key: cord-0814577-j2r0zj39 authors: Karst, Matthias; Hollenhorst, Josef; Achenbach, Johannes title: Life-threatening Course in Coronavirus Disease 2019 (COVID-19): Is There a Link to Methylenetetrahydrofolic Acid Reductase (MTHFR) Polymorphism and Hyperhomocysteinemia? date: 2020-09-02 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110234 sha: 2f2008a5981e0b4bc42ba642d8629f7891b405e5 doc_id: 814577 cord_uid: j2r0zj39 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. One-carbon metabolism Hyper-homocysteinemia Originating from China at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak evolved into a pandemic. Patients with SARS-CoV-2 infection can develop coronavirus disease 2019 (COVID- 19) , which is associated with an 8.8% mortality rate in the cohort aged 60 years and above in comparison to 0.46% for patients aged below 60 years (1) . Countries with the highest mortality rates are Italy, Spain, Iran, France, and the USA (1). A very recent report from Italy including 1591 critically ill COVID-19 patients showed that the vast majority were older men (2) . This is consistent with the mortality rate worldwide showing a predilection for the male gender (M:F = 1.7:1) (1) and presence of at least one comorbidity in 68% of cases. Similar to previous reports (1) , hypertension was the most common comorbidity, followed by cardiovascular disease, hypercholesterolemia and diabetes (2) . Compared to other western countries, in Italy high rates of ICU admission (9%) and ICU mortality (26%) were observed (2) while the death rate of 12.8% for the whole country appears to be quite high (2) . Sharply increased values of neutrophils and pro-inflammatory cytokines such as IL-6 and TNF-alpha (1), abnormal coagulation tests and disseminated intravascular coagulation are frequently observed in deaths from COVID-19 (3). The 5,10-methylenetetrahydrofolic acid reductase (MTHFR) enzyme is most important in the one-carbon-methionine pathway regulating fundamental processes in cell physiology such as DNA repair, neurotransmitter functions and membrane transport (4) . The T allele of the MTHFR-gene (C677T polymorphism), in which cytosine is replaced by thymine at the 677th position, has been suggested to be protective against malignancies such as colon cancer and acute lymphatic leukemia (4, 5) . This mutation leads to a thermolabile enzyme variant in which the dissociation rate of the cofactor flavin adenine dinucleotide (FAD) is increased reducing its activity to an extent of 50% or more (4, 5) . In people possessing a medium skin tone, which evolutionarily developed in Eurasia under moderate UV radiation, the basic MTHFR function is largely preserved as long as there is sufficient dietary folic acid (4, 5) . However, with insufficient folate intake the reduced activity of the MTHFR enzyme leads to reduced levels of 5-methyltetrahydrofolate (5-MTHF) and thus reduced activity of methionine synthetase culminating in accumulation of the key metabolite homocysteine (Hc) to toxic levels (4) . MTHFR C677T polymorphism is the most common MTHFR single nucleotide polymorphism (SNP) and the most common genetic cause of hyperhomocysteinemia (H-Hcy).(4) The global prevalence of both the CT and TT genotype was found to be highest in Europeans (54,0 %) and North Americans (42,8 %) and lowest in Asians (35,4 %) and Africans (19,6 %).(5) However, subgroup analysis showed remarkable regional differences. Among East Asian countries, both genotypes were found to be most prevalent in China (67,1%) and least prevalent in India (20,3 %). In European countries the highest prevalence was found in Italy (66,3 %), the lowest in Finland (44,2 %) (5, 6). While the TT genotype was found significantly more often in males of the Indian cohort (5), generally, the C677T polymorphism seems to be distributed equally between genders (7). However, low folate status resulted in significant higher levels of Hc only in male subjects (7, 8) . Further, the C677T mutation seems to be associated with a significantly increased risk for coronary artery disease only in homozygous men. (9) Regardless of the folate plasma level, other risk factors for the development of H-Hcy are chronic renal failure, hypothyroidism and malignant tumors of the breast, ovary, and pancreas (10) . Furthermore, adverse lifestyle factors such as smoking, alcohol consumption, and physical inactivity can elevate Hcy levels (11) . Additionally, H-Hcy is more often found in the elderly and in men (10) which may in part be caused by lower serum levels of folic acid and