Early life stress unravels epistatic genetic associations of cortisol pathway genes with depression.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (ß = -0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

International Migration, Refugees, and Spread of Tuberculosis in Brazil: Analysis of Clusters, Trends, and Associated Factors (2010-2021).

BACKGROUND: International migration is a global phenomenon with significant implications on the health-disease process due to exposures along transit routes and local/destination epidemiological indicators. We aimed to analyze the transmission and spread of tuberculosis among international migrants and refugees from a spatiotemporal perspective and the associated factors. METHOD: This was an ecological study of cases of tuberculosis in international migrants in Brazil, between 2010 and 2021. Annual incidence rates were calculated and spatiotemporal scan techniques were used to identify municipalities at risk. Multiple logistic regression was used to identify factors associated with tuberculosis in international migrants. RESULTS: A total of 4037 cases of tuberculosis were reported in Brazil in international migrants. Municipalities at risk for this event were identified using the spatiotemporal scan technique, and a cluster was identified with ITT: +52.01% and ETT: +25.60%. A higher probability of TB infection was identified in municipalities with a TB incidence rate >14.40 cases/100 inhabitants, population >11,042 inhabitants, Gini index >0.49, and illiteracy rate >13.12%. A lower probability was found in municipalities with average per capita household income >BRL 456.43. CONCLUSIONS: It is recommended that health authorities implement monitoring and rigorous follow-up in affected areas to ensure proper diagnosis and treatment completion for international migrants, preventing disease spread to other communities.

The Association of Biochemical and Genetic Biomarkers in VEGF Pathway with Depression.

VEGF is an important neurotrophic and vascular factor involved in mental disorders. The objective of this study was to verify the effect of genetic polymorphisms in the VEGF pathway on the risk for depression, symptom intensity, and suicide attempts. To examine the association between the VEGF pathway and depression, we genotyped polymorphisms and measured the plasma concentrations of VEGF, KDR, and FLT1 proteins. The participants were 160 patients with depression and 114 healthy controls. The questionnaires that assessed the clinical profile of the patients were the MINI-International Neuropsychiatric Interview, GRID-HAMD21, CTQ, BSI, and the number of suicide attempts. Genotyping of participants was performed using the real-time PCR and protein measurements were performed using the enzyme-linked immunosorbent assay (ELISA). VEGF and its inhibitors were reduced in depression. Individuals with depression and displaying the homozygous AA of the rs699947 polymorphism had higher plasma concentrations of VEGF (p-value = 0.006) and were associated with a greater number of suicide attempts (p-value = 0.041). Individuals with depression that were homozygous for the G allele of the FLT1 polymorphism rs7993418 were associated with lower symptom severity (p-value = 0.040). Our results suggest that VEGF pathway polymorphisms are associated with the number of suicide attempts and the severity of depressive symptoms.

TRPA1 Polymorphisms Modify the Hypotensive Responses to Propofol with No Change in Nitrite or Nitrate Levels.

Anesthesia with propofol is frequently associated with hypotension. The TRPA1 gene contributes to the vasodilator effect of propofol. Hypotension is crucial for anesthesiologists because it is deleterious in the perioperative period. We tested whether the TRPA1 gene polymorphisms or haplotypes interfere with the hypotensive responses to propofol. PCR-determined genotypes and haplotype frequencies were estimated. Nitrite, nitrates, and NOx levels were measured. Propofol induced a more expressive lowering of the blood pressure (BP) without changing nitrite or nitrate levels in patients carrying CG+GG genotypes for the rs16937976 TRPA1 polymorphism and AG+AA genotypes for the rs13218757 TRPA1 polymorphism. The CGA haplotype presented the most remarkable drop in BP. Heart rate values were not impacted. The present exploratory analysis suggests that TRPA1 genotypes and haplotypes influence the hypotensive responses to propofol. The mechanisms involved are probably other than those related to NO bioavailability. With better genetic knowledge, planning anesthesia with fewer side effects may be possible.

