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Abstract

BACKGROUND:

Angioneurotic edema is the most dangerous complication in angiotensin-converting enzyme inhibitors (ACEIs) therapy. Based on the current data, the clinical and genetic predictors of angioedema development are still understudied, which demonstrates the relevance of this study.

OBJECTIVE:

To reveal the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension.

METHODS:

The study enrolled 111 subjects randomized into two groups: study group, patients with the angioedema as a secondary side effect to enalapril; and control group, patients without adverse drug reaction. All patients underwent pharmacogenetic testing.

RESULTS:

An association between the development of the angioneurotic edema and the genotypes AA rs2306283 of gene SLCO1B1, TT rs4459610 of gene ACE, and CC rs1799722 of gene BDKRB2 in patients was revealed.

CONCLUSION:

The findings justify further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Keywords

ACE inhibitors enalapril adverse drug reaction hypertensive disease angioedema

1. Introduction

Angiotensin-converting enzyme inhibitors (ACEIs) are among the widest-used and most efficacious drugs to treat cardiovascular pathologies [1,2]. At the same time, a major problem with the ACEIs is the angioneurotic edema (angioedema), whose development stops the drugs intake in 19–30% of cases [3–5].

Angioedema is one of the most dangerous ACEI-induced adverse reactions: according to certain studies it is responsible for about 40% of all Quincke’s edemas in the patients that enter emergency care units [6]. With this, the incidence of the angioedema in the totality of the adverse drug reactions (ADRs) as secondary side effects to the drugs of this group is about 0.1–0.3% [7–9]. Besides, findings have shown that angioedema occurs most often within the first week following the treatment initiation; however, in 20% of cases this ADR developed within the 6 weeks after the therapy started [10]. According to Beltrami et al. 46% of patients experienced recurrences of the Quincke’s edema after discontinuation of the ACEIs. With this, in 88% of the examined patients, the first recurrence of angioedema was observed within the first month, and 3 months after in one case (2%) [11]. Given the severe clinical implications of angioedema in the patients on ACEIs, finding the predictors of this ADR is a hot issue.

As of today, some studies that investigate the association of the polymorphisms of the candidate genes with the ACEI-induced complications, including angioedema, are available [12–15]; however, their findings are ambiguous. Investigating the possible genetic backgrounds of the ACEI-associated edema will allow for the development of a personalized approach to the use of the ACEIs, which will reduce the risk of the development of life-threatening conditions and improve the quality of life of the patients with cardiovascular pathologies who take ACEIs. Therefore, the objective of the current study was to identify the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension.

2. Materials and methods

Over a two-year period, 663 patients with the diagnosis essential arterial hypertension were assessed. Based on the retrospective analysis of the outpatient records and outpatient visit findings, 111 patients who met the inclusion (patients with stage 2–3 hypertensive disease (HD) who took enalapril) and exclusion (patients with heart defects, myocardites, secondary forms of arterial hypertension, prior pulmonary embolism and infective endocarditis, acute myocardial infarction and decompensated chronic cardiac insufficiency, acute cerebral circulation disorder, oncological diseases, chronic obstructive pulmonary disease, and bronchial asthma) criteria were enrolled; these were 71 (64%) women and 40 (36%) men, whose mean age was 65.13 ± 8.16 years.

The study group (Group 1) included 7 patients (3 men and 4 women) with the angioedema as a secondary side effect to enalapril in past histories and outpatient records; their mean age was 66.7 ± 7.6 years. The time of development of the angioedema following the enalapril intake was 4 to 9 days, 6 ± 1.82 days on average. After discontinuation of enalapril, angioedema recurred in 3 (42.8%) patients, within 13 to 22 days.

The control group (Group 2) involved 104 subjects without ADRs secondary to enalapril, their mean age was 65.5 ± 8.4 years. The control group involved 21 men (20.1%) and 83 women (79.9%).

