| Contributors: |
Cappadona, C; Paraboschi, E; Ziliotto, N; Bottaro, S; Rimoldi, V; Gerussi, A; Azimonti, A; Brenna, D; Brunati, A; Cameroni, C; Campanaro, G; Carloni, F; Cavadini, G; Ciravegna, M; Composto, A; Converso, G; Corbella, P; D'Eugenio, D; Ri, G; Di Giorgio, S; Grondelli, M; Guerrera, L; Laffoucriere, G; Lando, B; Lopedote, L; Maizza, B; Marconi, E; Mariola, C; Matronola, G; Menga, L; Montorsi, G; Papatolo, A; Patti, R; Profeta, L; Rebasti, V; Smidili, A; Tarchi, S; Tartaglia, F; Tettamanzi, G; Tinelli, E; Stuani, R; Bolchini, C; Pattini, L; Invernizzi, P; Degenhardt, F; Franke, A; Duga, S; Asselta, R |
| Description: |
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement of hemostasis associated with thromboembolic events. To date, large-scale studies confirmed that genetic predisposition plays a role in COVID-19 severity, pinpointing several susceptibility genes, often characterized by immunologic functions. With these premises, we performed an association study of common variants in 32 hemostatic genes with COVID-19 severity. We investigated 49,845 single-nucleotide polymorphism in a cohort of 332 Italian severe COVID-19 patients and 1668 controls from the general population. The study was conducted engaging a class of students attending the second year of the MEDTEC school (a six-year program, held in collaboration between Humanitas University and the Politecnico of Milan, allowing students to gain an MD in Medicine and a Bachelor’s Degree in Biomedical Engineering). Thanks to their willingness to participate in the fight against the pandemic, we evidenced several suggestive hits (p < 0.001), involving the PROC, MTHFR, MTR, ADAMTS13, and THBS2 genes (top signal in PROC: chr2:127192625:G:A, OR = 2.23, 95%CI = 1.50–3.34, p = 8.77 × 10−5). The top signals in PROC, MTHFR, MTR, ADAMTS13 were instrumental for the construction of a polygenic risk score, whose distribution was significantly different between cases and controls (p = 1.62 × 10−8 for difference in median levels). Finally, a meta-analysis performed using data from the Regeneron database confirmed the contribution of the MTHFR variant chr1:11753033:G:A to the predisposition to severe COVID-19 (pooled OR = 1.21, 95%CI = 1.09–1.33, p = 4.34 × 10−14 in the weighted analysis). |