Association between endothelial nitric oxide synthase and the renin-angiotensin-aldosterone system polymorphisms, blood pressure and training status in normotensive/pre-hypertension and hypertensive older adults: a pilot study.

Introduction:Variations in blood pressure (BP) are, in part, genetically determined and some polymorphisms of renin-angiotensin- aldosterone system (RAAS) and synthase of endothelial nitric oxide (eNOS) have been related to hypertension (HT). Conversely, physical exercise is considered a non-pharmacological tool for HT control, treatment, and prevention.Objective: The purpose of this study is to investigate the relationship between eNOS and RAAS polymorphisms, their epistatic interaction, and the respective humoral factors in the BP control in normotensive/pre-hypertension and hypertensive older adults and how this relationship can be modulated by training status (TS) level.Methods:A total of 155 older adults (66.94 ± 6.83 years old) performed the following evaluations: AAHPERD battery test to determine the general functional fitness index (GFFI), systolic and diastolic blood pressure (SBP and DBP), blood collection for DNA extraction, analysis of eNOS gene polymorphisms rs2070744; rs61722009 and rs1799983 and RAAS polymorphisms rs699; rs1799752 and rs5186, and quantification of ACE activity (Fluorimetric Assay) and nitrite concentration (Chemiluminescence Method).Results and Conclusion:Good TS level appears to exert greater influence on SBP for G2 and G3 (G1: 125.79 ± 14.03/ G2: 119.91 ± 11.72/G3: 119.71 ± 10.85) and on NO2 for G3 (G1: 0.42 ± 0.25/ G2: 0.54 ± 0.45/ G3: 0.71 ± 0.52). No associations were observed between eNOS and RAAS polymorphisms, but the epistasis was identified between eNOS polymorphism, rs2070744, and RAAS polymorphism, rs699, revealing a statistically significant interaction (p = .0235) with training score of 0.63, a training test accuracy of 0.61 and a cross-validation consistency of 10/10. This result suggests an increased risk of hypertension.

NOS3 Polymorphisms Can Influence the Effect of Multicomponent Training on Blood Pressure, Nitrite Concentration and Physical Fitness in Prehypertensive and Hypertensive Older Adult Women.

Associations of endothelial nitric oxide synthase (NOS3) polymorphisms with hypertension and response to exercise training in prehypertensive and hypertensive older adult women remain unclear. This study used a multicomponent program (various capacities and motor skills) in the physical training intervention. It analyzed the influence of NOS3 polymorphisms [-786T > C, 894G > T (Glu298Asp), and intron 4b/a] on the response of blood pressure (BP), nitrite concentration, and physical fitness in older adult women. Fifty-two participants aged between 50 and 80 underwent body mass index, BP, 6-min walk, elbow flexion, and sit and stand-up tests to assess physical fitness. The intervention duration was 12 weeks, twice a week, on non-consecutive days. Each session lasted 90 min, maintaining an intensity between 13 (moderate) and 15 (intense), controlled by the Subjective Effort Perception Scale. Plasma/blood samples were collected to assess nitrite concentration and genotyping. The statistical analysis included Fisher's exact test and linear mixed-effects models. The multicomponent training's positive effect was observed with a similar response in both prehypertensive and hypertensive groups. However, carriers of different genotypes demonstrated different responses to training: the decreases in systolic and diastolic BP and increases in nitrite expected from the physical training were smaller in variant genotype than ancestral genotype carriers, especially in the hypertensive group. At positions -786T > C and Glu298Asp, only the ancestral genotypes showed a decrease in diastolic BP (Δ% = -8.1, and Δ% = -6.5, respectively) and an increase on nitrite (Δ% = 19.1, and Δ% = 24.1, respectively) in the hypertensive group. Our results show that the benefits of a multicomponent training intervention seem to be genotype-dependent. It should be possible to consider genetic variants when selecting an exercise treatment intervention.

