | 0.52 | 1.17 | 0.23 | 0.64 | 0.41 | 1.01 | 0.06 | 0.66 | |
HLA-DRB1 | 32551939GG>AT (rs16822512) | 0.8 | 0.6 | 0.97 | 0.03 | 0.83 | 0.59 | 1.15 | 0.27 | 0.6 | 0.4 | 1 | 0.05 | 0.89 | 0.54 | 1.47 | 0.70 | 0.8 | 0.6 | 0.97 | 0.03 | 0.72 | 0.51 | 1.02 | 0.66 | 0.75 | 0.51 | 1.11 | 0.16 | 0.59 |
32552092A>T (rs1059569) | 1.5 | 1.1 | 3.07 | 0.05 | 1.8 | 1.2 | 2.9 | 0.01 | 2.2 | 1.1 | 4.4 | 0.03 | 1.17 | 0.6 | 2.3 | 0.73 | 1.6 | 1 | 2.46 | 0.04 | 1.91 | 0.99 | 3.68 | 0.05 | 1.3 | 0.69 | 2.45 | 0.43 | 0.62 | |
HAL-DRB5 | 32487256G>A (rs112401921) | 0.5 | 0.3 | 0.94 | 0.03 | 0.4 | 0.2 | 0.9 | 0.05 | 0.2 | 0.6 | 0.1 | 6*10-3 | 0.84 | 0.22 | 3.21 | 1 | 0.4 | 0.2 | 0.87 | 0.02 | 0.3 | 0.1 | 0.6 | 4*10-3 | 0.95 | 0.3 | 3.03 | 1 | 0.40 |
HLA Gene | Haplotype ID # | Whole Population | Males | Females | M vs. F | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
# of Alleles | OR | CI | p | # of Alleles | OR | CI | p | # of Alleles | OR | CI | p | p | ||||||||
Cases n = 964 | Ctrls n = 396 | Low | Up | Cases n = 654 | Ctrls n = 186 | Low | Up | Cases n = 310 | Ctrls n = 210 | Low | Up | |||||||||
-B | 3 | 633 | 270 | 0.89 | 0.7 | 1.15 | 0.41 | 411 | 144 | 0.49 | 0.34 | 0.72 | 3*10-4 | 222 | 126 | 1.68 | 1.16 | 2.44 | 0.01 | 0.75 |
5 | 184 | 75 | 1.01 | 0.75 | 1.36 | 1 | 121 | 48 | 0.65 | 0.44 | 0.96 | 0.04 | 63 | 27 | 1.73 | 1.06 | 2.82 | 0.04 | 0.2 | |
9 | 23 | 1 | 9.65 | 1.3 | 71.74 | 0.01 | 11 | 1 | 3.16 | 0.41 | 24.67 | 0.42 | 12 | 0 | - | - | - | 0.01 | 0.23 | |
15 | 53 | 11 | 2.04 | 1.05 | 3.94 | 0.04 | 35 | 5 | 2.05 | 0.79 | 5.3 | 0.19 | 18 | 6 | 2.1 | 0.82 | 5.37 | 0.17 | 0.9 | |
-C | 4 | 114 | 73 | 0.59 | 0.43 | 0.82 | 2*10-3 | 80 | 40 | 0.51 | 0.33 | 0.77 | 2*10-3 | 34 | 33 | 0.66 | 0.39 | 1.11 | 0.15 | 0.47 |
8 | 66 | 23 | 1.19 | 0.73 | 1.95 | 0.56 | 42 | 17 | 0.68 | 0.38 | 1.23 | 0.26 | 24 | 6 | 2.85 | 1.15 | 7.11 | 0.03 | 0.36 | |
17 | 73 | 23 | 1.33 | 0.82 | 2.16 | 0.30 | 46 | 15 | 0.86 | 0.47 | 1.58 | 0.75 | 27 | 8 | 2.41 | 1.07 | 5.41 | 0.04 | 0.71 | |
19 | 2 | 4 | 0.2 | 0.04 | 1.12 | 0.11 | 1 | 4 | 0.07 | 0.01 | 0.63 | 0.01 | 1 | 0 | - | - | - | 1 | 0.28 | |
44 | 1 | 4 | 0.1 | 0.01 | 0.91 | 0.04 | 1 | 1 | 0.28 | 0.02 | 4.55 | 0.92 | 0 | 3 | - | - | - | 0.13 | 0.32 | |
-F | 1 | 34 | 4 | 3.58 | 1.26 | 10.16 | 0.01 | 20 | 2 | 2.9 | 0.67 | 12.53 | 0.22 | 14 | 2 | 4.92 | 1.11 | 21.87 | 0.04 | 0.74 |
