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The Egyptian Journal of Bronchology
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Incidence of thrombophilic gene polymorphism (MTHFR C677T) in Egyptian COVID-19 patients and its clinical implications

The Egyptian Journal of Bronchology volume 17, Article number: 72 (2023) Cite this article

Abstract

Background

COVID-19 has an important component of organ damage which is COVID-19-associated coagulopathy. It is necessary to assess the risk in patients to develop a thrombophylaxis plan. The higher prevalence of key thrombophilic genetic variants, such as mutation of the C677T-methylenetetrahydrofolate reductase (MTHFR) gene in Eastern Mediterranean countries, makes it challenging to use the same criteria in other world countries with differing thrombophilic panels.

Objective

To find the incidence of MTHFR gene polymorphism in a cohort of Egyptian patients with COVID-19, and its association with thromboembolic events.

Subjects and methods

This was a prospective observational cohort study, done at Ain-Shams University isolation Hospitals, Cairo, Egypt. It included 33 patients with COVID-19 and 13 healthy controls. The patients underwent lab investigations: HRCT chest in which the extent of radiological affection was described in terms of severe form (> 50% of lungs are affected) and non-severe form (< 50% of lungs are affected) and assessment of MTHFR-C677T genotypes. Then follow-up for 28 days for vascular thrombotic manifestations.

Results

Out of 33 patients, MTHFR-gene mutation was found in 10 (incidence rate 30.3%). Severe form of affection in the HRCT chest was significantly related to mutation of the MTHFR gene (P value = 0.009). Patient cure and discharge were significantly related to the absence of mutation of MTHFR-gene (P value = 0.025), whereas death and radiological evidence of thrombosis were significantly related to the presence of MTHFR-gene mutation (P value = 0.027 and 0.022 respectively). Age > 55 years (60% sensitivity, 100% specificity, PPV 100%), albumin ≤ 3.2 gm/dl (50% sensitivity, 95.65% specificity, PPV83.3%), and ferritin > 453 ng/L (70% sensitivity, 82.61% specificity, PPV 63.6%) were predictors of mutation of MTHFR-gene.

Conclusion

Incidence of mutation of MTHFR-gene was 30.3% in COVID-19 patients. Results suggest a potential association between inherited MTHFR gene mutation and severe form of COVID-19, thromboembolic events, and mortality.

Trial registration

ClinicalTrials.gov ID: NCT05679414. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000CU2V&selectaction=Edit&uid=U00056R5&ts=2&cx=lrrb7q. Retrospectively registered. 9th Jan 2023.

Background

Due to the persistence of a hypercoagulability state, infection by SARS-CoV-2 is linked to numerous microvascular and macrovascular thrombotic events known as “COVID-19-associated coagulopathy” (CAC), which contributes significantly to organ damage in COVID 19. Up to one-third of these patients experience thrombotic events, which are linked to worsening disease severity and higher mortality [1].

As a result, COVID-19 patients require risk stratification to develop an appropriate thrombophylaxis plan. There have been numerous recommended methods and scores, including those from the American Society of Hematology [2] and the International Society on Thrombosis and Haemostasis [3].

Applying the same standards to other world areas with various pro-thrombotic characteristics is challenging. Though, compared to other regions of the world, the Eastern Mediterranean region has an increased prevalence of major mutations in thrombophilic genes, of them the mutation in C677T methylenetetrahydrofolate reductase (MTHFR) gene [4], with 11% of the population having the homozygous mutation of the C677T genotype [5]. A crucial enzyme in the metabolism of homocysteine, (MTHFR) produces the 5-methyl-tetrahydrofolate, which is present in the blood and provides methyl groups, so homocysteine changed to methionine by re-methylation [6]. A modest increase in the risk of thrombosis is linked to hyperhomocysteinemia, which results from MTHFR’s reduced activity [7].

