key: cord-0996967-wgpty5w3
authors: Ponti, Giovanni; Pastorino, Lorenza; Manfredini, Marco; Ozben, Tomris; Oliva, Gabriella; Kaleci, Shaniko; Iannella, Raffaele; Tomasi, Aldo
title: COVID‐19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence
date: 2021-06-01
journal: J Clin Lab Anal
DOI: 10.1002/jcla.23798
sha: 2916395a8b17fd881ef4bf168e310f6ab1724df5
doc_id: 996967
cord_uid: wgpty5w3

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.

At present, there are over 119 million confirmed COVID-19 cases with 2.6 million deaths. Looking at the worldwide epidemiologic data, there are remarkable differences among countries regarding COVID-19 infection rates and mortality, especially comparing very high data relative to the United States of America or South America and sub-Saharan Africa or Finland, where incidence and mortality appear remarkably low (WHO Coronavirus Disease (COVID- 19) Dashboard https://covid 19.who.int/). This simple epidemiological observation represents the base for searching genetic differences among populations or ethnicities, which may explain different clinical manifestations of COVID-19 infection). 1 In addition to serological and clinical biomarkers that are clearly correlated with a severe clinical course of COVID-19 infection, 1,2 the role of Hcy as an important prognostic marker has been recently hypothesized. 3, 4 The role of Hcy in several metabolic and inflammatory processes has already been demonstrated, and different populations with different ethnical predominances show different prevalences for MTHFR gene mutations and MTHFR activities. 5 The population frequency of C677 T homozygosity ranges from 1% or less among Blacks from Africa and the Finnish population to 20% or more among Latino and US Hispanics. Intriguingly, the world distribution of MTHFR 677 T polymorphism has a high degree of heterogeneity following a geographical gradient of south-north and west-east both in Europe and Americas. [6] [7] [8] Homocysteine has been under a lot of speculation since its discovery in 1932. 9 It is known that a high plasma level of homocysteine significantly increases the incidence of vascular damage in both small and large vessels. 9,10 Hyperhomocysteinemia has neurotoxic, neuroinflammatory, neurodegenerative, proatherogenic, prothrombotic, and prooxidative effects. 11 Homocysteine concentrations above the 90 th percentile are associated with increased risk of degenerative and atherosclerotic processes 12 in the coronary, cerebral and peripheral circulatory system. In this regard, determining homocysteine together with other cardiovascular risk markers (Apo B, Lp (a), LDL, fibrinogen, PAI-1) now is implemented in the clinical practice; 13 moreover, recent evidence suggests the role of homocysteine as a risk factor for thromboembolism, given its effect on platelet reactivity. 14 Homocysteine has been found to be a predictor of disease progression in 273 patients with mild COVID-19 disease in Shanghai: 72 of the patients showed disease progression as assessed by lung CT scan. More than 40 parameters were measured in these 273 patients at admission of which only age, homocysteine and monocyte-tolymphocyte ratio (MLR) were found as significant predictors of disease progression as shown by CT changes in the lung. Patients with hyperhomocysteinemia (>15.4 µmol/L) had a threefold increased risk of CT changes progression. Of the three predictor markers, only homocysteine is readily modifiable. Very recent data witnessed a predictive value of Hcy (together with age, MLR, and period from disease onset to hospital admission) for severe pneumonia on chest CT at first week from COVID-19 patients, but did not report additional organ involvement. 4 To our knowledge, till today, no evidences have been published about the MTHFR gene polymorphisms that are implicated in a defective Hcy metabolism and COVID-19 disease. The purpose of our research was to illustrate the relationship between the prevalence of the genetic polymorphism of MTHFR C677 T and COVID-19 incidence and mortality rates, demonstrating that COVID-19 incidence and mortality rates are strongly correlated to the majority of MTHFR C677 T mutation, which is linked explicitly to prothrombotic events due to altered homocysteine metabolism.

Data regarding MTHFR status, 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.broad insti tute.org." COVID-19 cases, including prevalence and mortality, were obtained from"https:// www.world omete rs.info/coron avirus" 27 August 2020, before that We speak of a positive correlation between two variables if when the first variable increases, the second also increases accordingly.

The P-value is the probability that the current result to be found if the correlation coefficient were, in fact, zero (null hypothesis). The correlation coefficient is defined as statistically significant if this probability is lower than the conventional 5% (p <0.05).

were analyzed using Pearson's correlation method. All statistical tests were performed at a significance level (α) of 0.05.

The analysis examined their associations for the allele frequency with cases of coronavirus COVID-19 death and incidence for the polymorphism. Subgroup analyses were stratified by ethnicity. Officially reported COVID-19 cases and the number of COVID-19-related deaths were stratified according to the ethnic groups (Table 1) .

A correlation between MTHFR 677 T prevalence and COVID-19 incidence and mortality rates can be observed if data were strat- The correlation between the allele frequency and coronavirus mortality was found very high (85%).

The relationship between the prevalence of the genetic polymorphism of MTHFR C677 T and COVID-19 incidence and mortality rates seem to be intriguing. It may be a useful biomarker to stratify The population frequency of the C677 T allele showed regional and ethnic variations ( Table 1 , Figures 1-4) . For example, the allele frequency was high in Italy and among Hispanics living in California and was low among US Blacks and in some areas of sub-Saharan Africa. The frequency of C677 T homozygosity showed similar variability. 24 Amongst the European, the homozygous allele was found highest in the Italians and lowest in the Germans. [25] [26] [27] The prevalence of the homozygous TT genotype was 10-12% in Europe's several areas (for example, Spain, France, and Hungary). In Britain, the percentage of homozygosity in the population was approximately 13%. However, the prevalence appeared to be lower (4% and 6%, respectively) in Finland, Helsinki, and the northern Netherlands.

In contrast, in some southern European areas, it was much higher (26% and 20% in Campania and Sicily, respectively). In the Americas, 

Genetic polymorphism of MTHFR C677 T may modulate the risk of COVID-19 incidence and severity.

Population data on correlation between the C677 T variant and COVID-19 incidence and mortality would be very useful in regional and national management strategy and might help the population and public health geneticists to assess the potential impact of preventive measures based on environmental modifications. Some adverse biochemical effects of the thermolabile enzyme coded by the T allele, such as the increase in total plasma homocysteine, appear to be reversible by increasing the consumption of the vitamin B and folic acid.

The data presented in this study are available on request from the corresponding author.

https://orcid.org/0000-0002-1971-7306

Marco Manfredini https://orcid.org/0000-0003-3601-655X

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