The effect of hereditary thrombotic factors and comorbidities on the severity of COVID-19 disease.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide and presents critical challenges for public health. Due to its chronic and systemic course, COVID-19 is currently accepted as a multi-systemic infectious disease. Here we explore the possible association between disease course and hereditary thrombotic factors and comorbidities. PATIENTS AND METHODS: The patients admitted to the COVID-19 center in the Istanbul Faculty of Medicine were recruited for the study. The patients were classified according to the clinical course, severe vs. mild. Five polymorphic loci were analyzed by multiplex PCR: Factor V Leiden (FVL), FII G20210A, Beta-fibrinogen G-455A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C. RESULTS: FII G20210A and Beta-fibrinogen G-455A genotypes were significantly higher in the study group compared to the literature. Wildtype genotype (GG) in Factor V Leiden locus was significantly associated with low D-Dimer levels (p =0.013). The GA genotype increased the D-Dimer levels 2.55-times compared to the GG genotype (p =0.003). Moreover, the Beta-fibrinogen G-455G genotype was significantly higher in the LDH>250 group (p =0.046). CONCLUSIONS: The presence of solid tumors in patients with COVID-19 was related to the severity of the disease course. No evidence of a correlation between the severity of the disease and all five thrombotic mutations was found, whereas the FII G20210A and Beta-fibrinogen G-455A mutations were significantly high compared to previously reported Turkish population data and global carrier rates. This finding will need to be verified by further studies with larger samples since it may reflect a likelihood of having the COVID-19 disease. The high carrier frequency of FVL mutation was more likely present in the D-dimer high group generating an increase in the D-dimer levels 2.55-times compared to the wildtype.

Integrative analyses of genes about venous thromboembolism: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND: In recent years, many studies have found possible links between gene polymorphisms and venous thromboembolism (VTE). By identifying genetic risk factors before facing environmental risk factors such as surgical interventions and COVID-19 vaccination, we could rapidly respond to the risk of VTE. The aim of this study was to perform an umbrella review of genetic variants related to VTE. Integrative gene analysis of VTE was performed to identify critical genetic variations. METHODS: This study conducted an umbrella review of systematic reviews and meta-analyses. All included studies were selected from the PubMed/MEDLINE database. To select eligible studies, the following variables were extracted: first author name; effect size of each study genetic variant; year of publication; the number of studies included in each article; ethnicity, sample size, P values, and heterogeneity estimates. To assess cumulative evidence in genetic epidemiology about effects of gene polymorphisms on VTE, Human Genome Epidemiology Network's Venice criteria were used. Methodological quality assessment was conducted with JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. RESULTS: Genes provided in the present study with genetic variants associated with VTE were FVL (G1691A), Prothrombin (G20210A), MTHFR (C677T, A1298C), PAI-1 (4G/5G), factor VII activating protease (1601G > A), and endothelial protein C receptor (g.6936A_G, c.4600A_G). Among them, variants in FVL, Prothrombin, MTHFR, and PAI-1 showed high significance. Particularly, variants in Prothrombin (G20210A), MTHFR (C677T), and PAI-1 (4G/5G) had more than 2 types of model significance. CONCLUSION: The present study performed a systematic review of genetic variants associated with VTE. Our results could lead to a more comprehensive understanding of VTE etiology. These results could give a strategy of prediagnosis about evaluating individual risks of VTE who might be exposed to environmental risk factors.

COVID-19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence.

BACKGROUND: Homocysteine assessment has been proposed as a potential predictive biomarker for the severity of COVID-19 infection. The purpose of this review was to analyze the correlation between the prevalence of MTHFR C677 T gene polymorphism and COVID-19 incidence and mortality worldwide. METHODS: Data regarding MTHFR C677 T gene mutation were obtained from the interrogation of the Genome Aggregation Database (genomAD), which is publicly available from the web"https://gnomad.broadinstitute.org." COVID-19 cases, including prevalence and mortality, were obtained from"https://www.worldometers.info/coronavirus" 27 August 2020. RESULTS: There is a clear trend toward the worldwide prevalence of MTHFR 677 T and COVID-19 incidence and mortality. The prevalence of MTHFR 677 T allele in the Latino population, and the incidence and mortality for COVID-19 was higher for this ethnic group than that reported for most other populations globally. Statistical analysis showed a relatively strong correlation between C677 T and death from coronavirus. CONCLUSIONS: Genetic polymorphism of MTHFR C677 T may modulate the incidence and severity of COVID-19 pandemic infection.

Folic acid as placebo in controlled clinical trials of hydroxychloroquine prophylaxis in COVID-19: Is it scientifically justifiable?

Using folic acid (FA) as placebo complicates the interpretation of the findings of few RCTs evaluating safety and efficacy of hydroxychloroquine prophylaxis in COVID-19. FA is found to bind to furin-protease and spike: ACE2 interface of SARS-CoV-2. In clinical studies, FA level was lowest among severe patients compared to mild and moderate disease. A single controlled study reported the benefit of combination of folic acid with Pyridoxine & cyanocobalamin in terms of clinical and laboratory cure parameters. One hypothesis associates the differences in geographical variation of disease severity with prevalence of methyl tertahydrofolic acid reductase (MTHFR) C677T polymorphism. Other possible domains, where FA is hypothesized to be beneficial are COVID-19 associated pulmonary hypertension and hyper-homocystinemia. So, scientific justification of using folic acid as placebo in COVID-19 trials seems scientifically not credible and this may be one of the major factors for failure of many agents. We need to be more careful in choosing our placebo especially when conducting a placebo controlled trial.

Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia?

As the current COVID-19 pandemic develops and epidemiological data reveals differences in geographical spread as well as risk factors for developing a severe course of illness, hypotheses regarding possible underlying mechanisms need to be developed and tested. In our hypothesis, we explore the rational for a role of MTHFR polymorphism C677T as a possible explanation for differences in geographical and gender distribution in disease severity. We also discuss the role of the resulting hyper-homocysteinemia, its interaction with the C677T polymorphism and its influence on immune state as well as risk factors for severe disease. Finally, we consider possible dietary ways to influence the underlying pathomechanisms prophylactically and supportively.