The MTHFR gene contains a common autosomal recessive mutation (C677T) that arises when alanine is changed into the amino acid valine. A higher risk of emerging cardiovascular illness, Alzheimer’s disease, depressive disorders, and neural tube abnormalities have been linked to the common C677T variant in MTHFR [8]. Additionally, compared to a heterozygous mutation, a homozygous mutation of that gene creates a higher thrombosis risk in patients [9]. Therefore, a thorough clinical and laboratory assessment should be used to determine the risk of thrombosis as well as the best anticoagulation strategy.

Objective

To find the incidence of MTHFR gene polymorphism in a cohort of Egyptian patients with COVID-19, and its association with thromboembolic events and outcome.

Subjects and methods

Study design

Prospective observational cohort study.

Study setting

The study was done at Ain-Shams University Isolation Hospitals, Cairo, Egypt, started on 1st October 2021 and ended on 31st March 2022.

Study population

Study arm

Thirty-three COVID-19 patients and positive reverse transcriptase polymerase chain reaction (RT-PCR).

Control arm

Thirteen healthy individuals (no clinical evidence of COVID-19 infection).

Patients underwent the following:

  1. 1.

    Medical history and examination.

  2. 2.

    RT- PCR for SARS-CoV2

  3. 3.

    Lab investigations: complete blood count (CBC), C reactive protein (CRP), serum Ferritin, D-dimers, lactate dehydrogenase (LDH)

  4. 4.

    HRCT chest in which the extent of radiological affection was described in terms of severe form (> 50% of lungs are affected) and non-severe form (< 50% of lungs are affected) [10].

  5. 5.

    COVID-19 disease severity classification of the study group according to WHO Living guidance for clinical management of COVID-19, 2021 [11].

  6. 6.

    The patient receives their standard of care treatment in accordance with the patient management protocol of the Egyptian Ministry of Health and Population (MOHP) for COVID-19 Sept. 2021 for Version 1.5 [10].

  7. 7.

    Testing RT-PCR of MTHFR-C677T genotypes using 2 ml EDTA blood.

  8. 8.

    Observe the patient for 28 days for the detection of vascular thrombotic manifestation (possible clinical data, lower limb duplex, rising D-dimer, or if necessary computed tomography of the chest using pulmonary angiography).

  9. 9.

    Follow the patient for 28 days to assess the patient’s outcome (cure or death).

Criteria of inclusion

Adult COVID-19 patients, ≥ 18 years with positive RT-PCR.

Criteria of exclusion

  • Patients’ refusion of study participation.

  • Patients aged less than 18 years old

  • Patients on antithrombotic treatment prior to COVID-19.

  • Patients with established blood coagulation disorders

Sample size

A sample size was calculated to recruit 33 patients with COVID-19 admitted at Ain-Shams University isolation Hospitals in addition to 13 healthy controls.

Sampling method

To get the study sample, convenient sampling was employed. Until the study’s sample size was reached, all patients who met the inclusion criteria were enrolled in it. There was no sample storage and no leftovers.

Assessment of MTHFR-C677T genotypes

The real-time PCR using a PCR kit was intended to identify the C677T-MTHFR gene mutation. Its technique relies on probes labeled by fluorophore which is specific for alleles to detect a sequence of the target amplification and detection. A single nucleotide polymorphism (C677T) exists between the cytosine and thymine bases. is the target sequence. In the FAM fluorescence channel, the wild-type allele (C677C) is found, and The HEX fluorescence channel has the mutant allele (T677T). A signal can be seen in both channels if the genotype is heterozygous (C677T). The kit specific for detection uses “hot start” technology and incorporates Ready to Use MasterMix to minimize reactions that are not specific and ensure it is optimally sensitive. Kit is intended for in vitro diagnosis.

Purification of nucleic acid consistent with the clinical material isolation protocols, nucleic acid isolation should be carried out using isolation kits that are readily accessible on the market. The following isolation kits are suggested by the manufacturer: croBEE NA16 Nucleic Acid Extraction System Gene Proof Pathogen Free DNA Isolation KitPCR set up:

  1. 1.

    Fill the PCR tubes with 18 µl of MasterMix.

  2. 2.

    Fill each PCR tube with 2 µl of the isolated nucleic acid sample or µl of the positive control. Twenty microliters will be the total volume of the reaction mix. During the PCR preparation, all components must be kept between + 2 and + 8 °C.

