Title: Regular physical activity can contribute to preventing cardiovascular risk factors in adolescents with ACE gene polymorphism

doi:10.21203/rs.3.rs-3006317/v1

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Research Article

Title: Regular physical activity can contribute to preventing cardiovascular risk factors in adolescents with ACE gene polymorphism

https://doi.org/10.21203/rs.3.rs-3006317/v1

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Background

The article aims to analyze the influence of the level of physical activity and the polymorphism in the ACE gene on cardiac autonomic modulation and the chance of cardiovascular risk in adolescents.

Methods

One hundred thirty-six adolescents, 14 years old (11 to 18), divided into active (AG) and sedentary (SG) groups. Blood pressure, body composition, physical activity level, and sexual maturation were assessed to characterize the groups. Afterward, an electrocardiogram was performed, and oral mucosal cells were collected to analyze heart rate variability and genotypic research of angiotensin-converting enzyme.

Results

Distribution frequency of D and I alleles, and time-domain variables of heart rate variability were similar between AG and SG subjects. AG presented lower systolic blood pressure and sympathetic modulation when compared to the SG DD. Additionally, the odds ratio for the cardiovascular events was increased in the SG DD compared with that in AG with DD allele (AG DD) adolescents, as verified for the autonomic variables LF%, HF%, LF/HF, and SBP.

Conclusions

Regular physical activity in adolescents can contribute to the maintenance of blood pressure levels, preventing autonomic imbalance and cardiovascular risk factors in adolescents with ACE gene polymorphism.

Adolescents

Angiotensin-converting enzyme

Physical activity

Autonomic nervous system

Cardiovascular

Understanding the genetic influence on health issues and preventing cardiovascular diseases is paramount. Epidemiological studies have shown that genetic factors influence about 30–50% of blood pressure variation [1, 2], contributing to hypertension and cardiovascular diseases. Polymorphisms can influence the expression and production of regulatory components in the endocrine system. These include the renin-angiotensin-aldosterone system (RAAS), which plays, along with other environmental factors, a fundamental role in the pathogenesis of essential arterial hypertension in both adults and adolescents [3].

Insertion/Deletion (I/D) angiotensin-converting enzyme (ACE) gene polymorphisms (rs1799752) stand out among these polymorphisms that contribute to unfavorable changes in blood pressure control. Individuals with the D allele display serum and cardiac ACE elevated levels. Thus, the ACE gene polymorphism is a genetic variant that can alter cardiovascular physiological function in individuals with a higher amount of angiotensin II [4]. This condition can increase the chances of developing cardiovascular diseases due to changes in several mechanisms such as electrolyte and endothelial imbalance, autonomic dysfunction, and, consequently, decreased heart rate variability (HRV) [5].

Studies showed that HRV impairment is an independent predictor of cardiovascular disease and mortality [6, 7]. Additionally, HRV can be influenced by factors such as general and abdominal obesity, higher blood pressure, and physical inactivity in different populations [8, 9]. These risk factors may occur as early as childhood, as shown by the study [10], and may be influenced by genetic factors [11].

Additionally, the sedentary lifestyle strongly contributes to all risk factors and is increasingly present in adolescents [12]. Given this fact, identifying autonomic dysfunctions in adolescents with ACE polymorphism becomes relevant, as their cardiac autonomic modulation may be altered even before the development of cardiovascular diseases. Regular physical exercises can act as a protective agent against these comorbidities [13]. However, few studies have studied the impact of polymorphism on the ACE gene (rs1799752) and the level of physical activity on adolescents' autonomic dysfunction.

Thus, this study aimed to analyze the influence of the level of physical activity and the polymorphism of the ACE gene (rs1799752) on cardiac autonomic modulation and the chance of cardiovascular risk in adolescents.

Sample collection

This analytical and cross-sectional study included adolescents of both sexes, aged between 11 and 18. The study included 136 adolescents (47 boys and 89 girls), which was divided into an active group (GA), composed of 76 individuals, and a sedentary group (GS), consisting of 60 individuals. The samples were classified into one of the three possible genotypes resulting from the ACE gene's polymorphism: two homozygous (DD and II) and one heterozygous (ID) genotype.