Arginase II polymorphisms modify the hypotensive responses to propofol by affecting nitric oxide bioavailability.

PURPOSE: Propofol anesthesia is usually accompanied by hypotensive responses, which are at least in part mediated by nitric oxide (NO). Arginase I (ARG1) and arginase II (ARG2) compete with NO synthases for their common substrate L-arginine, therefore influencing the NO formation. We examined here whether ARG1 and ARG2 genotypes and haplotypes affect the changes in blood pressure and NO bioavailability in response to propofol. METHODS: Venous blood samples were collected from 167 patients at baseline and after 10 min of anesthesia with propofol. Genotypes were determined by polymerase chain reaction. Nitrite concentrations were measured by using an ozone-based chemiluminescence assay, while NOx (nitrites + nitrates) levels were determined by using the Griess reaction. RESULTS: We found that patients carrying the AG + GG genotypes for the rs3742879 polymorphism in ARG2 gene and the ARG2 GC haplotype show lower increases in nitrite levels and lower decreases in blood pressure after propofol anesthesia. On the other hand, subjects carrying the variant genotypes for the rs10483801 polymorphism in ARG2 gene show more intense decreases in blood pressure (CA genotype) and/or higher increases in nitrite levels (CA and AA genotypes) in response to propofol. CONCLUSION: Our results suggest that ARG2 variants affect the hypotensive responses to propofol, possibly by modifying NO bioavailability. TRIAL REGISTRATION: NCT02442232.

Caracterização da variabilidade da frequência cardíaca em indivíduos com síndrome metabólica / Characterization of the heart rate variability in individuals with metabolic syndrome / Caracterización de la variabilidad de la frecuencia cardiaco en pacientes con síndrome metabólico

RESUMO Introdução: A variabilidade da frequência cardíaca (VFC) tem sido considerada um mecanismo de modulação do sistema nervoso autônomo. A diminuição da VFC pode estar associada à síndrome metabólica (SM). Objetivo: Comparar a VFC e variáveis de saúde em indivíduos com e sem SM. Métodos: Cento e dezenove participantes foram divididos em dois grupos: sem SM (SSM, n = 68) e com SM (CSM, n = 51). Foi avaliada a análise espectral da VFC em repouso, durante teste cardiopulmonar de exercício (TCPE) e na recuperação em bandas de baixa frequência (LF = 0,04-0,15 Hz), alta frequência (HF = 0,15-0,4 Hz) e razão LF/HF. Adicionalmente, a frequência cardíaca (FC) de repouso (FCrep), FC máxima (FCmáx), pressão arterial sistólica (PAS) e diastólica (PAD), glicemia, perfil lipídico, consumo de oxigênio pico (VO2pico) e composição corporal foram avaliados. Resultados: A FCrep e o VO2pico não apresentaram diferenças entre o CSM e o SSM (73,3 ± 9,1 vs. 70,1 ± 11,0 bpm) (26,8 ± 4,6 vs. 28,1 ± 6,6 ml.kg-1.min-1), respectivamente. A VFC foi similar entre os grupos nos diferentes momentos analisados. A glicemia (99,8 ± 22,5 vs. 87,6 ± 8,6 mg/dl) foi superior no CSM comparado ao SSM. Os valores de triglicérides (159,5 ± 68,8 vs. 89,2 ± 34,3 mg/dl) e VLDL-c (31,9 ± 13,8 vs. 17,8 ± 6,9 mg/dl) foram superiores no CSM comparado ao SSM. O HDL-c (40,7 ± 11,5 vs. 49,3 ± 9,8 mg/dl) foi menor no CSM comparado ao SSM. O IMC (33,1 ± 4,7 vs. 30,8 ± 3,8 Kg/m²) foi superior no CSM comparado ao SSM. A PAS (128,6 ± 12,9 vs. 119,5 ± 11,3 mmHg) e a PAD (77,2 ± 10,5 vs. 72,9 ± 8,1 mmHg) foram superiores no CSM comparado ao SSM, p < 0,05. Conclusão: Os resultados sugerem que a presença de SM não é suficiente para provocar alterações nos índices de VFC em repouso, durante teste cardiopulmonar de exercício (TCPE) e na recuperação quando os pacientes são comparados a indivíduos sem a doença.

