Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
- Medical Genetics, University of Siena, Italy
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy
- Department of Mathematics, University of Pavia, Italy
- University of Siena, DIISM-SAILAB, Italy
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Italy
- Infectious Diseases Clinic, "Santa Maria" Hospital, University of Perugia, Italy
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Italy
- Chirurgia Vascolare, Ospedale Maggiore di Crema, Italy
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Italy
- III Infectious Diseases Unit, ASST-FBF-Sacco, Italy
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Italy
- Molecular Mechanisms of Oncogenesis, ISPRO Core Research Laboratory (CRL), Italy
Figures
Figure 1
Rare TLR7 variants and association with COVID-19.
LASSO logistic regression on boolean representation of rare variants of all genes of the X chromosome is presented. TLR7 is picked up by LASSO logistic regression as one of the most important genes …
Figure 2
Gene expression profile analysis in peripheral blood mononuclear cells (PBMCs) and in HEK293 cells transfected with the functional variants after stimulation with a TLR7 agonist for 4 hr.
(A) 5 × 105 PBMCs from COVID-19 patients and six unaffected male and female controls were stimulated for 4 hr with the TLR7 agonist imiquimod at 5 μg/mL or cell culture medium. Quantitative PCR …
Figure 3
Segregation analysis.
Fold change in mRNA expression following Imiquimod stimulation of TLR7 itself and its main effectors, IRF7, ISG15, IFN-alpha, and IFN-gamma is shown in Panel A. Gray columns represent individuals …
Tables
Table 1
Fisher exact test of the overall combined cohorts in young males (<60 years).
| Clinical category | N. wild-type variants (97.84%) | N. pathological variants (2.15%) | Total |
|---|---|---|---|
| Severely affected males | 129 | 6 | 135 |
| Asymptomatic males | 104 | 0 | 104 |
| Total | 233 | 6 | 239 (Grand Total) |
-
p-value=0.0037.
Table 2
TLR7 variants in severely affected Italian males -all ages- (cases).
| Nucleotide change | Amino acid change | dbSNP | CADD | ExAC_ NFE | Function* | N. of patients | Clinical category† | Age | Cohort | Patient ID |
|---|---|---|---|---|---|---|---|---|---|---|
| c.901T>C | Ser301Pro | - | 26.4 | N/A | LOF | 1 | 3 | 46 | Italian | P3 |
| c.2759G>A | Arg920Lys | rs189681811 | 16.52 | 0.0002 | LOF‡ | 1 | 4 | 49 | Italian | P6 |
| c.3094G>A | Ala1032Thr | rs147244662 | 22.3 | 0.0006 | LOF | 2 | 3 | 65/66 | Italian | P7/P8 |
| c.655G>A | Val219Ile | rs149314023 | 12.28 | 0.0003 | HYPO | 1 | 4 | 32 | Italian | P1 |
| c.863C>T | Ala288Val | rs200146658 | 15.37 | 0.000012 | Neutral | 1 | 3 | 57 | Italian | P2 |
| c.1343C>T | Ala448Val | rs5743781 | 13.08 | 0.00465 | Neutral | 2 | 3 | 53/58 | Italian | P4/P5 |
-
CADD, Combined Annotation Dependent Depletion; ExAC, Exome Aggregation Consortium; NFE, Non-Finnish European;
*Function: HYPO, hypomorphic; LOF, loss-of-function;
-
†Clinical category: 4, Hospitalized and intubated; 3, Hospitalized and CPAP-BiPAP and high-flows oxygen treated; 2, Hospitalized and treated with conventional oxygen support only; 1, Hospitalized without respiratory support; 0, Not hospitalized oligo/asymptomatic individuals.
‡based on in silico prediction.
Additional files
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Reporting standard 1
STROBE checklist.
- https://cdn.elifesciences.org/articles/67569/elife-67569-repstand1-v2.docx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/67569/elife-67569-transrepform-v2.pdf