Students of the selected age group were invited to participate in the study upon furnishing the informed consent form (ICF) signed by the parents or guardians, which authorized their participation. This study followed the recommendations of the Helsinki Declaration and Resolution no. 466/2012 of the National Health Council of the Brazilian Ministry of Health.

The following exclusion criteria were used for the study sample: participants who did not attend all the study visits, those who presented any pathophysiological changes during the study, and those undergoing pregnancy or lactation. The data were collected during a single session on the scheduled days.

Collection of oral mucosal cells

Exfoliated oral mucosal cells were obtained from the participants by gently brushing the buccal mucosa and buccal groove using a sterile swab. The collected cells were then stored at − 20°C until DNA isolation.

Clinical assessment and body composition analysis

An anthropometric evaluation was performed with the participant in the orthostatic position. The weight was measured using a Balmak digital scale (kg), while the height was measured using a compact stadiometer, type EST 23 (in mm). A trained professional performed all the measurements according to NHBLI [14].

The bioelectrical impedance method (BIA) was carried out with the Maltron@ device, model BF906 (Maltron; Essex, UK), tetrapolar, 50 kHz. The procedure was performed during the morning after fasting for 10–12 hours in a supine position.

Evaluation of sexual maturation

For the evaluation of sexual maturation, the criteria used by Tanner were adopted [15]. It is a self-evaluation method using images, considering the development of breasts in girls, penis in boys, and hair on genitals in both genders.

Subsequently, the individuals were classified in one of the following five stages:

1st stage: Indicates that the individual is still in childhood (pre-pubertal),

2nd stage: Represents the beginning of the maturational period,

3rd and 4th stages: Shows the continuity of the maturation process,

5th stage: Indicates that the individual is a complete adult.

Measurement of blood pressure

The protocol for blood pressure measurement (Omron® HEM-711 and Omron® 905) followed the norms of the Brazilian Guideline of Hypertension [2] and the IV Report on the Diagnosis, Evaluation, and Treatment of Hypertension in Children and Adolescents [16]. An optimal cuff size was used according to the arm size of the participants.

Assessment of the heart rate variability

The HRV data were obtained in the supine position with spontaneous breathing. The time series of HR was acquired (Micromed Biotecnologia, WinCardio) by determining the RR interval with a 12- lead electrocardiogram, 1000 Hz sample rate, during 10 min and was analyzed in the time domain through the analysis of standard deviation of the range of regular beats (SDNN) and root-mean-square differences of successive R-R intervals (RMSSD). After visual inspection, the series of RR intervals was made by tuning the frequency cubic spline interpolation (fi = 250 Hz) and reducing the number of dots per decimation (18 times).

Then each beat was identified using the algorithm by Matlab™ program (Welch's method) that generates the result of spectral analysis with the respective bands of interest (HF, high-frequency: 0.4 to 0.15 Hz; LF, low-frequency: 0.15 to 0.04 Hz). Normalized LF and HF components of R–R variability were considered markers of cardiac sympathetic and parasympathetic modulation, and the ratio between them (LF/HF) was considered an index of the heart's autonomic modulation [17]. The results were expressed in absolute values (HF ms² and LF ms²) and percentages (HF% and LF%).

Physical Activity Level Assessment

The physical activity level was analyzed using the International Physical Activity Questionnaire (IPAQ). The data were converted into METS (Metabolic Equivalent of Task) for better visualization. The IPAQ allows the evaluation of the physical activity carried out by the individual during the previous week, classifying it into high (greater than 1500 MET-min/week) vs. low levels of physical activity (less than 600 MET-min/week) [18].

DNA Extraction and PCR

The DNA extraction from the oral mucosa cells was carried out using the Axyprep™ Mailsource Genomic DNA Miniprep Kit (axygen scientific - USA), following the manufacturer's instructions. The DNA was quantified, and subsequently, the DNA fragment containing the polymorphic site I/D of the ACE gene was sequenced using polymerase chain reaction (PCR). The primers used in this PCR allowed amplification of sequences with 190 base pairs (bp) for the DD genotype and 490 bp for the II genotype. Used the sequences hECAf (5′-CTG GAG ACC ACT CCC ATC CTT TCT-3′) and hECAr (5′-GAT GTG GCC ATC ACA TTC GTC AGA T -3′). The presence of both fragments served to identify the heterozygotes (ID).

