MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Cohorts for Genetic Analyses
2.2. Imputation
2.3. SNP Selection
2.4. Statistical Analysis
2.5. Polygenic Risk Score (PRS)
2.6. Meta-Analysis
2.7. Role of MEDTEC Students
3. Results
3.1. Hemostatic Gene Variants and the Predisposition to COVID-19 Severity
3.2. Set up of a Poligenic Risk Score Based on Hemostatic Gene Variants
3.3. Meta-Analysis Confirms the Involvement of MTHFR in Severe COVID-19 Predisposition
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Chr | Gene | Protein | Gene Size (kb) | Analyzed Region (kb) | Coordinates of the Analyzed Region (hg38) | Analyzed SNPs (n) |
---|---|---|---|---|---|---|
1 | MTHFR | MTHR | 20.3 | 520.3 | 1:11535729-12056103 | 1821 |
1 | F5 | FA5 (FV) | 74.5 | 574.5 | 1:169261953-169836531 | 2276 |
1 | F13B | F13B (FXIII) | 28.0 | 528 | 1:196789190-197317267 | 956 |
1 | MTR | METH | 108.7 | 608.7 | 1:236545280-237153981 | 2270 |
2 | TFPI | TFPI | 90.2 | 590.2 | 2:187214230-187804492 | 1655 |
2 | PROC | PROC | 10.8 | 510.8 | 2:127168419-127679246 | 1492 |
3 | PROS1 | PROS | 101.0 | 601 | 3:93623036-94224090 | 592 |
4 | FGB | FIBB | 49.7 | 549.7 | 4:154312979-154862750 | 1606 |
4 | FGA | |||||
4 | FGG | |||||
4 | F11 | FA11 (FXI) | 23.7 | 523.7 | 4:186015963-186539681 | 2251 |
5 | ITGA2 | ITA2 (GPIa) | 105.4 | 605.4 | 5:52739325-53344779 | 2469 |
5 | THBS4 | TSP4 | 47.9 | 547.9 | 5:79785348-80333284 | 2047 |
5 | F12 | FA12 (FXII) | 7.4 | 507.4 | 5:177152137-177659576 | 890 |
6 | F13A1 | F13A (FXIII) | 176.6 | 676.6 | 6:5894077-6570691 | 2895 |
6 | THBS2 | TSP2 | 38.3 | 538.3 | 6:168965779-169504114 | 2080 |
7 | CD36 | CD36 (GPIIIb) | 304.8 | 804.8 | 7:80119575-80924418 | 2110 |
7 | SERPINE1 | PAI-1 | 12.1 | 512.1 | 7:100877088-101389266 | 1929 |
8 | PLAT | TPA | 32.9 | 532.9 | 8:41924717-42457676 | 927 |
9 | ADAMTS13 | ATS13 (ADAMTS13) | 37.4 | 537.4 | 9:133171999-133709403 | 2195 |
11 | F2 | THRB | 20.3 | 520.3 | 11:46469192-46989506 | 697 |
12 | VWF | VWF | 175.7 | 675.7 | 12:5698873-6374670 | 2122 |
13 | CPB2 | CBPB2 (TAFI) | 51.8 | 551.8 | 13:45803186-46355076 | 1811 |
13 | F7 | FA7 (FVII) | 14.8 | 514.8 | 13:112855787-113370681 | 1411 |
13 | F10 | FA10 (FX) | 26.7 | 526.7 | 13:112872798-113399529 | 1540 |
15 | THBS1 | TSP1 | 17.8 | 517.8 | 15:39331078-39848921 | 1443 |
17 | GPIBA | GPIBA | 2.7 | 502.7 | 17:4682274-5185030 | 1502 |
17 | ITGB3 | ITB3 (GPIIIa) | 58.8 | 558.8 | 17:47003841-47562711 | 1695 |
18 | LMAN1 | LMAN1 | 31.4 | 531.4 | 18:59077823-59609276 | 2327 |
20 | THBD | TRBM | 4.0 | 504 | 20:22795632-23299664 | 1488 |
X | F8 | FA8 (FVIII) | 186.9 | 686.9 | 23:154585788-155272723 | 570 |
X | F9 | FA9 (FIX) | 32.7 | 532.7 | 23:139280735-139813458 | 778 |
Total | 32 genes | - | 1893 | 16,893 | - | 49,845 |
(a) | |||||||||
---|---|---|---|---|---|---|---|---|---|
