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Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.

RESUMO

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.

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BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disease, causes ventricular tachycardia, sudden cardiac death, and heart failure (HF). We investigated ARVC clinical features, genetic findings, natural history, and the occurrence of life-threatening arrhythmic events (LTAEs), HF death, or heart transplantation (HF-death/HTx) to identify risk factors. METHODS: The clinical course of 111 consecutive patients with definite ARVC, predictors of LTAE, HF-death/HTx, and combined events were analyzed in the entire cohort and in a subgroup of 40 patients without sustained ventricular arrhythmia before diagnosis. RESULTS: The 5-year cumulative probability of LTAE was 30% and HF-death/HTx was 10%. Predictors of HF-death/HTx were reduced right ventricle ejection fraction (HR: 0.93; P=0.010), HF symptoms (HR: 4.37; P=0.010), epsilon wave (HR: 4.99; P=0.015), and number of leads with low QRS voltage (HR: 1.28; P=0.001). Each additional lead with low QRS voltage increased the risk of HF-death/HTx by 28%. Predictors of LTAE were prior syncope (HR: 1.81; P=0.040), number of leads with T wave inversion (HR: 1.17; P=0.039), low QRS voltage (HR: 1.12; P=0.021), younger age (HR: 0.97; P=0.006), and prior ventricular arrhythmia/ventricular fibrillation (HR: 2.45; P=0.012). Each additional lead with low QRS voltage increased the risk of LTAE by 17%. In patients without ventricular arrhythmia before clinical diagnosis of ARVC, the number of leads with low QRS voltage (HR: 1.68; P=0.023) was independently associated with HF-death/HTx. CONCLUSIONS: Our study demonstrated the characteristics of a specific cohort with a high prevalence of arrhythmic burden at presentation, male predominance, younger age and HF severe outcomes. Our main results suggest that the presence and extension of low QRS voltage can be a risk predictor for HF-death/HTx in ARVC patients, regardless of the arrhythmic risk. This study can contribute to the global ARVC risk stratification, adding new insights to the international current scientific knowledge.

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BACKGROUND: Evidence of multimorbidity has come mainly from high-income regions, while disparities among racial groups have been less explored. This study examined racial differences in multimorbidity in the multiracial cohort of the Longitudinal Study of Adult Health (Estudo Longitudinal de Saúde do Adulto), ELSA-Brasil. METHODS: The study examined baseline (2008-2010) data for 14 099 ELSA-Brasil participants who self-reported being white, mixed-race, or black. A list of 16 morbidities was used to evaluate multimorbidity, operationalised by simple count into ≥ 2, ≥ 3, ≥ 4, ≥ 5 and ≥ 6 morbidities, in addition to evaluating the number of coexisting conditions. Prevalence ratios (PR) were estimated from logistic models and a quantile model was used to examine racial differences graphically in the distribution quantiles for the number of morbidities. RESULTS: Overall prevalence of multimorbidity (≥ 2 morbidities) was 70% and, after controlling for age and sex, was greater among mixed-race and black participants - by 6% (PR: 1.06; 95% CI: 1.03-1.08) and 9% (PR: 1.09; 95% CI: 1.06-1.12), respectively - than among white participants. As the cutoff value for defining multimorbidity was raised, so the strength of the association increased, especially among blacks: if set at ≥ 6 morbidities, the prevalence was 27% greater for those of mixed-race (PR: 1.27; 95% CI: 1.07-1.50) and 47% greater for blacks (PR: 1.47; 95% CI: 1.22-1.76) than for whites. The disparities were smaller in the lower morbidity distribution quantiles and larger in the upper quantiles, indicating a heavier burden of disease, particularly on blacks. CONCLUSIONS: Multimorbidity was common among adults and older adults in a Brazilian cohort, but important racial inequalities were found. Raising the cutoff point for defining multimorbidity revealed stronger associations between race/skin colour and multimorbidity, indicating a higher prevalence of multimorbidity among mixed-race and black individuals than among whites and that the former groups coexisted more often with more complex health situations (with more coexisting morbidities). Interventions to prevent and manage the condition of multimorbidity that consider the social determinants of health and historically discriminated populations in low- and middle-income regions are necessary.