PCR was performed in a final reaction mixture of 12 µL volume, comprising 6 µL of gotaq (Promega, cat. No. M7122), 0.06 µL of primers (hECAr e hECAf), 1 µL of DNA, and 5 µL of ultrapure water. The reaction conditions in the thermocycler alternated between temperatures of 95.55°C and 75°C, following: 5 min at 95°C, 40 cycles of 10 s at 95°C, 10 s at 58°C, 20 s at 72°C, and 5 min at 72°C. The steps in this protocol promoted denaturation of the DNA, annealing the primers to sample DNA strands, and then an extension of the DNA strands, respectively.

The PCR products were separated on 1% agarose gel, using 6 µL of the sample and 490 bp and 190 bp markers. The samples were run for 1 h 40 min at 80V. Afterward, the samples were stained with ethidium bromide (40 min), and electrophoresis was performed at 100V. The fragments were subsequently observed under ultraviolet light. The samples were classified into one of the three possible genotypes resulting from the polymorphism of the ACE gene: two homozygous (DD and II) genotypes and one heterozygous (ID) genotype.

To increase the specificity of the genotyping, the samples that presented the DD genotype were re-evaluated by a second PCR, using a specific primer for the incorporation were used the sequences: sense (5' TGG GAC CAC AGC GCC CGC CAC TAC-3'), hECAf, and anti-sense (5’-TCG CCA GCC CTA CCA TGC CCA TAA − 3'), hECAr.

Statistical analysis

Data were subjected to the Kolmogorov-Smirnov normality test. To analyze the differences between the groups, t-test and two-way ANOVA with Bonferroni posthoc test were used. The chi-squared test was performed to evaluate the association between qualitative variables. The level of significance was established at p < 0.05. Data are represented as mean ± standard error of the mean. Statistica® 5.0 software was used for data analysis.

The study included 136 adolescents (47 boys and 89 girls), with an average age of 14. The active group (AG) was composed of 76 individuals, (24) boys and (52) girls, and the sedentary group (SG) of 60 individuals, (23) boys and (37) girls. The statistical analysis did not reveal significant differences related to sex, indicating that the groups were homogeneous.

The Hardy-Weinberg balance was calculated, and the data were distributed in the frequency of the alleles D (n = 50 / 83%) and (n = 53 / 70%) and I (n = 10 / 17%) and (n = 23 / 30%) between the SG and AG groups, respectively, based on the Chi-squared test (χ² = 3.37 and p-value 0.66). The genotypes DD (n = 38 / 63%) and (n = 38 / 50%), DI (n = 12 / 20%) and (n = 15 / 20%), and II (n = 10 / 17%) and (n = 23 / 30%) between the SG and AG groups, respectively, based on the Chi-squared test (χ² = 3.62 and p-value 0.16). There was no difference in distribution frequency after a Fisher's test (Table 1).

Table 1

– Frequency of the D and I alleles and the genotypes (DD, DI, and II)
	SG	AG	χ ²
Alelo D	50 = (83%)	53 = (70%)	[3.37] 0.66
Alelo I	10 = (17%)	23 = (30%)
Genótipo DD	38 = (63%)	38 = (50%)
Genótipo DI	12 = (20%)	15 = (20%)	[3.62] 0.16
Genótipo II	10 = (17%)	23 = (30%)	[3.62] 0.16
SG: sedentary group; AG: active group; Statistical difference (P < 0.05), based on Chi-squared test (χ2).

For the division of sexual maturation between tanner stages, there were no differences in distribution between groups. With the following distribution of internships: 1: n = 5 (5.29%) and n = 7 (6.71%), 2: n = 15 (14.12%) and n = 17 (17.88%), 3: n = 30 (34.41%) and n = 48 (43.59%), n = 4: 10 (6.18%) and n = 4 (7.82%) between the SG and AG groups, respectively, based on the Chi-squared test (χ² = 5.37 and p-value 0.14) (Table 2).