  3. 3.

    The tubes should be sealed, quickly centrifuged, inserted into the instrument, and allowed to amplify using the following PCR profile.

Statistical analysis methodology

Version 23 of the Statistical Package for the Social Sciences (IBM SPSS) was produced in Hong Kong, China, and used for data collection, revision, coding, and entry. Where the data were found to be parametric, they were presented as mean, SDs, and ranges; where they were nonparametric, the interquartile range and median were given. Numbers and percentages were also used to display qualitative variables. Using qualitative data, groups were compared using the 2 tests. Two groups with quantitative data and a nonparametric distribution were compared using the Mann–Whitney test, while two groups with quantitative data and a parametric distribution were compared using an independent t-test. The 95% confidence interval and the permitted margin of error were both set at 5%. The odds ratios (OR) and associated 95% confidence intervals (CI) for both univariate and multivariate logistic regression models were evaluated. This led to the P value being classified as significant in the following ways: P values less than 0.05 are considered significant, and those less than 0.01 are highly significant.

Ethical consideration

Consent to participate and ethical approval upon receiving assurances of confidentiality, each patient who was invited to take part in the study provided written informed consent. They had the option to withdraw from the study at any time, either on their own or with the consent of their legal guardian; in this case, they continued to be monitored and treated as needed. The ethics committee of scientific research, Faculty of Medicine, Ain Shams University, gave its approval. (REC number: FMASU R 130/2022).

Results

The current study included 33 Covid 19 patients and 13 healthy controls. In the study group, 19 patients were males and 14 were females with a mean age of 45.42 ± 10.56 years. In the control group, 6 subjects were males and 7 were females with a mean age of 34.85 ± 13.13 years.

Table 1 displays descriptive data about the study group’s age (years), sex, MTHFR gene mutation, smoking status, symptoms and their duration, and comorbidities. Out of 33 patients, a heterozygous form of MTHFR-gene mutation was found in 9 (27.3%), homozygous form was found in 1 (3.0%).

Table 1 Descriptive data of the study group regarding age (years), sex, MTHFR gene mutation, smoking status, symptoms and their duration, and comorbidities
Full size table

Table 2 displays laboratory results for the study group for serum IL-6, CRP, albumin, ferritin, D dimer, TLC, and lymphocyte count.

Table 2 The study group’s laboratory results as regards serum IL-6, CRP, albumin, ferritin, D dimer, TLC, and lymphocyte count
Full size table

The clinical course of the study group regarding vital data, the need for mechanical ventilation, site of care, disease severity classification, HRCT chest radiological affection, and outcome (cured/discharged, continued hospitalization, death, duration of hospital admission, and radiological evidence of thrombosis) are shown in Table 3.

Table 3 The study group’s clinical data regarding vital data, the need for mechanical ventilation, site of care, disease severity classification, HRCT chest radiological affection, standard of care treatment, outcome, and radiological evidence of thrombosis
Full size table

Age was statistically higher in the study group, as displayed in Table 4, when age, sex, and mutation of the MTHFR gene were compared in the 2 groups.

Table 4 Comparison between the study and control groups as regards age, sex, and MTHFR gene mutation
Full size table

This study found that among clinical factors associated with the mutation of the MTHFR gene, age, diarrhea, abdominal pain, diabetes, and hypertension were significantly related to the MTHFR gene mutation. Also, radiological affection > 50% in the HRCT chest showed the same relation as displayed in Table 5. Regarding the laboratory data associated with the presence of MTHFR gene mutation, lower levels of albumin and higher ferritin levels were significantly associated with the mutation of the MTHFR gene as displayed in Table 6.

Table 5 Clinical variables linked to the MTHFR gene mutation in the study group
Full size table
Table 6 Laboratory data in the study group according to mutation of the MTHFR gene
Full size table

Patient cure and discharge were significantly related to the absence of MTHFR gene mutation, on the other hand, death and radiological evidence of thrombosis were significantly related to the mutation of the MTHFR gene as Table 7 illustrates.