HD was diagnosed based on the criteria of the Russian clinical guidelines of 2020 [1]. All subjects underwent a standard general clinical examination, which included collecting the complaints, past and current medical histories, physical examination, laboratory instrumental tests: complete blood count and blood biochemistry (biochemical analyzer Architectc 8000. Abbott, USA), urinalysis (automated urine analyzer iChemVelocity, BeckmanCoulter, USA), electrocardiography (ECG) (electrocardiograph Med-Mos ECG300G, China), echocardiography (ECHO-CG) (ultrasound scanner ToshibaXario SSA-660A, Japan), daily blood pressure monitoring (DBPM) (BPLab, Russia), Holter ECG monitoring (HECGM) (Astrocard^®, Miocard-Holter, HE2 3-channel ECG recorder, Russia). The “office” blood pressure (BP) was measured using the auscultatory method, with the help of the professional mechanic blood pressure meter (Little Doctor LD-71, Singapore), sitting, three times, with 1–2-minute intervals. To reveal the arm-to-arm BP difference, the BP was measured at both arms.

The groups were comparable as of the gender-age characteristics, systolic and diastolic BP levels, HD stages, disease durations, shares of patients with achieved target BPs, incidence rates of ischemic heart disease, presence of stage I-IIa chronic cardiac insufficiency, hemodynamic characteristics (ECHO-CG and DBPM values), core laboratory findings (complete blood count, blood biochemistry, and urinalysis).

The study was approved by the Ethics Committee of Ogarev Mordovia State University (Protocol No. 91 of 12/23/2020) and complied with the requirements of the Declaration of Helsinki. Before enrollment, all subjects gave their written informed voluntary consent to examination.

2.1. Molecular genetic testing

To investigate the carriage of the polymorphism of the genes possibly related to the induction of development of the angioedema as a secondary side effect to ACEIs, the patients of the study and control groups underwent molecular genetic testing of their genes.

2.2. Justification of selection of genes for the study

As of today, the mechanism of development of the ACEI-induced angioneurotic edema is still understudied. Most authors associate angioedema with the inhibition of kinase II (analog of ACE), which is involved in the degradation of bradykinin; as a result, it accumulates and induces plasma extravasation both directly by acting on receptors and indirectly through the stimulation of P substance release, which leads to plasma transsudation via the NK1 receptors [16].

The other possible mechanism of development of the angioedema as a secondary side effect to ACEI involves the bradykinin degradation defect. Half of the patients with ACEI-induced angioedema have, as it has been shown, a deficiency of the enzymes directly involved in the bradykinin active molecule decomposition. As a result, when ACEIs are used, much greater peptide activity is observed [17,18].

These mechanisms of development of angioedema directly associate with the bradykinin receptor function, angiotensin-converting enzyme level, and enalapril concentration in the body, which depends on the drug distribution and metabolism.

To find the pharmacogenetic markers of development of the angioedema as a secondary side effect to enalapril, the data from the specialized resource PharmGKB (https://www.pharmgkb.org/) were analyzed; based on the findings, the following polymorphisms of genes were selected: rs4149056 of gene SLCO1B1, rs2306283 of gene SLCO1B1, rs495828 of gene ABO, and rs8176746 of gene ABO, which, according to findings, have effect on the pharmacokinetic parameters of enalapril [19,20], and rs4459610 of gene ACE, rs1799722 of gene BDKRB2, and rs62151109 of gene CLASP1, which were associated with the level and tissue accumulation of bradykinin and angiotensin-converting enzyme. [14,15,21,22].

Literature sources describe individual studies aimed at revealing the correlation between the angioedema as a secondary side effect to ACEI and the above polymorphisms of genes.

2.3. Genotyping

The genetic study used as material the blood sampled with the help of the VACUETTE^® (Greiner Bio-One, Austria) vacuum system into test tubes with EDTA (ethylenediaminetetraacetate). The whole blood and extracted DNA were stored at −80 °C and transported at −20 °C. The carriage of the selected polymorphisms of genes was determined by the real-time allele-specific polymerase chain reaction (Real-Time PCR) method using the CFX96 Touch Real-Time PCR Detection System (Bio-Rad Laboratories, Inc., USA).

2.4. Statistical processing

Statistical processing of the findings used the standard Stat Soft Statistica 10.0 (USA) application software package. To evaluate the normality of distribution of the quantitative data, the graphic (frequency histogram) and calculation Kolmogorov-Smirnov and Shapiro-Wilk methods were used.