Table 2

– Sexual maturation of adolescents
SEXUAL MATURATION	SG (n = 74)	AG (n = 214)	χ ²
Stage 1	5 (5.29%)	7 (6.71%)	[5.37] 0.14
Stage 2	15 (14.12%)	17 (17.88%)
Stage 3	30 (34.41%)	48 (43.59%)
Stage 4	10 (6.18%)	4 (7.82%)
Statistical difference (P < .05), based on Chi-squared test (χ2).

Table 3 shows the body composition, Age (years), Weight (kg), Height (cm), BMI (kg/cm²), WC (cm), heart rate, SBP, and DBP of the SG and AG groups. Each group was divided into three subgroups, considering Alleles D and I. Reduced values of SBP were observed in AG-DD compared to SG-DD and SG-DI. HR values were reduced in AG-DD as compared with that in SG-DI.

Table 3

Body composition, heart rate, SBP, and DBP of SG divided into groups with DD vs. alleles. DI vs. II and AG divided into groups with DD vs. alleles. DI vs. II.
	SG (n = 60)			AG (n = 76)
	DD(n = 38)	DI(n = 12)	II (n = 10)	DD(n = 38)	DI(n = 15)	II(n = 23)
Age (Years)	15 ± 1.5	15 ± 1.6	15 ± 1.5	15 ± 1.4	15 ± 1.9	15 ± 2
Weight (kg)	57 ± 12	58 ± 14	50 ± 13	51 ± 8	55 ± 10	54 ± 11
Height (cm)	162 ± 8	161 ± 9	162 ± 11	161 ± 7	157 ± 27	162 ± 11
BMI (kg/cm²)	21 ± 4	21 ± 5	19 ± 2	19 ± 3	21 ± 4	20 ± 2
WC (cm)	71 ± 8	72 ± 11	67 ± 6	66 ± 5	68 ± 5	69 ± 7
DBP (mmHg)	82 ± 12	89 ± 10	81 ± 12	79 ± 13	77 ± 18	80 ± 14
SBP (mmHg)	114 ± 11	118.5 ± 13	110 ± 15	107 ± 12 ^{* #}	113 ± 9	111 ± 2.0
HR (bpm)	67 ± 7	72 ± 10	66 ± 7	64 ± 8 ^#	67 ± 9	62 ± 6
Waist circumference (WC); BMI: Body Mass Index; HR: Heart Rate; SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure (*) comparison between SG vs. AG DD, (#) comparison between SG DI vs. AG DD with statistical difference p < 0.05, two-way ANOVA and Bonferroni posthoc test).

In Table 4 of the autonomic evaluation, in time-domain, (RR(ms), SDNN(ms), RMSSD(ms), SD1(ms), and SD2(ms)) nowhere observed difference among the groups. In the frequency domain, the SG group with the DD allele had higher values for sympathetic modulation (LF%); lower values for parasympathetic modulation (% HF%), and higher sympathovagal balance (LF/HF) when compared to the AG group with DD, DI, and II allele.

Table 4

Heart rate variability in time and frequency domain divided into SG groups with DD vs. alleles. DI vs. II and AG divided into groups with DD vs. alleles. DI vs. II.
	SG (n = 60)			AG (n = 76)
	DD(n = 38)	DI(n = 12)	II (n = 10)	DD(n = 38)	DI(n = 15)	II(n = 23)
Time Domain
RR (ms)	772 ± 86	735 ± 95	735 ± 111	799 ± 85	778 ± 113	788 ± 122
SDNN (ms)	57 ± 21	45 ± 14	43 ± 14	51 ± 13	49 ± 18	53 ± 16
RMSSD (ms)	55 ± 28	41 ± 17	40 ± 16	51 ± 23	50 ± 24	55 ± 24
SD1 (ms)	40 ± 19	31 ± 14	32 ± 15	40 ± 12	40 ± 18	40 ± 18
SD2 (ms)	70 ± 25	56 ± 18	56 ± 18	66 ± 11	64 ± 22	65 ± 18
Frequency Domain
LF (ms²)	1787 ± 2108	552 ± 452	735 ± 644	781 ± 681	660 ± 516	852 ± 663
HF (ms²)	1240 ± 3820	997 ± 1241	832 ± 842	1714 ± 2627	1658 ± 2992	1397 ± 1083
LF (%)	60 ± 14	44 ± 15	49 ± 14	40 ± 14*	44 ± 20*	41 ± 14*
HF (%)	40 ± 14	56 ± 15	51 ± 14	60 ± 14*	56 ± 20*	59 ± 14*
LF/HF	1.16 ± 0.79	0.96 ± 0.79	1.04 ± 0.70	0.80 ± 0.49*	0.78 ± 0.34*	0.80 ± 0.52*
RR: normal RR interval; SDNN: Standard deviation from the mean of normal RR intervals; RMSSD: Root mean square of the successive differences; LF: low frequency component in absolut (ms²) and percentual values (%); HF: high frequency component; in absolut (ms²) and percentual values (%); * p < 0.05 in SG DD vs AG. two-way ANOVA, Bonferroni post-hoc.