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Alzheimer's Disease (AD) is the most common cause of dementia among elderly individuals worldwide, leading to a strong motor-cognitive decline and consequent emotional distress and codependence. It is traditionally characterized by amyloidogenic pathway formation of senile plaques, and recent studies indicate that dysbiosis is also an important factor in AD's pathology. To overcome dysbiosis, probiotics-as kefir-have shown to be a great therapeutic alternative for Alzheimer's disease. In this present work, we explored kefir as a probiotic and a metabolite source as a modulator of microbiome and amyloidogenic pathway, using a Drosophila melanogaster model for AD (AD-like flies). Kefir microbiota composition was determined through 16S rRNA sequencing, and the metabolome of each fraction (hexane, dichloromethane, ethyl acetate, and n-butanol) was investigated. After treatment, flies had their survival, climbing ability, and vacuolar lesions accessed. Kefir and fraction treated flies improved their climbing ability survival rate and neurodegeneration index. In conclusion, we show that kefir in natura, as well as its fractions may be promising therapeutic source against AD, modulating amyloidogenic related pathways.

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Considering that the incidence of type 2 diabetes mellitus (T2DM) has been increasing especially in developing countries and becoming a global public health problem, this study aims to evaluate the association between triglyceride glucose index (TyG) - which is a mathematical product of the fasting blood glucose and triglyceride levels - and incident T2DM in an adult sample in the Baependi Heart Study (BHS). The data were from the BHS cohort consisting of two periods: cycle 1 (2005-2006; n = 1712; 119 families) and cycle 2 (2010-2013; n = 3017; 127 families). A total of 1121 individuals (both sexes, 18-100 years) were selected if they were assessed in both cycles and not diagnosed with T2DM at baseline (cycle 1). Our findings showed that a participant's risk of developing T2DM increased almost 10 times for a one-unit increase in the TyG (odds ratio OR = 10.17, 95% CI, 7.51-13.93). The association when stratified by age was OR = 28.13 [95% CI, 14.03-56.41] for young adults, meaning that the risk of developing T2DM increased more than 28 times for a one-unit increase in the TyG. For the other groups, young middle-aged adults, old middle-aged adults, and seniors, we found OR = 4.84 [95% CI, 2.91-8.06], OR = 28.73 [95% CI, 10.63-77.65, and OR = 9.88 [95% CI, 3.16-30.90], respectively. A higher TyG implies a significant increase in the risk of developing T2DM, which could be an important screening tool to target early lifestyle intervention in Brazil.

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BACKGROUND: The association between diabetes and obesity is very well established. Faced with this, several anthropometric indices of adiposity are often involved in studies on diabetes. Our main goal in this paper is to evaluate the association between body adiposity index (BAI) and type 2 diabetes mellitus (T2DM) in a sample of the Brazilian population after 5-year follow-up. METHODS: The data used come from the Baependi Heart Study cohort, which consists of two periods: cycle 1 (2005-2006) and cycle 2 (2010-2013). Individuals of both sexes (n = 1121) were selected by excluding participants with type 2 diabetes mellitus at baseline or those that were lost to follow-up. RESULTS: The diabetic subjects showed higher systolic blood pressure, BAI, body mass index, waist circumference and fasting glucose levels. In addition, using mixed-effects logistic regression, we found that the elevation of a single unit of BAI represented an increase of 8.4% in the risk of a patient developing T2DM (OR = 1.084 [95% CI 1.045-1.124]). CONCLUSIONS: Obesity is recognised as one of the most important risk factors for T2DM and BAI has proven to be a useful tool in estimating the risk of a patient developing T2DM in a Brazilian population.