ABSTRACT Introduction: Heart rate variability (HRV) has been considered a modulation mechanism of the autonomic nervous system. The reduction of HRV may be associated with metabolic syndrome (MS). Objective: To compare the HRV and health variables in individuals with and without MS. Methods: One hundred and nineteen participants were divided into two groups: without MS (WOMS, n=68) and with MS (WMS, n=51). We evaluated the spectral analysis of HRV at rest, during cardiopulmo-nary exercise testing (CPET) and recovery in low frequency bands (LF = 0.04-0.15 Hz), high frequency (HF = 0.15-0.4 Hz) and LF/HF ratio. Resting heart rate (HRres), maximum heart rate (HRmax), systolic blood pressure (SBP) and diastolic (DBP), blood glucose, lipid profile, peak oxygen consumption (VO2peak) and body composition were also evaluated. Results: There were no differences between HRres and VO2peak between the WMS and WOMS groups (73.3±9.1 vs. 70.1±11.0 bpm), (26.8±4.6 vs. 28.1±6.6 ml.kg-1.min-1), respectively. HRV was similar between the groups at the different moments analyzed. The blood glucose levels (99.8±22.5 vs. 87.6±8.6 mg/dl) were higher in WMS compared to WOMS. Triglyceride values (159.5±68.8 vs. 89.2±34.3 mg/dl) and VLDL-c (31.9±13.8 vs. 17.8±6.9 mg/dl) were higher in WMS compared to WOMS. HDL-c (40.7±11.5 vs. 49.3±9.8 mg/dl) was lower in WMS compared to WOMS. BMI (33.1±4.7 vs. 30.8±3.8 kg/m²) was higher in WMS compared to WOMS. The SBP (128.6±12.9 vs. 119.5±11.3 mmHg) and DBP (77.2±10.5 vs. 72.9± 8.1mmHg) were higher in WMS com-pared to WOMS, p<0.05. Conclusion: The results suggest that the presence of MS is not sufficient to induce changes in HRV at rest, during cardiopulmonary exercise test (CPET), and in recovery when patients are compared to healthy individuals.

RESUMEN Introducción: La variabilidad de la frecuencia cardiaca (VFC) ha sido considerada como un mecanismo de modulación del sistema nervioso autónomo. La disminución de VFC puede estar asociada con el síndrome metabólico (SM). Objetivo: Comparar la VFC y variables de salud en individuos con y sin SM. Métodos: Ciento diecinueve sujetos se dividieron en dos grupos: sin SM (SSM, n = 68) y con SM (CSM, n = 51). Se evaluó el análisis espectral de la VFC en reposo durante las pruebas de ejercicio cardiopulmonar (PECP) y la recuperación en banda de baja frecuencia (LF = 0,04-0,15 Hz), alta frecuencia (HF = 0,15-0,4 Hz) y la relación LF/HF. Además, se evaluaron la frecuencia cardiaca en reposo (FCrep), FC máxima (FCmáx), presión arterial sistólica (PAS) y diastólica (PAD), glicemia, perfil lipídico, consumo pico de oxígeno (VO2pico) y composición corporal. Resultados: FCrep y VO2pico no mostraron diferencias entre CSM y SSM (73,3 ± 9,1 vs. 70,1 ± 11,0 bpm) (26,8 ± 4,6 vs. 28,1 ± 6,6 ml.kg-1.min-1), respectivamente. La VFC fue similar entre los grupos en diferentes momentos analizados. La glicemia (99,8 ± 22,5 vs. 87,6 ± 8,6 mg/dl) fue mayor en CSM en comparación con SSM. Los valores de triglicéridos (159,5 ± 68,8 vs. 89,2 ± 34,3 mg/dl) y VLDL-C (31,9 ± 13,8 vs. 17,8 ± 6,9 mg/dl) fueron más altos en CSM en comparación con SSM. HDL-C (40,7 ± 11,5 vs. 49,3 ± 9,8 mg/dl) fue menor en CSM en comparación con el SSM. El IMC (33,1 ± 4,7 vs. 30,8 ± 3,8 kg/m²) fue mayor en CSM en comparación con SSM. La PAS (128,6 ± 12,9 vs. 119,5 ± 11,3 mmHg) y la PAD (77,2 ± 10,5 vs. 72,9 ± 8,1 mmHg) fueron más altas en CSM en comparación con SSM, p < 0,05. Conclusión: Los resultados sugieren que la presencia de SM no es suficiente para provocar cambios en los índices de VFC en reposo durante las pruebas de ejercicio cardiopulmonar (PECP) y en la recuperación cuando se comparan los pacientes y los individuos saludables.