Additionally, when we evaluated the odds ratio for a cardiovascular event to occur in a group, we found that the SG DD has a higher chance of occurrences compared to the AG DD, as verified for the variables LF%, HF%, LF/HF, and SBP (Table 5 and Fig. 1).

Table 5

Cutoff points and indicators for detecting Heart rate variability and systolic blood pressure as cardiovascular risk factors in GS and GA with DD alleles.
	Cutoff	Odds ratio	SG DD (events/nonevents)	AG DD (events/nonevents)	95% CI	p-values
SDNN (ms)	< 63.70	0.5128	25/13	30/8	[0.183–1.434]	0.20
RMSSD (ms)	< 49.60	0.8944	23/15	24/14	[0.354–2.251]	0.81
LF (%)	> 46.10	2.6286	23/15	14/24	[1.0412–6.636]	0.04
HF (%)	< 53.80	2.6286	23/15	14/24	[1.0412–6.636]	0.04
LF/HF	> 0.85	3.0321	21/17	11/27	[1.1739–7.831]	0.02
SD1(ms)	< 35.10	1.2346	20/18	18/20	[0.501–3.038]	0.64
SD2(ms)	< 84.80	0.6724	26/12	29/9	[0.244–1.852]	0.44
SBP (mmHg)	> % 90	5.5862	9/29	2/36	[1.118–27.901]	0.03
CI: confidence interval; SDNN: Standard deviation from the mean of normal
RR intervals; RMSSD: Root mean square of the successive differences;
LF: low frequency component; HF: high frequency component;
SBP: Systolic blood pressure.

This study aimed to analyze the influence of physical activity level and polymorphism in the ACE gene (rs1799752) on cardiac autonomic modulation and the chance of cardiovascular risk in adolescents. It is essential to mention that, as far as we know, our study was the first to show possible relationships between the variables of the ACE gene polymorphism and the physical activity level in adolescents, together with cardiac autonomic modulation and risk of cardiovascular disease.

Thus, the most significant findings of this study demonstrate that the SG DD had higher blood pressure levels accompanied by higher sympathetic modulation and less vagal modulation than GA DD. Also, SG DD has been shown to increase cardiovascular disease risk. These data suggested that regular physical activity provides a protective action to physically active individuals even when the ACE gene polymorphism is present.

Studies show that the single D allele of the ACE gene polymorphism is sufficient to increase serum ACE production in individuals with it [19, 20]. As a result, individuals with the DD genotype showed approximately twice as much ACE activity as homozygotes II. Individuals with the ID genotype have an intermediate level of ACE activity between groups [21]. Thus, individuals with the DD genotype may be more exposed to higher levels of angiotensin II than those with genotype II.

Thus, the increase in the synthesis of ACE potentiates the increase in sympathetic activity and the systemic vasoconstrictor responses due to greater angiotensin II production and other mechanisms as a decrease in the endothelial signaling pathways triggered by bradykinin, which has vasodilating action, consequently increasing blood pressure [22].

On the other hand, physical exercise may decrease ACE activity, allowing higher blood flow and vascular conductance, which would be beneficial during exercise [23]. Furthermore, physical exercise reduces sympathetic activity and increases the vagal tonus.

Our results also demonstrate that the AG DD had higher vagal modulation values of HF (nu). The reduction in parasympathetic modulation of the SG DD is also implicated in the low values for HF (nu) since the importance of this frequency domain index mainly reflects vagal tone. These values are associated with increased cardiovascular abnormalities due to impaired autonomic function. The association of the ACE DD genotype with the decrease in the HRV high-frequency band leads to an autonomic imbalance, increasing the risk of cardiovascular events [24].

