PROGNOSTIC VALUE OF CYP1A2 (rs2069514 AND rs762551) POLYMORPHISMS IN COVID-19 PATIENTS
Bozkurt I, Gözler T, Yüksel I, Ulucan K, Tarhan KN
*Corresponding Author: Prof.Dr. Korkut Ulucan, Saray, Site Yolu Cd No:27, Umraniye/ Istanbul, Turkey, 34768, email: korkutulucan@hotmail.com.tr; +902164002222
page: 35
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DISCUSSION
In this study, we examined 60 patients with a diagnosis
of COVID-19; the predictability of CYP1A2 polymorphisms
with comorbidities and symptoms on the risk of ICU
(intensive care unit) admission was examined. The mean
age of 60 patients evaluated in the study was 56.75±19.70
years. 53.3% of the patients were male and 46.7% were
female. Although the rates of male patients were higher
in our study, there was no statistically significant difference
between genders and admission to the intensive care
unit. In a meta-analysis study, a total of 48 studies related
to intensive care unit admission among COVID-19 cases
were reported. In these studies, the rate of intensive care
admission in hospitalized patients due to COVID-19 was
higher in men than in women [22]. In our study, 64.5%
of the patients admitted to the intensive care unit were 65
years or older; this rate was also statistically significant. In
a meta-analysis study involving 8,088 patients diagnosed
with COVID-19, it was reported that patients aged 65 and
over had higher rates of intensive care admission [23].
Teker et al. (2021) stated that the course of COVID-19
disease gets worse with age and deaths increase [24].
Wang et al. (2020) reported that the elderly are at
higher risk for chronic diseases and infections and that
mortality due to COVID-19 increases in those with hypertension
and coronary heart disease [15]. In our study,
68.2% of the patients hospitalized in the intensive care
unit had a chronic disease and it was also statistically significant.
This may be due to how chronic diseases weaken
the immune system, or it may be related to the higher
prevalence of other diseases in the elderly with COVID-19.
In a meta-analysis study by Jain and Yuan (2020),
including 1813 people, the most common symptoms in
patients in the intensive care group were cough (67.2%),
fever (62.9%), and shortness of breath (61.2%). Similarly,
the most common symptoms in our cohort who were hospitalized
in the intensive care unit were respiratory distress
(95.2%), cough (52.2%), and fatigue (55.6%) [25].
There are many studies in the literature on the relationship
between ACE genotypes with COVID-19. Like
CYP1A2, ACE I/D polymorphism is also related with adaptation
to O2 pressure conditions in blood and tissues. Yamamoto
et al. (2020) showed that the ACE II genotype was
negatively associated with the number of SARS-CoV-2
cases and deaths in East Asia [26]. In a case-control study
involving 204 patients who were SARS-CoV positive,
the ACE DD genotype was associated with a higher risk
for COVID-19 [27]. In another study on the relationship
between ACE I/D and ACE-2 gene polymorphism with
COVID-19, the ACE-2 G allele and DD / GG+GA haplogroup
together with the ACE D allele were reported as
a risky genotype. The II / AA genotype has been reported
to be protective [28]. However, the impact of CYP1A2
genotypes on the poor prognosis of COVID-19 has not
been focused on. When the studies in the literature about
the CYP1A2 gene are examined; it seems that the focus
is on the effects of CYP1A2 activity on drug efficacy and
side effects in the treatment of COVID-19, as well as on
the course and treatment response of COVID-19.
Lenoir et al. (2021) conducted a study evaluating the
effects of SARS-CoV-2 infection on the activity of 6 different
forms of the cytochrome P450 enzyme (CYP1A2,
CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A)
in 28 moderate to severe COVID-19 patients [29]. The
study showed that CYP1A2, CYP2C19, and CYP3A activities
were decreased and CYP2B6 and CYP2C9 activities
were increased in COVID-19 patients. As a result of the
study, the activity of CYP2D6 did not show any significant
change. The study also found that inflammatory marker
levels such as C-reactive protein, interleukin 6, and tumor
necrosis factor-α were higher in COVID-19 patients. This
suggests that SARS-CoV-2 infection may specifically alter
the activity of these cytochrome P450 enzymes.
Clozapine is an effective antipsychotic drug approved
for use in schizophrenia but is not used frequently due to
its side effects and risk of agranulocytosis (reduction in
blood cells). However, clozapine levels may need to be
measured from time to time because many factors can affect
the level of the drug. For example, the simultaneous
use of certain medications, smoking cessation, and diseases
such as COVID-19 can cause clozapine levels to increase
and an increased risk of being toxic. Clozapine is metabolized
by the cytochrome P450 system, primarily CYP1A2.
