Further comment on articles pertaining to: “Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19”

Abstract

Recent studies have found a correlate between higher homocysteine (Hcy) levels and higher COVID-19 mortality rates. In October 2020, researchers in Italy noted vasculitic damage in seriously ill patients and suspected Hcy played a contributing role. After initially observing a small cohort of only 40 patients, they conducted a study of Hcy levels in 313 patients and definitively identified Hcy as a predictive marker for COVID-19 mortality risk [1] , [2] . In addition, Hcy is associated with many conditions that share comorbidity with SARS-CoV-2, including cardiovascular disease, diabetes, and stroke [3] , [4] . Hcy is found in higher quantities in men, Hcy levels increase with age, and high Hcy is also associated with poor nutrition/low folate which may correlate to socioeconomic disparities for COVID-19 fatalities within the United States [5] . Decreasing homocysteic acid, a homocysteine metabolite, has been shown to decrease serum Creactive protein in Kawasaki Disease—a disease similar to Multisystem Inflammatory Syndrome in Children (MIS-C) [6] . High Hcy has also been found in first-episode schizophrenia [7] ; the MTHFR C677T polymorphism that contributes to Hcyimbalances has also been associated with schizophrenia [8] ; and schizophrenia was recently linked to an increased risk of death in COVID-19 [9] . Given these numerous correlates, it is relevant to explore how Hcy may be impacting COVID-19 severity. Three Hcy-related GPCRs have repeatedly surfaced in studies on SARS-CoV-2; namely, AT1R, B2 , and CXCR6. I hypothesize that Hcy interference with these GPCRs may be contributing to COVID-19 severity in two primary ways. Firstly, Hcy can act as an alternate agonist to AT1R at c289s [10] , which could exacerbate the reninangiotensin system (RAS) imbalances induced by SARS-CoV-2 interactions with angiotensin-converting enzyme 2 (ACE2). A recent paper also hypothesized that SARS-CoV-2 may be disrupting GPCR signaling and dysregulating adenylyl cyclase [11] . Because AT1 -B2 receptor heterodimer activity is known to enhance Gi/o and Gq/11 activation, SARS-CoV-2 GPCR signaling disruption may be attributed to potential heterodimeric overexpression in severe COVID-19 as well as to potential heterodimeric hypersensitivity to c289s Hcy agonism. Secondly, Hcy upregulation of CXCL16 [12] in conjunction with SARS-CoV-2 possible binding to CXCL16 and chemotactic disabling [13] could be problematic in those with a chromosome 3 locus that exhibits lower CXCR6 expression [14] .

Serum homocysteine level in pediatric patients with COVID‐19 and its correlation with the disease severity

“…CRP was elevated in 85% of our cases, in contrast to the Qi et al 20 study (14%). CRP and Hcy have a positive correlation, according to Berbert 4 but there was no significant correlation between CRP and Hcy in our study. Caldeira‐Arajo et al 33 reported that the level of Hcy in pediatric patients was altered by age; however, this was not confirmed in our study.…”

“… 3 Several potential mechanisms were suggested by which Hcy would trigger severe COVID‐19 disease or prevent its control. 4 , 5 High Hcy levels cause thrombus development by increasing inflammatory cytokines that are overproduced in cytokine release syndrome or "cytokine storm." They also cause limit nitric oxide generation and promote endothelial dysfunction.…”

“…It is a prothrombotic factor since it is involved in the generation of reactive oxygen species, which causes oxidative stress, endothelial disruption, and irreversible inactivation of protein C and thrombomodulin 3 . Several potential mechanisms were suggested by which Hcy would trigger severe COVID‐19 disease or prevent its control 4,5 . High Hcy levels cause thrombus development by increasing inflammatory cytokines that are overproduced in cytokine release syndrome or "cytokine storm."…”

COVID-19 and One-Carbon Metabolism

“…It has also been suggested that B-vitamins should be used to lower HHcy coexisting with COVID-19 [36]. Consequently to the proposed involvement of HHcy in COVID-19, it was suggested that Hcy may contribute to severe COVID-19 by interfering with G-protein-coupled receptors (GPCRs) (AT1R, B2 and CXCR6), by their upregulation, being an alternative agonist and inducing their heteromerization [38]. However, most of these proposals lack an experimental support.…”

Dermatological Manifestations in COVID-19: A Case Study of SARS-CoV-2 Infection in a Genetic Thrombophilic Patient with Mthfr Mutation

“…Thus, some mechanisms can be suggested for the MTHFR mutation, with high levels of the prothrombotic factor H-Hcy and the development of skin lesions due to coagulation disorders, characteristic of severe COVID-19: increased pro-inflammatory cytokines (IL-6, IL-2, IL-4, TNFα) or “cytokine storm”, platelet cell hyperactivity, platelet aggregation, clot formation, and thrombus development. In addition to endothelial dysfunction, promoted by limited nitric oxide generation, and endothelial disruption, combined with irreversible thrombomodulin inactivation, by ROS [ 52 , 53 , 54 , 55 ]. The presence of the MTHFR mutation can, therefore, make the disease related to the coagulation cascade more complex, with a greater possibility of death due to thrombosis [ 56 ].…”