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BACKGROUND: Physiological pathways such as bradykinin, renin-angiotensin, neurohormones and nitric oxide have been shown to play an important role in the regulation of cardiovascular function. Genetic variants of these pathways may impact blood pressure and left ventricular (LV) mass in different populations. To evaluate associations of genetic polymorphisms of bradykinin B2 receptor (BDKRB2), alpha-adrenergic receptors (ADRA) and endothelial nitric oxide synthase (eNOS) on the modulation of the blood pressure and the left ventricular mass. METHODS: We enrolled 758 individuals without overt heart disease. Blood pressure was estimated by auscultatory method during the clinical examination. Left ventricular (LV) mass was assessed by echocardiography. Genotypes for ADRA1A rs1048101, ADRA2A rs553668, ADRA2B rs28365031, eNOS rs2070744, eNOS rs1799983, and BDKRB2 rs5810761 polymorphisms were assessed by high-resolution melting analysis. RESULTS: BDKRB2 polymorphism rs5810761 was associated with blood pressure. Carriers of DD genotype had higher levels of SBP and DBP than carrier of II genotype (p = 0.013 and p = 0.007, respectively). eNOS polymorphism rs1799983 was associated with DBP. Carriers of GT genotype had lower levels of DBP than carriers of GG genotype (p = 0.018). eNOS polymorphism rs2070744 was associated with LV mass. Carriers of TC genotype had higher LV mass than carriers of TT genotype (p = 0.028). CONCLUSIONS: In a cohort of individuals without overt heart disease, the BDKRB2 rs5810761 polymorphism (DD genotype carriers) were associated higher systolic and diastolic blood pressures, and the eNOS rs1799983 polymorphism (T allele carriers) were associated with lower diastolic blood pressure. The eNOS rs2070744 polymorphism (C allele carriers) was associated with higher left ventricular mass. These data suggest that eNOS and bradykinin receptor genetic variants may be potential markers of common cardiovascular phenotypes.

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PURPOSE: Evidence exists which suggests that a vegetarian diet is a predisposing factor to erosive tooth wear. The aim of this study was to assess the influence of dietary pattern (vegetarian, lacto-ovo vegetarian and omnivore) on erosive tooth wear. MATERIALS AND METHODS: Two hundred seven subjects (29 vegetarians, 96 lacto-ovo vegetarians and 82 omnivores) underwent an oral assessment and were asked to answer questionnaires about diet and oral care. RESULTS: Individuals who followed vegetarian and lacto-ovo vegetarian diets had statistically significantly more erosive tooth wear than did omnivores (p = 0.004). Conversely, omnivores presented more tooth loss than did lacto-ovo vegetarians (p = 0.027). Being a vegetarian or a lacto-ovo vegetarian entailed an increased risk (4 times and 2.5 times, respectively) of presenting erosive tooth wear than being omnivorous. CONCLUSION: Vegetarian and lacto-ovo vegetarian dietary patterns seem to favour the loss of dental structure by erosion. Vegetarian patients should thus be informed about preventive measures and treated accordingly.

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Purpose. Chemokines are important in the immune response against viral infections, and may play a role in human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis. Polymorphisms in the Duffy antigen receptor for chemokines (DARC), such as rs12075 (A>G; FY*B>FY*A) and rs281477 (-46T>C; GATA-1 box) may influence circulating concentrations of proinflammatory chemokines. We investigate whether Duffy genotypes influence the HTLV-1 proviral load (PVL) level, HTLV-1 infection outcome and chemokine concentrations in HTLV-1 asymptomatic carriers (AC=162), HAM/TSP patients (HAM=135) and seronegative individuals (SN=71).Methodology. Quantification of plasmatic IL8, CCL2 and CCL5 were performed by flow cytometry and Duffy genotypes were investigated by real-time PCR. HTLV-1 PVL was quantified in peripheral blood. To control for spurious association, individual ancestry profiles in AC and HAM groups were investigated.Results/Key findings. PVL and IL8 level were significantly higher in the HAM group than in the AC group, but were not associated with Duffy genotypes. The highest CCL2 and CCL5 levels were seen in the SN group, and there was no difference when comparing the infected groups. The level of CCL5 was not associated with Duffy genotypes. The polymorphism -46 C/C that abrogates the DARC expression on the erythrocytes was significantly associated with lower levels of CCL2, neutrophil and white blood cell (WBC) counts in HTLV-1-infected individuals.Conclusion. We conclude that although the Duffy null genotype was associated with leukopenia, neutropenia and lower levels of CCL2, the data do not suggest the influence of Duffy genotypes on the neurologic outcome of HTLV-1 infection, but may be a confounding factor in comparison HTLV-1-infected populations with different ancestries, especially when defining inflammatory biomarkers.