The qualitative values are presented as the absolute values (n) and percentages (%). The frequency distribution of the genotypes of all studied polymorphic markers was examined for compliance with the Hardy-Weinberg equilibrium. To reveal the inter-group differences of the qualitative parameters frequencies and to evaluate their statistical significance, the 𝜒² test was used; at the small number of observations, the Fisher’s exact test was calculated. To evaluate the correlation between: the studied parameters, the odds ratio (OR) of development of event with 95% confidence interval (CI) was calculated. The significance of the revealed differences and correlations in all types of analysis was assumed at the level p < 0.05.

3. Results

Along with the general clinical examinations, all patients were checked for the carriage of the genetic markers rs4149056 of gene SLCO1B1, rs2306283 of gene SLCO1B1, rs4459610 of gene ACE, rs495828 of gene ABO, rs8176746 of gene ABO, rs1799722 of gene BDKRB2, and rs62151109 of gene CLASP1. Based on the analysis of the findings, the association between the genetic markers and the adverse reactions in the form of angioneurotic edema was studied.

To justify the selection of the model of inheritance for analysis in this study, the distribution of frequencies of the genotypes of the above genes was checked for compliance with the Hardy-Weinberg equilibrium. (Table 1)

Table 1
Results of evaluation of compliance of distribution of genotypes of studied genes with Hardy-Weinberg criterion

Gene Genotypes Group 1 n = 7 HWE 1 𝜒²∕p Group 2 n = 104 HWE 2 𝜒²∕p

SLCO1B15* rs4149056 C/C 1.000 1.000 0.00/1 0.615 0.614 0.00/1

C/T 0.000 0.000 0.337 0.339

T/T 0.000 0.000 0.048 0.047

SLCO1B1 rs2306283 A/A 0.857 0.735 3.09/0.08 0.221 0.290 3.91/0.05

A/G 0.000 0.245 0.635 0.497

G/G 0.143 0.020 0.144 0.213

ACE rs4459610 A/A 0.000 0.000 0.00/1 0.202 0.191 0.08/0.78

A/T 0.000 0.000 0.471 0.492

T/T 1.000 1.000 0.327 0.316

ABO rs495828 G/G 0.000 0.250 4.77/0.03 0.663 0.692 3.63/0.06

G/T 1.000 0.500 0.337 0.280

T/T 0.000 0.250 0.000 0.028

ABO rs8176746 G/G 1.000 1.000 0.00/1 0.769 0.749 1.06/0.3

G/T 0.000 0.000 0.192 0.233

T/T 0.000 0.000 0.038 0.018

BDKRB2 rs1799722 C/C 1.000 1.000 0.00/1 0.192 0.231 1.24/0.27

C/T 0.000 0.000 0.577 0.499

T/T 0.000 0.000 0.231 0.270

CLASP1 rs62151109 C/C 1.000 1.000 0.00/1 0.923 0.925 0.00/1

C/T 0.000 0.000 0.077 0.074

T/T 0.000 0.000 0.000 0.001

Gene	Genotypes	Group 1 n = 7	HWE 1	𝜒²∕p	Group 2 n = 104	HWE 2	𝜒²∕p
SLCO1B15* rs4149056	C/C	1.000	1.000	0.00/1	0.615	0.614	0.00/1
	C/T	0.000	0.000		0.337	0.339
	T/T	0.000	0.000		0.048	0.047
SLCO1B1 rs2306283	A/A	0.857	0.735	3.09/0.08	0.221	0.290	3.91/0.05
	A/G	0.000	0.245		0.635	0.497
	G/G	0.143	0.020		0.144	0.213
ACE rs4459610	A/A	0.000	0.000	0.00/1	0.202	0.191	0.08/0.78
	A/T	0.000	0.000		0.471	0.492
	T/T	1.000	1.000		0.327	0.316
ABO rs495828	G/G	0.000	0.250	4.77/0.03	0.663	0.692	3.63/0.06
	G/T	1.000	0.500		0.337	0.280
	T/T	0.000	0.250		0.000	0.028
ABO rs8176746	G/G	1.000	1.000	0.00/1	0.769	0.749	1.06/0.3
	G/T	0.000	0.000		0.192	0.233
	T/T	0.000	0.000		0.038	0.018
BDKRB2 rs1799722	C/C	1.000	1.000	0.00/1	0.192	0.231	1.24/0.27
	C/T	0.000	0.000		0.577	0.499
	T/T	0.000	0.000		0.231	0.270
CLASP1 rs62151109	C/C	1.000	1.000	0.00/1	0.923	0.925	0.00/1
	C/T	0.000	0.000		0.077	0.074
	T/T	0.000	0.000		0.000	0.001

Remark: HWE 1: distribution of frequencies according to Hardy-Weinberg criterion for group 1; HWE 2: distribution of frequencies according to Hardy-Weinberg criterion for group 2.