Table 7 Outcome data in the study group according to MTHFR gene mutation
Full size table

ROC curve of age, albumin level, and ferritin level as predictors of MTHFR gene mutation revealed that: age > 55 years showed 60% sensitivity, 100% specificity with 100% PPV, Albumin ≤ 3.2 gm/dl showed 50% sensitivity, 95.65% specificity with 83.3% PPV. Lastly, Ferritin > 453 ng/L showed 70% sensitivity, and 82.61% specificity with 63.6% PPV as detailed in Table 8 and illustrated in Fig. 1.

Table 8 MTHFR gene mutation risk factors in the study group
Full size table
Fig. 1
figure 1

ROC curve of age, albumin and ferritin as predictors of MTHFR gene mutation

Full size image

Regarding the 13 control healthy individuals: 5 (38.4%) of them the expressed presence of the MTHFR gene heterozygous mutation with no thromboembolic disease manifestation detected.

Discussion

In the metabolism of folate, MTHFR is a crucial enzyme. The enzyme in a “thermolabile” form that was marginally less efficient was identified in 1988 [12]. The polymorphism that caused this, a nucleotide 677 C > T transition, was identified in 1995 [13]. A1298C transition, a further polymorphism with diminished activity had been identified shortly after [14]. According to demographic research, these polymorphisms are quite prevalent, with 60% to 70% of the population carrying just one variant. In fact, homozygous polymorphisms or compound heterozygotes were discovered in 10% of the population [15]. Studies showed that individuals with this polymorphism had increased homocysteine levels as soon as they were discovered. Later studies hypothesized a connection between thromboembolism and the existence of these polymorphisms [16]. Performing MTHRF mutation assays soon joined the list of reliable “classic tests” for thrombophilia, Antithrombin activity, factor V Leiden assays, and other circumstances that have all been conclusively related to a higher risk of VTE. It was undoubtedly an interesting topic about a common mutation that causes high homocysteine levels to lead to thrombosis [17].

Since MTHFR mutation raises serum homocysteine in low folate situations, folate supplementation of grain products was made mandatory in nations like the USA in 1996 [18, 19].

The cytokine storm-like COVID-19 coagulopathy, which manifests as hyperinflammation, coagulation, and platelet activation, is thought to be the result of interactions between the immune and inflammatory systems and the coagulation system. VTE (and particularly pulmonary embolism) was of high incidence when compared to historical controls, as well as in situ pulmonary embolism associated with microthrombi, suggested a classic macro vessel disease as well as thrombotic microangiopathic process; and critically ill COVID-19 patients most significantly had a high rate of VTE [2].

Inherited thrombophilia may contribute to the increased risk of thrombosis in people with COVID-19, according to various reviews or editorials [20]. However, a review of the bibliographical sources from PubMed (January 2023) using the phrases “COVID-19” and “thrombosis” reveals that there is a small number of research that discusses congenital thrombophilia [21].

There are undoubtedly other factors contributing to COVID-19 patients’ high risk of thrombosis; nevertheless, the available information is sparse and requires more research. Investigating the role of MTHFR gene mutation in the COVID-19 course in this context seems interesting [22].

In the study group, 14 patients had mild COVID-19, 14 patients had moderate COVID-19, and 5 patients had critical COVID-19, where 10 patients (33.3%) had MTHFR gene mutation.

By utilizing two separate groups, we found a significant number of patients in a study group (10 patients,33.3%) with MTHFR gene mutation who suffered from COVID-19 (9 patients with Heterozygous MTHFR gene mutation, 1 patient with Homozygous MTHFR gene mutation), with mild COVID-19 in three patients (DVT was detected in one of them), moderate COVID-19 in four patients (PE was detected in one of them), and critical degree of COVID-19 in three patients (one of them developed PE, while two died with sepsis). These match the correlation between poor prognosis of COVID-19 with MTHFR mutation and increased risk that was previously mentioned [23].

Five patients with MTHFR mutation had IHD (2 of them died, while 2 patients developed PE). However, more firm conclusions cannot be drawn because of the limited sample size and the low incidence of thrombotic events.