vitamin B12, reduced methionine metabolism, and higher serum creatinine levels in men compared to women. (12) H-Hcy is associated with the development of atherosclerotic vascular disease including arterial hypertension and congestive heart failure (10) . The underlying mechanisms are nitric oxide (NO) antagonism, production of reactive oxygen species (ROS), prothromboplastic activity, loss of blood vessel vasorelaxation and alterations in the elastin/collagen ratio (10) . Further, there is a correlation between H-Hcy and arterial hypertension that especially applies to males as androgen hormones, in contrast to estrogen, increase ACE and angiotensin receptor 1 (AT1R) activity. (13, 14) Altogether, these changes result in vascular cell dysplasia, endothelial dysfunction and a procoagulant state (10) . (20) , subjects at high risk for adverse outcomes when infected with COVID-19, such as the elderly with comorbidities, should be screened for H-Hcy. Concentrations above 8 µmol/L should lead to the implementation of improvements in diet quality (fruit, vegetables, whole grains, fresh meats, and seafood) (21) and the additional application of 5-MTHF (the most biologically active form of folic acid) which bypasses MTHFR ± B-vitamins (22) . Supplementation of folic acid alone, especially in countries practicing dietary folic acid fortification, can even lead to the opposite effect in regular subjects and even more pronounced in patients with MTHFR polymorphism. The proposed mechanism is an accumulation of unmetabolized folic acid which inhibits MTHFR through excess-substrate inhibition and binding competition with 5-MTHF (22) . As co-factors of enzymes in Hcy metabolism the vitamins B6 (21) and B12 (10) and B2 (riboflavin) (a precursor of FAD which stabilizes MTHFR) should be added (23) (24) (25) . Vitamin B6 and riboflavin have been previously shown to lower Hcy levels. (24, 26) . To test the hypothesis of dietary down-regulation of Hcy levels to prevent poor outcomes in Covid-19, a prospective controlled trial including genetic testing for MTHFR polymorphism could be helpful. Such an interventional study is particularly important since supplementation of synthetic folic acid and vitamins in H-Hcy and cardiovascular disease showed mixed and modest preventative effects on final outcomes so far (10, 11) . In active COVID-19 disease, the determination of H-Hcy through serum levels as opposed to genetic testing for MTHFR polymorphism may be used as an early biomarker for adverse outcomes and higher mortality and may serve as indication for vigorous supportive nutritional interventions. In addition to B vitamins, vitamins A, C, D, and E, omega-3 polyunsaturated fatty acids (PUFA), selenium, zinc and iron have been shown to possess direct antiviral properties. (27) As diet-derived antioxidants make the most significant contribution to the body`s antioxidant defense system (28) , the administration of strong antioxidants, i.e. Vitamin C, may help to prevent both, further tissue damage and increased viral replication. In 2003, Vitamin C was already proposed as a treatment option in the SARS CoV-1 outbreak ( (29) . In COVID-19 a randomized controlled trial with 12 g Vitamin C administered twice daily IV has been started in China. (30) In conclusion, we propose a theory of specific vulnerability to a severe course of COVID-19 initiated by H-Hcy, which can be triggered by the presence of the C677T polymorphism. Male gender, nutritional factors, life-style factors and several underlying diseases seem to be further significant risk factors for an increased vulnerability to SARS-CoV-2. During the SARS-CoV-2 pandemic early risk stratification by measurement of Hc-plasma levels and possibly screening for the presence MTHFR polymorphism appears promising. Additionally, treatment with vitamins and micronutrients in addition to standard supportive care seems to be warranted to protect and support the most vulnerable patient groups. No grants and funding were received by any of the authors. There are no conflicts of interest to declare. Each of the authors confirms that this manuscript has not been previously published and is not currently under consideration by any other journal. Additionally, all of the authors have approved the contents of this paper and affirm that this manuscript is an honest, accurate and transparent account of the topic being reported; no important aspects have been omitted. They have agreed to Medical Hypotheses' submission policies. 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