Uncorrected Analyses | Corrected Analyses | ||||||||
Chr | Gene | SNP | MAF Cases | MAF Controls | p Value | OR (95%CI) | p Value | OR (95%CI) | |
2 | PROC | chr2:127192625:G:A | 0.065 | 0.037 | 8.51 × 10−4 | 1.82 (1.28–2.61) | 8.77 × 10−5 | 2.23 (1.50–3.34) | |
1 | MTHFR | chr1:11753033:G:A | 0.247 | 0.183 | 1.33 × 10−4 | 1.47 (1.20–1.79) | 1.08 × 10−4 | 1.56 (1.25–1.95) | |
1 | MTR | chr1:237145686:A:G | 0.023 | 0.010 | 4.53 × 10−3 | 2.39 (1.29–4.43) | 3.14 × 10−4 | 3.49 (1.77–6.88) | |
9 | ADAMTS13 | chr9:133179750:G:C | 0.030 | 0.011 | 1.58 × 10−4 | 2.77 (1.60–4.80) | 4.26 × 10−4 | 2.90 (1.60–5.24) | |
6 | THBS2 | chr6:169195156:A:T | 0.039 | 0.021 | 6.25 × 10−3 | 1.87 (1.19–2.96) | 7.84 × 10−4 | 2.35 (1.43–3.87) | |
17 | ITGB3 | chr17:47019591:G:C | 0.321 | 0.270 | 7.05 × 10−3 | 1.28 (1.07–1.53) | 1.41 × 10−3 | 1.39 (1.14–1.71) | |
7 | SERPINE1 | chr7:101070945:A:G | 0.324 | 0.267 | 2.55 × 10−3 | 1.32 (1.10–1.58) | 1.73 × 10−3 | 1.38 (1.13–1.69) | |
6 | F13A1 | chr6:6163858:G:C | 0.108 | 0.070 | 6.99 × 10−4 | 1.61 (1.22–2.13) | 1.80 × 10−3 | 1.67 (1.21–2.31) | |
18 | LMAN1 | chr18:59208206:A:G | 0.401 | 0.337 | 1.57 × 10−3 | 1.32 (1.11–1.56) | 1.81 × 10−3 | 1.36 (1.12–1.65) | |
4 | F11 | chr4:186056516:A:G | 0.065 | 0.106 | 1.31 × 10−3 | 0.59 (0.42–0.82) | 1.84 × 10−3 | 0.56 (0.39–0.81) | |
7 | CD36 | chr7:80591832:AAATCAGC:A | 0.039 | 0.021 | 6.25 × 10−3 | 1.87 (1.19–2.96) | 1.98 × 10−3 | 2.15 (1.33–3.50) | |
15 | THBS1 | chr15:39455553:G:C | 0.178 | 0.133 | 2.17 × 10−3 | 1.42 (1.13–1.77) | 2.50 × 10−3 | 1.46 (1.14–1.86) | |
12 | VWF | chr12:6068637:T:C | 0.054 | 0.031 | 3.71 × 10−3 | 1.76 (1.20–2.60) | 2.50 × 10−3 | 1.95 (1.27–3.01) | |
13 | F7–F10 | chr13:113257337:C:T | 0.288 | 0.234 | 3.50 × 10−3 | 1.32 (1.10–1.59) | 3.13 × 10−3 | 1.37 (1.11–1.69) | |
20 | THBD | chr20:22949512:A:G | 0.048 | 0.025 | 1.51 × 10−3 | 1.94 (1.28–2.93) | 3.18 × 10−3 | 2.01 (1.26–3.19) | |
4 | FG_genes | chr4:154774926:G:A | 0.054 | 0.033 | 8.81 × 10−3 | 1.67 (1.13–2.45) | 4.45 × 10−3 | 1.88 (1.22–2.91) | |
1 | F13B | chr1:196913749:A:AT | 0.036 | 0.017 | 1.84 × 10−3 | 2.12 (1.31–3.44) | 5.04 × 10−3 | 2.12 (1.25–3.59) | |
13 | CPB2 | chr13:45931697:A:G | 0.008 | 0.026 | 3.59 × 10−3 | 0.28 (0.12–0.70) | 5.29 × 10−3 | 0.18 (0.056–0.61) | |
8 | PLAT | chr8:42278531:C:T | 0.017 | 0.007 | 1.79 × 10−2 | 2.33 (1.13–4.77) | 5.69 × 10−3 | 2.88 (1.36–6.08) | |
5 | ITGA2 | chr5:53162220:CAGAG:C | 0.029 | 0.013 | 4.56 × 10−3 | 2.15 (1.25–3.71) | 7.60 × 10−3 | 2.30 (1.25–4.23) | |
2 | TFPI | chr2:187303697:A:G | 0.030 | 0.013 | 1.13 × 10−3 | 2.38 (1.39–4.07) | 8.74 × 10−3 | 2.25 (1.23–4.14) | |
1 | F5 | chr1:169677905:G:A | 0.116 | 0.151 | 1.90 × 10−2 | 0.74 (0.57–0.95) | 9.74 × 10−3 | 0.68 (0.51–0.91) | |
5 | THBS4 | chr5:80174425:G:T | 0.203 | 0.163 | 1.23 × 10−2 | 1.31 (1.06–1.61) | 9.83 × 10−3 | 1.37 (1.08–1.73) | |