Among our cohort, at a significance level (P value) of 0.05, the expected statistical power to identify a significant difference in the rate of vascular events (5%) between the two groups is low (30%). It is noteworthy, however, that only one of the two patients who had a thrombotic event had a homozygous MTHFR gene mutation, while the other two had heterozygous MTHFR gene mutation, as determined by PCR. This agreed with research by Ponti et al. who discovered a significant correlation between the incidence and mortality of COVID-19 and the prevalence of homozygous MTHFR677 mutation. They also came to the conclusion that MTHFR C677T genetic polymorphism may affect COVID-19 incidence and severity. This data raises the possibility that COVID-19 patients with MTHFR gene mutations may have a higher thrombosis risk. However, additional research looking for MTHFR gene mutations in larger cohorts would significantly boost the statistical power to support this claim [24].

In the same context as our discovery that MTHFR-positive patients exhibit statistically significant radiological evidence of severe disease in their HRCT chest, according to a theory put forth by Karst et al., the MFTHR C677T polymorphism causes hyperhomocysteinemia, which in turn causes a severe course of COVID-19 [9].

In the end, it is noteworthy that the majority of MTHFR gene mutation patients (7 patients, 70%) did not experience symptomatic thrombotic events throughout COVID-19, including one subject with a history of IHD (of the other four IHD patients, two experienced PE, while the other two died). Stronger evidence is needed, but it is possible that the fact that these patients were in the early stages of the disease or were receiving early anticoagulation was the reason why the hypercoagulable state that caused the previously mentioned vascular events did not facilitate the development of new thrombotic episodes during SARS-CoV-2 infection. In agreement with this, a prior study indicates that long-term anticoagulation at admission might prevent thrombosis in COVID-19 patients [25]. One argument against routinely testing for MTHFR gene mutations could be the financial burden.

There is insufficient evidence to say if vitamin B and folic acid supplements will lower the cardiovascular risks linked to hyper-homocysteinemia or MTHFR genetic status if administered by MTHFR-positive individuals [16].

Limitations of the study

First, only a few patients were included in this single-center trial, which might reduce the applicability of findings to other populations. Second, the study did not target the relationship between the MTHFR gene mutation and other conditions that increase the risk of thromboembolism or affect outcomes in COVID-19 for example obesity and ischemic heart disease.

Conclusion

The findings of this pilot study, the first to examine the role of the MTHFR gene mutation in COVID-19 in Egypt, the incidence of MTHFR gene mutation was 30.3% of COVID-19 patients. Results suggest a potential association between inherited MTHFR gene mutation and severe form of COVID-19, thromboembolic events, and mortality. This connection should stimulate more investigation into the biology, and clinical implications of inherited MTHFR gene mutation in COVID-19, and the most effective management of anticoagulation in these patients.

Availability of data and materials

Tables included.

Abbreviations

AUC:

Area under the curve

COVID-19:

Coronavirus disease of 2019

CRP:

C-reactive protein

DVT:

Deep venous thrombosis

EDTA:

Ethylenediaminetetraacetic acid

FMASU:

Faculty of Medicine–Ain Shams University

HRCT:

High-resolution computed tomography

ICU:

Intensive care unit

IHD:

Ischemic heart disease

IL-6:

Interleukin 6

IQR:

Interquartile range

LDH:

Lactate hydrogenase

MOHP:

Ministry of health and population

MTHFR:

Methylenetetrahydrofolate reductase

NPV:

Negative predictive value

OR:

Odds ratio

PE:

Pulmonary embolism

PPV:

Positive predictive value,

ROC curve:

Receiver operating characteristic curve

RT-PCR:

Real-time polymerase chain reaction

SARS COV2:

Severe acute respiratory syndrome coronavirus 2

SD:

Standard deviation

SpO2 (%):

Peripheral oxygen saturation

TLC:

Total leucocytic count

References

  1. Lorini FL, Di Matteo M, Gritti P, Grazioli L et al (2021) Coagulopathy and COVID-19. Eur Heart J Suppl 23(Supplement E):E95–E98. https://doi.org/10.1093/eurheartj/suab100. The Heart of the Matter