Association of genetic polymorphisms with physical capacities and body composition in older women / Associação de polimorfismos genéticos com capacidades físicas e composição corporal em idosas

Abstract The elderly population has grown substantially, and the decline in physical capacities and increase in the body fat percentage are important characteristics of aging. Genetic factors may explain these declines and studies related to this issue are justified because they predict what physical capacities present larger declines in different individuals and enable the adoption of strategies to slow them. Thus, the aim of this study was to evaluate the effect of ACE I / D and ACTN3 R / X genetic polymorphisms on body fat, muscle strength and power levels, aerobic capacity, flexibility and agility in older women. Sixty-six older women were genotyped with respect to ACTN3 and ACE polymorphisms for the division of groups and submitted to anthropometric measurements, physical tests in the AAHPERD and RIKLI and JONES test batteries and IPAQ to determine the level of physical activity and the Food Consumption Marker Form. Older women with XX genotype in relation to ACTN3 genotype had lower levels of flexibility of upper and lower limbs and lower cardiorespiratory fitness. Moreover, in relation to the ACE genotype, ID individuals exhibited higher cardiorespiratory fitness and lower body fat percentages. In relation to the other variables, there was no statistical difference among groups. It was concluded that the genetic variants under study play a role in some of the physical capacities and body composition in elderly women. In the future, data of this nature will enable each individual to have specific health interventions directed to the variables showing higher genetic potential for decline.

Resumo A população idosa tem crescido de forma substancial e o declínio nas capacidades físicas, além do aumento na porcentagem de gordura corpórea, são características importantes do envelhecimento. Fatores genéticos podem explicar estes declínios e pesquisas relacionadas a essa temática se justificam porque predizer quais capacidades físicas apresentarão maiores declínios em cada indivíduo possibilita a adoção de estratégias para retardá-los. Assim objetivamos avaliar o efeito dos polimorfismos genéticos ECA I/D e ACTN3 R/X nos níveis de gordura corporal, força e potência muscular, capacidade aeróbia, flexibilidade e agilidade em idosas. 66 idosas foram genotipadas em relação aos polimorfismos da ACTN3 e da ECA para divisão dos grupos e submetidas a medidas antropométricas, testes físicos da bateria de testes da AAHPERD e RIKLI E JONES, IPAQ para determinar o nível de atividade física e o Formulário de Marcadores de Consumo Alimentar. Mulheres idosas com o genótipo XX em relação ao gene da ACTN3 apresentaram menores níveis de flexibilidade dos membros superiores e menor capacidade cardiorrespiratória. Por outro lado, em relação ao gene da ECA, os indivíduos ID apresentaram maior capacidade cardiorrespiratória e menor porcentagem de gordura. Em relação às outras variáveis não houve diferença estatística entre os grupos. Concluímos que as variantes genéticas estudadas têm influência em algumas das capacidades físicas e na composição corporal em idosas. No futuro dados desta natureza possibilitarão cada indivíduo ter suas intervenções em saúde direcionadas às variáveis que ele apresenta maior potencial genético para declínio.