-DQA1 | 1 | 784 | 299 | 1.41 | 1.07 | 1.87 | 0.02 | 503 | 158 | 0.59 | 0.38 | 0.92 | 0.02 | 281 | 141 | 4.74 | 2.94 | 7.65 | 4*10-11 | 0.27 |
2 | 111 | 56 | 0.79 | 0.56 | 1.12 | 0.21 | 74 | 35 | 0.55 | 0.35 | 0.85 | 0.01 | 37 | 21 | 1.22 | 0.69 | 2.15 | 0.59 | 0.32 | |
-DRB1 | 1 | 665 | 257 | 1.2 | 1.54 | 0.94 | 0.14 | 430 | 136 | 0.71 | 1.01 | 0.49 | 0.06 | 235 | 121 | 2.3 | 3.36 | 1.58 | 10-4 | 0.68 |
2 | 22 | 18 | 0.49 | 0.26 | 0.92 | 0.04 | 15 | 11 | 0.37 | 0.17 | 0.83 | 0.02 | 7 | 7 | 0.67 | 0.23 | 1.94 | 0.64 | 0.25 | |
3 | 193 | 112 | 0.63 | 0.48 | 0.83 | 10-3 | 117 | 62 | 0.44 | 0.3 | 0.63 | 10-5 | 76 | 50 | 1.04 | 0.69 | 1.57 | 0.94 | 0.21 | |
-DRB5 | 1 | 13 | 13 | 0.4 | 0.18 | 0.88 | 0.03 | 6 | 8 | 0.21 | 0.07 | 0.6 | 10-3 | 7 | 5 | 0.95 | 0.3 | 3.03 | 1 | 0.53 |
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Spartano, S.; Faggiano, M.V.; Guidi, G.; D’Ambrosio, P.; Vaisfeld, A.; Novelli, A.; Falqui, S.; Cingolani, A.; Lambertenghi, L.; Visentin, A.; et al. Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity. Int. J. Mol. Sci. 2024, 25, 13198. https://doi.org/10.3390/ijms252313198
Spartano S, Faggiano MV, Guidi G, D’Ambrosio P, Vaisfeld A, Novelli A, Falqui S, Cingolani A, Lambertenghi L, Visentin A, et al. Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity. International Journal of Molecular Sciences. 2024; 25(23):13198. https://doi.org/10.3390/ijms252313198
Chicago/Turabian StyleSpartano, Serena, Maria Vittoria Faggiano, Giovanna Guidi, Pino D’Ambrosio, Alessandro Vaisfeld, Agnese Novelli, Salvatore Falqui, Antonella Cingolani, Lorenza Lambertenghi, Alessandro Visentin, and et al. 2024. "Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity" International Journal of Molecular Sciences 25, no. 23: 13198. https://doi.org/10.3390/ijms252313198
APA StyleSpartano, S., Faggiano, M. V., Guidi, G., D’Ambrosio, P., Vaisfeld, A., Novelli, A., Falqui, S., Cingolani, A., Lambertenghi, L., Visentin, A., Azzini, A., Righi, E., Trecarichi, E. M., Mazzitelli, M., Coletti, S., Mous, J., Rademacher, T. W., Torti, C., Tacconelli, E., ... Tiziano, F. D. (2024). Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity. International Journal of Molecular Sciences, 25(23), 13198. https://doi.org/10.3390/ijms252313198