Due to the small number of patients in study group 1, the multiplicative model of inheritance was not calculated. Given the revealed compliance of the groups as of the distribution of frequencies of genotypes with the Hardy-Weinberg equilibrium, the common inheritance model was selected for the further analysis. The investigation of the carriage of genotypes for polymorphic markers of studied genes in the patients with edema and control group has yielded the values shown in Table 2.

Table 2

Distribution of frequencies of genotypes and analysis of odds ratios of studied genes between study and control groups

Gene	Genotypes	Group 1n (%)	Group 2n (%)	𝜒²	p	OR
						Value	95% CI
SLCO1B15* rs4149056	T/T	7 (100%)	5 (4.8)			9.42	0.52–169.41
	T/C	0 (0%)	35 (33.7)	4.21	0.12	0.13	0.01–2.35
	C/C	0 (0%)	64 (61.5)			1.21	0.06–23.95
SLCO1B1 rs2306283	A/A	6 (85.7%)	23 (22.1)			21.13	2.42–184.53
	A/G	0 (0%)	66 (63.5)	14.60	0.0007	0.04	0.00–0.69
	G/G	1 (14.3%)	15 (14.4)			0.99	0.11–8.81
ACE rs4459610	A/A	0 (0%)	21 (20.2)			0.26	0.01–4.71
	A/T	0 (0%)	49 (47.1)	12.76	0.002	0.07	0.00–1.34
	T/T	7 (100%)	34 (32. 7)			30.65	1.70–552.41
ABO rs495828	G/G	0 (0%)	69 (66.4)			0.03	0.00–0.61
	G/T	7 (100%)	35 (33.6)	12.27	0.002	29.37	1.63–529.02
	T/T	0 (0%)	0			inf	inf
ABO rs8176746	G/G	7 (100%)	80 (76.9)			4.57	0.25–82.83
	G/T	0 (0%)	20 (19.2)	2.06	0.36	0.27	0.02–5.01
	T/T	0 (0%)	4 (3.9)			1.49	0.07–30.34
BDKRB2 rs1799722	C/C	7 (100%)	20 (19.2)			61.83	3.39–1127.24
	C/T	0 (0%)	60 (57.7)	23.24	<0.001	0.05	0.00–0.88
	T/T	0 (0%)	24 (23.1)			0.22	0.01–3.97
CLASP1 rs62151109	C/C	7 (100%)	96 (92.3)			1.32	0.07–25.18
	C/T	0 (0%)	8 (7.7)	0.58	0.75	0.76	0.04–14.42
	T/T	0 (0%)	0			0.00	0.00

Note. OR, odds ratio; CI, confidence interval; p, level of significance; 𝜒², Pearson’s chi-squared test.

Results of the analysis of the association between the polymorphic markers rs4149056 and rs2306283 of gene SLCO1B1 and the angioedema as a secondary side effect to enalapril demonstrate that the patients of the study group have a statistically significant association between angioedema and carriage of the genotype AA for the polymorphism rs2306283 of gene SLCO1B1 (OR = 21,13 (2.42–184.53), 𝜒² = 14.60. p < 0.001).

Thus, our study has revealed the association between the angioedema as adverse reaction to enalapril with the genotype TT for the polymorphism rs4459610 of gene ACE in patient (OR = 30.65 (1.70–552.41), 𝜒² = 9.54, p < 0.01).

The analysis of distribution of the frequency of genotypes for the polymorphism rs495828 of gene ABO between the study and control group has revealed statistically significant differences in the patients with carriage of the genotype GT (OR = 29.37 (1.63–529.02), 𝜒² = 12.27, p < 0.01). The analysis for the polymorphic marker rs8176746 of gene ABO has not revealed any significant differences.