Associação de polimorfismos genéticos com parametros de saúde em mulheres a partir de 50 anos de idade / Association of genetic polymorphisms with health parameters in women over 50 years of age

O processo de envelhecimento é marcado por diversos estilos de vivências e experiências e traz consigo alterações morfológicas e fisiológicas. Estas mudanças ocorrem devido a componentes celulares e moleculares, os quais são controladas por fatores genéticos e não genéticos. Por isso, é de grande importância investigar sobre as associações existentes entre as alterações genéticas, o envelhecimento e o ambiente para a compreensão das características próprias do processo de envelhecimento. O objetivo foi estudar a associação dos polimorfismos genéticos AKT1 G205T (rs1130214), AGTR1 A1166C (rs5186) e visfatina (rs4730153) com parâmetros de saúde (cognição, qualidade de vida, depressão, capacidade funcional, pressão arterial, perfil lipídico sanguíneo, glicemia e medidas antropométricas) em mulheres a partir de 50 anos de idade. A amostra foi composta por 97 mulheres (>= 50 anos) que tinham o interesse em se ingressar em programa de Educação Física na USP. Elas foram submetidas inicialmente a uma entrevista, na qual é aplicado o MEEM - critério de inclusão. Na sequência foram realizados testes físicos (sentar e levantar, FPMD e E, agilidade, caminhar 6 min, mãos nas contas e sentar e alcançar), aplicados questionários e houve coleta de sangue. Com relação ao polimorfismo da AKT1, o grupo GT/TT apresentou melhores resultados na massa corporal, índice de massa corporal e HDL-colesterol, e piores resultados em FPMD/E comparado com o genótipo GG. Em relação ao AGTR1, o genótipo AA exibiu melhores resultados comparado com o AC/CC nas variáveis de caminhada e atividade física moderada. Por fim, para a visfatina o grupo AA/AG apresentou melhores resultados em HDL e TG comparado com o genótipo GG. Dados desta natureza podem possibilitar a predição das variáveis de saúde de cada indivíduo que serão mais prejudicadas antes dele envelhecer e, consequentemente, planejar intervenções específicas que previnam estes declínios

The aging process is marked by many different experiences and experiences can bring their own morphological and physiological changes of aging. These changes occur because the arrangement of cellular and molecular components, which are controlled by genetic and nongenetic factors. So it is of great importance investigate the associations between the genetic changes, aging and the environment to understanding the very physical characteristics of the aging process. The objective was to study the association of polymorphisms AKT1 G205T (rs1130214), AGTR1 A1166C (rs5186) and visfatin (rs4730153) with health parameters (cognition, quality of life, depression, functional capacity, blood pressure, blood lipids, blood glucose and measures anthropometric) in women over 50 years of age. The sample consisted of 97 women (>= 50 years) who had an interest in joining the OFW - EEFERP - USP. These were initially submitted to an interview, in which the MMSE is applied - inclusion criteria after was carried out physical tests (sitting and standing, LDCF and E, agility, walk 6 min, hands on the bills and sit and reach), application questionnaires and blood collection. Regarding the polymorphism AKT1, the GT / TT genotype showed better results in body mass, body mass index and HDL-cholesterol and worst results LDCF / E compared to the GG genotype in AGTR1 AA genotype showed better results compared with the AC/CC to variables of walking and moderate physical activity, in order to visfatin AA/AG genotype showed better results in HDL and TG compared with the GG genotype. Through presented associations we observed existing relationships and new partnerships in health variables