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Eurasian Journal of
Medicine and Oncology The genetics of chronic stress in cervical lesions

model, and p<0.001, OR = 4.856, 95% CI: 2.188 – 10.776 desensitize β2-AR in their basal state, a process that is
for the recessive model). Regarding CHRNA5, the variant more pronounced in the Gly variant compared to the
allele (A) has a protective effect in the dominant (p=0.030, Arg variant. Furthermore, after exposure to isoprenaline,
OR = 0.529, 95% CI: 0.296 – 0.946) and overdominant the Gly variant exhibits significantly enhanced receptor
(p=0.029, OR = 0.517, 95% CI: 0.284 – 0.940) models. downregulation. This suggests that individuals with the
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AA (Arg) genotype may exhibit a stronger physiological
4. Discussion response to stress compared to those with the GG (Gly)
In this study, our investigation revealed associations genotype.
between HPV-related cervical lesions and three out Our results also demonstrate a protective effect of the
of the seven candidate genes under consideration. All presence of the variant allele (A) in the CHRNA5 gene.
candidate genes were linked to chronic stress-responsive CHRNA5 encodes a subunit of the nicotinic acetylcholine
mechanisms. Chronic stress has been associated with receptor. In the adrenal medulla, acetylcholine released
tumor progression, 5,6,39,40 including gynecological cancers. from the splanchnic sympathetic nerves activates
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Multiple physiological systems, including the autonomic acetylcholine receptors on the membrane of chromaffin
nervous system and the HPA, are engaged during the stress cells, which release catecholamines into the bloodstream.
response. This response is initiated by the production of As mentioned above, catecholamines are one of the main
key mediators, such as the catecholamines norepinephrine mediators of the stress response. Rs16969968 is a missense
and epinephrine, which are released by the sympathetic variant resulting in an amino acid substitution at codon
nervous system and adrenal medulla. Norepinephrine, 398 (D398N) of CHRNA5. In vitro functional studies have
epinephrine, and cortisol are regarded as the primary shown that nicotinic receptors that contain this variant
stress hormones, and their levels are elevated during have a reduced response to agonists. Therefore, since the
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chronic stress. Catecholamines exert their effects through variant allele is functionally less active, it may promote a
adrenergic receptors coupled to G-proteins, which activate lower release of catecholamines, protecting individuals
the cAMP-dependent PKA system, subsequently triggering from the physiological response to chronic stress.
several downstream signaling pathways, including those
related to cell growth. 42,43 Among adrenergic receptors, Multiple studies have demonstrated that serotonin
β2-ARs are predominant, mediating the majority of cellular and serotonergic drugs influence various components
responses to external stimuli. The ADRB2 gene encodes of the HPA axis and the stress response. 50-52 The SLC6A4
these receptors, which are located on cell membranes, gene encodes an integral membrane protein (SERT)
and function pre-synaptically to stimulate the release of whose primary function in the central nervous system
epinephrine. β-blockers, which inhibit β-adrenergic is to regulate serotonergic signaling by transporting
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receptors, have been shown to offer therapeutic benefits serotonin molecules from the synaptic cleft back into the
in managing several types of tumors. 45,46 Given the central pre-synaptic terminal for reuse. A loss of SERT function
role of catecholamines and their interaction with β2-AR in has been associated with an increased sympathetic stress
the stress response, we hypothesized that genetic variations response. 53-55 SERT is highly expressed in chromaffin cells
in the ADRB2 gene could influence susceptibility to HPV of the adrenal medulla, where it plays a local role within
infection and cervical lesions. Our study identified an the adrenal gland in regulating the sympathetic stress
association between the AA genotype and the A allele response. 14,56 Evidence suggests that SERT coordinates
of ADRB2 with an increased risk of HPV infection and serotonergic regulation of catecholamine exocytosis
cervical lesions. Dominant and recessive models both through 5-hydroxytryptamine receptor 1A-mediated
showed a risk effect, which was slightly higher for the inhibition of catecholamine secretion, contributing to the
recessive model. In multifactorial conditions such as stress response. Although serotonin is not synthesized
cervical lesion development, the distinction between in adrenergic chromaffin cells, SERT facilitates its
dominant and recessive genetic models is often blurred accumulation. In this study, we analyzed a known
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because the complex interplay of multiple factors shapes polymorphic variation of this gene, 5-HTT VNTR, which
the risk associated with genetic variants. However, this consists of a VNTR in the second intron. Only the two
study shows us that at least one A allele is sufficient for most common alleles were identified, those with 10 or
susceptibility. The A allele corresponds to a missense 12 tandem repeats of a 17 bp sequence. The 10 allele has
mutation in which glycine (Gly) is replaced by arginine been linked to lower transcriptional activity compared to
(Arg) at codon 16 of the intron-less ADRB2 gene. According the 12 allele. 57,58 Our findings revealed that the presence of
to the “dynamic model of receptor regulation” proposed the 10 allele is a risk factor. We propose that the SLC6A4
by Liggett, endogenous catecholamines dynamically genotype may influence catecholamine secretion, thereby
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Volume 9 Issue 2 (2025) 255 doi: 10.36922/EJMO025100047