During COVID-19, cytokines such as interleukin-1β (IL-
1β), IL-6, tumor necrosis factor-α (TNF-α), interferon-α
(IFN-α), and IFN-γ can slow down this metabolism. This
may cause an increase in clozapine levels [30,31,32]. In
a case study presented by DiAngelo et al. (2022), it was
stated that frequent monitoring of clozapine levels and
appropriate adjustment of clozapine doses would be of
great importance in the setting of COVID-19 infection to
avoid potential clozapine toxicity [33].
The results of a study by Reis et al. (2022) showed
that the use of fluvoxamine (an antidepressant drug) can
help to reduce the need for hospitalization in patients with
COVID-19 [34]. However, it has also been stated that fluvoxamine
has the potential to interact with many drugs and
caution should be exercised during its use. Fluvoxamine is
metabolized by CYP enzymes and therefore may interact
with many other drugs. On the other hand, fluvoxamine
is a potent inhibitor of CYP1A2 and CYP2C19 as well as
a moderate inhibitor of CYP2C9, CYP2D6, and CYP3A4,
and as a result, it may increase the exposure of drugs metabolized
by these enzymes. Therefore, the dosage of the
drug should be determined correctly and kept under control.
The authors emphasized that COVID-19 patients are
usually patients with more than one disease and use more
than one drug, and therefore, caution should be exercised
in terms of drug-drug interactions.
A case study presented by Tio et al. (2021) stated that
COVID-19 is associated with hyperinflammation and extremely
severe pneumonia [35]. Additionally, factors such
as discontinuation of smoking and stimulant drugs, and coadministration
of drugs that inhibit CYP1A2, such as caffeine,
may cause a decrease in metabolic activity with this
disease. Elfaki et al. (2022) emphasized that COVID-19
infection reduces liver functions, including clearance or
detoxification of drugs administered by CYP450s [36].
Health care providers have stated that they should be aware
of this disease-drug interaction when prescribing drugs
for the treatment of COVID-19 and other comorbidities.
In our cohort, CYP1A2 rs2069514 genotypes of the
patients hospitalized in the intensive care unit were as 44%
for AG, 40% for GG, and 16% for AA. For rs762551 polymorphism,
60% had CC, 20% had AC, and 20% had AA
genotypes. The number of patients with CYP1A2 *1A/*1C
+ *1C/*1C genotype (68.8% vs 31.3%) was found to be
significantly higher in patients admitted to the intensive
care unit compared to those without intensive care. However,
the number of patients with CYP1A2 *1A/*1F +
*1F/*1F genotype (16.1% vs 83.9%) was found to be
significantly lower.
In addition, the risk of hospitalization in intensive
care, was determined that those with CYP1A2 *1A/*1C
+ *1C/*1C genotype increased 5.23 times compared to
those with *1A/*1A + *1F/*1F, and those with chronic
diseases increased 4.68 times compared to those without.
Those at ≥65 years of age increased 5.17 times compared
to those under 65 years of age. Compared with CYP1A2
*1A, CYP1A2 *1C and CYP1A2 *1K are associated with
decreased induction and *1F with increased induction
[37]. In the early stages of COVID-19, hypoxia has been
reported to occur before the excessive inflammatory response
occurs [9, 10]. Recent experimental findings have
shown that sustained hypoxia leads to the downregulation
of CYP1A2 expression [38,15]. Multiple genetic polymorphisms,
mostly single nucleotide polymorphisms (SNPs),
have been associated with susceptibility to viral respiratory
infections [20].
Loss of taste and smell, which is widely used to
predict infection and disease is an important marker for
COVID-19. There are some controversial results about
smell and taste loss in the terms of different populations
and different virus variants. Our cohort showed the importance
of loss of taste and smell in the severity of the
disease. Like the loss of taste and smell, intubated conditions
were statistically different between groups. But for
intubation, it is impossible to discuss it with the data we
have, there should be much more information about the
patients’ conditions. Therefore, for intubation, although
we had a statistically significant difference, with the data
we have, we can not speculate on the condition.
Our results show that the CYP1A2 gene, whose association
with hypoxia has been shown in studies, increases
the risk of hospitalization in intensive care in patients with
*1A/*1C + *1C/*1C genotype, and CYP1A2 polymorphisms
may be of great importance in predicting prognosis
in patients with COVID-19. However, more research needs
to be carried out to fulfill the role of CYP1A2 polymorphisms,
not only in the terms of COVID-19 but also in
other hypoxia conditions.
Declaration of Interest
The authors report no conflict of interest. The authors
alone are responsible for the content and writing of this
article.
Author Contributions
IB: Evaluation of the manuscript, study design, clinical
data; IY: manuscript design; TY: Laboratuvary design,
study protocol, manuscript design; KU: Evaluation of the
genetic results, manuscript design; KNT: Study protocol,
clinical evaluation, genetic results.
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