The analysis of the incidence of the polymorphic marker rs1799722 of the gene of receptor 2 to bradykinin (BDKRB2) in the studied groups has revealed the association between the angioedema as adverse reaction to enalapril and the genotype CC (OR = 61.83 (3.39–1127.24), 𝜒² = 23.24, p < 0.0001).

The analysis of the incidence and distribution of the genotypes for the polymorphic marker rs62151109 of gene CLASP1 revealed the prevalence of the genotype CC in both groups, notwithstanding the presence or absence of the adverse reaction in the form of angioedema, while no one of the enrolled patients showed the genotype TT for this marker. No statistically valid differences between the two groups relative to the distribution of genotypes were revealed. Hence, despite the small number of the study group patients, the study revealed a statistically significant association between the investigated polymorphisms of genes and the angioedema as a secondary side effect to enalapril. The risk of development of angioedema increased 21-fold at the carriage of the genotype AA for the polymorphic marker rs2306283 SLCO1B1, 30-fold at the carriage of the genotype TT for the polymorphic marker rs4459610 of gene ACE, 61-fold at the carriage of the genotype CC for the polymorphic marker rs1799722 of gene BDKRB2, and 29-fold at the carriage of the genotype GT for the polymorphic marker rs495828 of gene ABO.

4. Discussion

Based on the data from literary sources, the studies dealing with the association between the polymorphisms of the candidate genes and the ACEI-induced complications, including angioedema, are not numerous, and their findings are ambiguous [12–15].

Some observations have shown that the risk of development of the ACEI-associated Quincke’s edema associates with the gender and racial origin; this supposes underlying genetic factors [23].

The analysis of certain works has revealed that the gene of solute carrier 1B1 (SLCO1B1) encodes the OATP1B1 protein, one of the major absorbing carrier proteins, which is expressed on the basolateral membrane of the human hepatocytes and is involved in the hepatic clearance of many drugs, including ACEIs. Variants of this gene can have effect on the pharmacokinetics of drugs, lead to disturbances of the mechanism of response to drugs, and expectedly lead to adverse reactions [19,24–26]. Our study has revealed a statistically significant association between the angioedema as adverse reaction to ACEIs, specifically enalapril, and the genotype AA for the polymorphism rs2306283 of gene SLCO1B1 in the patient.

Supposedly, the development of angioedema in the patients taking ACEIs is provoked mostly by the elevation of the bradykinin concentration, which results in the vasodilatation under the effect of the inflammation mediators, and in the flow of the liquid part of blood into the subcutaneous tissue. This hypothesis is based on that ACE is a nonspecific peptidase, which is involved in the metabolism of many small-size peptides. The development of angioedema is associated with the effect of the ACEI group drugs on the kinin system. The pharmacologic effect of the ACEIs is based on the competitive blocking of ACE, which transforms the inactive octapeptide angiotensin I into angiotensin II, and is the kininase II involved in the bradykinin inactivation. ACEIs block the degradation of bradykinin, this leads to a greater release of the vasodilating prostaglandins and nitric oxide [27–30]. Bradykinin is a kinin-family nonapeptide, which cleaves off the high molecular weight kininogen under the effect of the plasma kallikrein. Its biologic effect is realized via the activation of the specific B2 receptors located in the membranes of the endothelial and smooth muscle cells. The plasma bradykinin is inactivated mainly via the enzymatic degradation under the effect of the two metallopeptidases: kininase I (carboxypeptidase N) and kininase II (ACE). Such enzymes as the aminopeptidase P, neutral endopeptidase, dipeptidyl peptidase IV, and aminopeptidase N can promote the bradykinin elimination as well [31]. The accumulation of bradykinin leads to the apparent vasodilatation, increased permeability of vessels, and development of local edema. Though bradykinin plays a major role in the pathogenesis of the ACEI-induced angioedema, other mechanisms of its development exist, too. This hypothesis is supported by the evidence that angioedema can occur when using the angiotensin ii receptor blockers that do not affect the kinin system [32,33]. Supposedly, a role in the development of angioedema can be played by such neuromediator as the substance P, in whose inactivation the dipeptidyl peptidase IV and aminopeptidase P are involved [34]. The genetically conditioned decreased activity of aminopeptidase P can associate with the higher risk of the ACEI-induced angioedema [33,35]. The bradykinin receptor 2 (BDKRB2) is involved in the vasorelaxation stimulating the production of the endothelial NO-synthase and the following NO generation. Currently, the issue of the effect of the carriage of the polymorphic variants of gene BDKRB2 on the occurrence of the ACEI-associated complications remains pending, as certain authors support the association between the polymorphisms in the candidate gene with angioedema [15,36], while other researchers deny this hypothesis [37,38]. Our study has revealed a statistically significant association between the angioedema as adverse reaction to enalapril and the carriage of the genotype CC for the allelic variant rs1799722 of gene BDKRB2 in the patient.