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Spyropoulos AC (2020) The management of venous thromboembolism in hospitalized patients with COVID-19. Blood Adv 4(16):4028. https://doi.org/10.1182/bloodadvances.2020002496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Marchandot B, Trimaille A, Curtiaud A, Matsushita K, Jesel L, Morel O (2020) Thromboprophylaxis: balancing evidence and experience during the COVID-19 pandemic. J Thromb Thrombolysis 50(4):799–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Taher A, Khalil I, Shamseddine A, El-Ahdab F, Bazarbachi A (2001) High prevalence of factor V Leiden mutation among healthy individuals and patients with deep venous thrombosis in Lebanon: is the eastern Mediterranean region the area of origin of this mutation? Thromb Haemost 86(08):723–724

    Article  CAS  PubMed  Google Scholar 

  5. Almawi WY, Finan RR, Tamim H, Daccache JL, Irani-Hakime N (2004) Differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene among the Lebanese population. Am J Hematol 76(1):85–87

    Article  CAS  PubMed  Google Scholar 

  6. Andreassi MG, Botto N, Cocci F, Battaglia D, Antonioli E et al (2003) Methylene tetrahydrofolate reductase gene C677T polymorphism, homocysteine, vitamin B12 and DNA damage in coronary artery disease. Hum Genet 112(2):171–177

    Article  CAS  PubMed  Google Scholar 

  7. Hanson N, Aras O, Yang F, Tsai M (2001) C677T and A1 298C polymorphisms of the methylene tetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 47:661–666

    Article  CAS  PubMed  Google Scholar 

  8. Trimmer EE (2013) Methylene tetrahydrofolate reductase: biochemical characterization and medical significance. Curr Pharm Des 19(14):2574–2593

    Article  CAS  PubMed  Google Scholar 

  9. Karst M, Hollenhorst J, Achenbach J (2020) Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia? Med Hypotheses 144:110234. https://doi.org/10.1016/j.mehy.2020.110234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Management Protocol for COVID-19 Patients COVID-19 Ministry of Health and Population, Egypt. version 1.5/ September 2021. https://www.researchgate.net/publication/354694237_Management_Protocol_for_COVID-19_Patients_COVID-19_Ministry_of_Health_and_Population_Egypt_version_15_September_2021

  11. Living guidance for clinical management of COVID-19 living guidance 23 November 2021. WHO publication: WHO reference number: WHO/2019-nCoV/clinical/2021.2. https://iris.who.int/bitstream/handle/10665/349321/WHO-2019-nCoV-clinical-2021.2-eng.pdf?sequence=1.

  12. Kang SS, Wong PW, Zhou JM et al (1988) Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 37:611–613. https://www.metabolismjournal.com/article/0026-0495(88)90076-5/pdf

    Article  CAS  PubMed  Google Scholar 

  13. Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113. https://www.nature.com/articles/ng0595-111

    Article  CAS  PubMed  Google Scholar 

  14. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64(3):169–172. https://www.sciencedirect.com/science/article/abs/pii/S1096719298927147?via%3Dihub

    Article  CAS  PubMed  Google Scholar 

  15. Long S, Goldblatt J (2016) MTHFR genetic testing: controversy and clinical implications. Aust Fam Physician 45(4):237–240. https://www.racgp.org.au/afp/2016/april/mthfr-genetic-testing-controversy-and-clinical-implications/

    PubMed  Google Scholar 

  16. Hickey SE, Curry CJ, Toriello HV (2013) ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 15(2):153–156

    Article  CAS  PubMed  Google Scholar 

  17. Deloughery TG, Hunt BJ, Barnes GD, Connors JM, WTD Steering Committee (2022) A call to action: MTHFR polymorphisms should not be a part of inherited thrombophilia testing. Res Pract Thromb Haemost 6(4):e12739. https://doi.org/10.1002/rth2.12739. PMID: 35702587; PMCID: PMC9175241

