Abstract
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).
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic
SNP association analysis revealed several suggestive hits (p < 0.001), with the top signal in the PROC region and additional suggestive associations involving
We did find only an unexpected weak protective signal with the prothrombin variant (OR = 0.23, 95%confidence intervals (CI) = 0.070–0.75, p = 0.015; Table 3)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides intrinsic characteristics of the virus, the genetic makeup of the host likely accounts for the observed clinical heterogeneity of COVID-19 [5] In this frame, several genome-wide association studies (GWAS) and meta-analyses have shown that genetic predisposition plays a role in COVID-19 severity and susceptibility [6–11]. The first reported genome-wide association signals were at the 3p21.31 and 9q34.2 loci, respectively pointing to a cluster of genes (coding for proteins regulating bronchial physiology, viral entry, and immune response) and to the ABO blood group gene. These associations have been repeatedly replicated in subsequent studies, which evidenced the existence of at least 13 additional genome-wide significant associations with SARS-CoV-2 infection or COVID-19 severity [7–11]. The contribution of rare variants to COVID-19 just started to be elucidated: exome/genome sequencing in 659 patients with life-threatening COVID-19 pneumonia and 534 positive asymptomatics demonstrated that 3.5% of patients had genetic defects at 8 of the 13 loci involved in inborn errors of type I interferon (IFN) immunity [12]
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