The ACE gene encodes the angiotensin converting enzyme (ACE), a protein circulating in the extracellular space, which plays a major role in the regulation of the blood pressure and electrolyte balance. ACE induces the formation of angiotensin-II, an extremely powerful vasoconstrictor, and the decomposition of bradykinin, which is responsible for the vasodilatation [39]. As of today, more than 160 polymorphisms of the gene ACE are known. Some studies deal with the polymorphism of the gene ACE insertion/deletion (I/D), including the presence or absence of the insertion of 287 base pairs (bp) in the intron 16. Patients with the genotype II have low levels of the serum ACE compared with the ID and DD ones [8]. Our study has revealed a statistically significant association between the angioedema as adverse reaction to enalapril and the carriage of the genotype TT for the polymorphic marker rs4459610 of gene ACE in the patient.

Gene ABO located in 9q34.2 encodes the glycosyl transferases, which catalyze the transfer of different carbohydrate groups onto the H-antigen, forming, in this way, the antigens A and B of the ABO system [20]. The literature shows only the data relative to the risk of the enalapril-induced cough. Thus, the frequency of the carriers of genotype TT for the allelic variant rs495828 of gene ABO was significantly higher in the group of patients with the cough as a secondary side effect to ACEI notwithstanding the gender, which can support the possible association with the angioedema due to similar pathogenetic processes. [40]. Our study has revealed a statistically significant association between the angioedema as adverse reaction to enalapril and the genotype GT for the polymorphic marker rs495828 of gene ABO in the patient.

The problem of this study is the small number of the study group patients; hence, the statistical methods could not prove certain clinically significant associations between factors.

5. Conclusion

Given the severe clinical implications of angioedema in the patients on ACEIs, the need arises to develop the personalized approach for the timely prognosis of the complications. The study demonstrates the association between the polymorphic variants of certain genes with the onset of the angioedema as a secondary side effect to enalapril in patients with cardiovascular pathology. Statistically significant association between the angioedema as adverse reaction to ACEIs (specifically enalapril) and the carriage of the genotype AA for rs2306283 of gene SLCO1B1, genotype TT for rs4459610 of gene ACE, genotype CC for rs1799722 of gene BDKRB2, and genotype GT for rs495828 of gene ABO in the patient has been revealed. The findings justify the further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Footnotes

Ethical approval

The study complied with the requirements of the Declaration of Helsinki and was approved by the Ethics Committee of Ogarev Mordovia State University (Protocol No. 91 of 12/23/2020).

Informed consent

Informed consent was obtained from all individuals included in this study.

Competing interests

The authors state no conflict of interest.

Funding

The work was performed as part of the Russian Federation Ministry of Health state assignment for the years 2021–2023, no. 121110800062-6 “New Pharmacogenetic Biomarkers of Safety of Pharmacotherapy for Certain Socially Significant Diseases”. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author contributions

All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Supplementary materials

The supplementary material is available in the electronic version of this article: .

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Pharmacogenetic markers of development of angioneurotic edema as a secondary side effect to enalapril in patients with essential arterial hypertension

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Materials and methods

2.1. Molecular genetic testing

2.2. Justification of selection of genes for the study

2.3. Genotyping

2.4. Statistical processing

3. Results

5. Conclusion

Footnotes

Ethical approval

Informed consent

Competing interests

Funding

Author contributions

Supplementary materials

References