    Article  PubMed  PubMed Central  Google Scholar 

  18. Crider KS, Bailey LB, Berry RJ (2011) Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 3(3):370–384. https://doi.org/10.3390/nu3030370. Epub 2011 Mar 15. PMID: 22254102; PMCID: PMC3257747

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yang Q, Cogswell ME, Hamner HC, Carriquiry A, Bailey LB, Pfeiffer CM, Berry RJ (2010) Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003–20061234. Am J Clin Nutr 91(1):64–72. https://doi.org/10.3945/ajcn.2009.28401

    Article  CAS  PubMed  Google Scholar 

  20. Badulescu OV, Sirbu PD, Filip N, Bordeianu G, Cojocaru E, Budacu CC, Badescu MC, Bararu-Bojan I, Veliceasa B, Ciocoiu M (2022) Hereditary thrombophilia in the era of COVID-19. Healthcare (Basel) 10(6):993. https://doi.org/10.3390/healthcare10060993. PMID:35742044;PMCID:PMC9223139

    Article  PubMed  Google Scholar 

  21. Burlacu A, Genovesi S, Popa IV, Crisan-Dabija R (2020) Unpuzzling COVID-19 prothrombotic state: are preexisting thrombophilic risk profiles responsible for heterogenous thrombotic events? Clin Appl Thromb 26:e107602962095288. https://doi.org/10.1177/1076029620952884

    Article  CAS  Google Scholar 

  22. Kichloo A, Dettloff K, Aljadah M, Albosta M, Jamal S, Singh J, Wani F, Kumar A, Vallabhaneni S, Khan MZ (2020) COVID-19 and hypercoagulability: a review. Clin Appl Thromb Hemost 26:1076029620962853. https://doi.org/10.1177/1076029620962853. PMID: 33074732; PMCID: PMC7592310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morales-Borges RH, Gonzalez MJ (2020) Covid-19 pandemic and possible links with Mthfr mutations, homocysteinemia, and metabolic disturbances: short review. J Diabetes Endocrinol Res 2(3):1–5

    Google Scholar 

  24. Ponti G, Pastorino L, Manfredini M, Ozben T, Oliva G, Kaleci S et al (2021) COVID-19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence. J Clin Lab Anal 35(7):e23798. https://doi.org/10.1002/jcla.23798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Klok FA, Kruip MJHA, van der Meer NJM et al (2020) Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 191:145–147. https://doi.org/10.1016/j.thromres.2020.04.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

No acknowledgments are necessary.

Funding

The current study did not get any funding.

Author information

Authors and Affiliations

  1. Chest Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Eman Badawy Abdelfattah, Heba Mohamed Shalaby & Hieba Gamal Ezzelregal

  2. Clinical Pathology Department, Ain Shams University, Cairo, Egypt

    Sahar Samir Abdelmaksoud

  3. Paediatric Medicine, Damanhur Medical National Institute, Damanhur, Egypt

    Saad Shehata Abo-zid

  4. MUST Faculty of Medicine, Cairo, Egypt

    Mahmoud M. Aboulmagd M. Youssef

  5. Anesthesiology Department. Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Ahmed Ali Elshebiny

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  1. Eman Badawy Abdelfattah
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The manuscript has been read and approved by all authors.

Corresponding author

Correspondence to Eman Badawy Abdelfattah.

Ethics declarations

Ethics approval and consent to participate

After the study’s protocol was revised and patients gave their written agreement, the ethics committee for scientific research at the Faculty of Medicine at Ain Shams University granted approval (the committee’s reference ID number is FMASU R 130/2022).

-ClinicalTrials.gov ID: NCT05679414. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000CU2V&selectaction=Edit&uid=U00056R5&ts=2&cx=lrrb7q. Retrospectively registered. 9th January 2023.

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Abdelfattah, E.B., Abdelmaksoud, S.S., Shalaby, H.M. et al. Incidence of thrombophilic gene polymorphism (MTHFR C677T) in Egyptian COVID-19 patients and its clinical implications. Egypt J Bronchol 17, 72 (2023). https://doi.org/10.1186/s43168-023-00246-x

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