Due to regular physical activity, our study's improvement in autonomic modulation is well observed and was consistent with previous investigations. These results show that physical activity stimulates the predominance of parasympathetic modulation and the reduction of cardiac sympathetic modulation, reducing the risk factors of cardiovascular diseases [25]. This is evidenced in our study, where the AG DD, DI, and II groups showed higher vagal modulation accompanied by a reduction in sympathetic modulation compared to the SG DD group. Parallel, there is also a reduction in the sympathovagal balance, in which studies report that the lower this index, the greater the individual’s vagal predominance [26].

Studies show that exercise promotes cardiovascular benefits. In the active vs. sedentary comparison, better cardiac autonomic modulation of the active group was also demonstrated, along with reduced SBP and DBP values, proving the effectiveness of physical exercise in improving autonomic modulation [27] and decreases in blood pressure [28] and weight control [29]. However, ACE polymorphism is not explored in these studies. Additionally, our study did not observe any difference in adolescents' weight.

In the association between heart rate variability parameters (HRV) with duration of leisure-time physical activity in adolescents, it was observed that leisure-time physical activity is associated with better HRV. These associations were improved when adolescents were physically active for more than six months [30].

The relationship between sports practice, school physical education, habitual physical activity, and cardiovascular risk indicators in adolescents observed that sports practice was related to more significant heart rate variability during rest [31]. With this, studies demonstrate that physical exercise, in addition to reducing ACE activity, would reduce the action of Ang II on ANS and can improve baroreflex control [32] by increasing the sensitivity of the aortic depressor nerve, leading to an attenuation of the sympathetic tone [33, 34].

Experimental evidence has shown that physical activity effectively reduces RAS activity and improves cardiac autonomic control, reducing the risk of cardiovascular diseases [35].

Our results demonstrated that the odds for developing cardiovascular disease increased after the association of sedentary lifestyle and DD genotype with indexes in the frequency domain of heart rate variability and systolic blood pressure. This result is evidenced by reduced parasympathetic modulation (HF%) and increased sympathetic modulation (LF%) and SBP.

The results have significant clinical applications since the monitoring of HRV values that discriminate cardiovascular risk in adolescents can help the multidisciplinary health team identify cardiovascular risk through HRV [36]. Considering that the frequency domain parameters are the best cardiovascular risk discriminants in adolescents, monitoring cardiac autonomic modulation in the early stages of life is emphasized, as it is considered an independent predictor of mortality [6].

Our results also reinforce the importance of regular physical activity in promoting health in young people. According to Zaffalon et al. (2018) [37], the sedentary lifestyle associated with genetic factors induces impairment of cardiac autonomic modulation, compromising the quality of life, even before changing any cardiovascular or metabolic clinical parameters.

However, the importance of interpreting these research results is emphasized by some limitations, one of which is using accelerometer sensors in mobile and biochemical marks.

Regular physical activity in adolescents can contribute to maintaining blood pressure levels and preventing autonomic imbalance and cardiovascular risk factors in adolescents with ACE gene polymorphism.

Statements and Declarations

Competing Interests: The authors did not receive support from any organization for the submitted work

ACKNOWLEDGMENTS

We thanks Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão - FAPEMA (Universal - 01293/16); Fundação de Amparo à Pesquisa

e ao Desenvolvimento Científico e Tecnológico do Maranhão - FAPEMA- (BEPP-01404/21, universal 00919/17) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of interest

The authors declare no conflict of interest.

Human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from the parents. Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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Title: Regular physical activity can contribute to preventing cardiovascular risk factors in adolescents with ACE gene polymorphism

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Abstract

Background

Methods

Results

Conclusions

Figures

INTRODUCTION

METHODS

Sample collection

Collection of oral mucosal cells

Clinical assessment and body composition analysis

Evaluation of sexual maturation

Measurement of blood pressure

Assessment of the heart rate variability

Physical Activity Level Assessment

DNA Extraction and PCR

Statistical analysis

RESULTS

DISCUSSION

CONCLUSION

Declarations

References

Additional Declarations

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