3 | PROS1 | chr3:94043799:A:C | 0.032 | 0.014 | 1.84 × 10−3 | 2.24 (1.33–3.76) | 1.19 × 10−2 | 2.10 (1.18–3.74) | |
11 | F2 | chr11:46517560:T:C | 0.331 | 0.382 | 1.39 × 10−2 | 0.80 (0.63–0.96) | 1.19 × 10−2 | 0.77 (0.63–0.95) | |
17 | GP1BA | chr17:4921551:T:C | 0.020 | 0.010 | 2.59 × 10−2 | 2.06 (1.08–3.95) | 1.31 × 10−2 | 2.50 (1.21–5.15) | |
5 | F12 | chr5:177464930:A:G | 0.026 | 0.013 | 1.71 × 10−2 | 1.97 (1.12–3.46) | 1.38 × 10−2 | 2.17 (1.17–4.03) | |
(b) | |||||||||
Chr | Gene | SNP | pValue_M | OR (95%CI)_M | pValue_F | OR (95%CI)_F | P_Comb_Stouffer | ||
X | F9 | chrX:139407485:G:C | 8.5 × 10−4 | 1.27 (0.96–1.68) | 0.49 | 0.91 (0.63–1.31) | 0.0046 |
Corrected Analyses | ||||||
---|---|---|---|---|---|---|
Chr | Gene | SNP | SNP ID | Minor Allele | p Value | OR (95%CI) |
1 | F5 | chr1:169549811:C:T | rs6025 | T | 0.92 | 0.96 (0.48–1.94) |
6 | F13A1 | chr6:6318562:C:A | rs5985 | A | 0.91 | 0.99 (0.78–1.24) |
11 | F2 | chr11:46739505:G:A | rs1799963 | A | 0.015 | 0.23 (0.070–0.75) |
Italians (Our Cohort) | Regeneron Cohort | Meta-Analysis | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Gene | SNP | Analysed Individuals (n) | p Value | OR (95%CI) | Analysed Individuals (n) | p Value | OR (95%CI) | Pooled OR (95%CI) | p Value (M-H) | p Value (F Weighted) |
PROC | chr2:127192625:G:A | 2000 | 8.51 × 10−4 | 1.82 (1.28–2.61) | 429151 | 0.026 | 0.71 (0.53–0.96) | 0.98 (0.79–1.22) | 0.87 | 0.12 |
MTHFR | chr1:11753033:G:A | 2000 | 1.33 × 10−4 | 1.47 (1.20–1.79) | 654056 | 0.030 | 1.13 (1.01–1.28) | 1.21 (1.09–1.33) | 2.55 × 10−4 | 4.34 × 10−14 |
MTR | chr1:237145686:A:G | 2000 | 4.53 × 10−3 | 2.39 (1.29–4.43) | 898324 | 0.98 | 1.00 (0.88–1.14) | 1.03 (0.91–1.18) | 0.61 | 0.0027 |
ADAMTS13 | chr9:133179750:G:C | 2000 | 1.58 × 10−4 | 2.77 (1.60–4.80) | 656078 | 0.030 | 0.75 (0.58–0.97) | 0.89 (0.72–1.11) | 0.33 | 0.056 |
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Cappadona, C.; Paraboschi, E.M.; Ziliotto, N.; Bottaro, S.; Rimoldi, V.; Gerussi, A.; Azimonti, A.; Brenna, D.; Brunati, A.; Cameroni, C.; et al. MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity. J. Pers. Med. 2021, 11, 1166. https://doi.org/10.3390/jpm11111166
Cappadona C, Paraboschi EM, Ziliotto N, Bottaro S, Rimoldi V, Gerussi A, Azimonti A, Brenna D, Brunati A, Cameroni C, et al. MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity. Journal of Personalized Medicine. 2021; 11(11):1166. https://doi.org/10.3390/jpm11111166
Chicago/Turabian StyleCappadona, Claudio, Elvezia Maria Paraboschi, Nicole Ziliotto, Sandro Bottaro, Valeria Rimoldi, Alessio Gerussi, Andrea Azimonti, Daniele Brenna, Andrea Brunati, Charlotte Cameroni, and et al. 2021. "MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity" Journal of Personalized Medicine 11, no. 11: 1166. https://doi.org/10.3390/jpm11111166