Abstract The choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are fundamental to neurophysiological functions of the central cholinergic system. We confirmed and quantified the presence of extracellular ChAT protein in human plasma and also characterized ChAT and VAChT polymorphisms, protein and activity levels in plasma of Alzheimer's disease patients (AD; N = 112) and in cognitively healthy controls (EC; N = 118). We found no significant differences in plasma levels of ChAT activity and protein between AD and EC groups. Although no differences were observed in plasma ChAT activity and protein concentration among ChEI-treated and untreated AD patients, ChAT activity and protein levels variance in plasma were higher among the rivastigmine-treated group (ChAT protein: p = 0.005; ChAT activity: p = 0.0002). Moreover, AD patients homozygous for SNP rs1880676 A allele exhibited higher levels of ChAT activity. Considering this is the first study to report the influence of genetic variability of CHAT locus over ChAT activity in AD patients plasma, it opens a new set of important questions on peripheral cholinergic signaling in AD.

Abstract ATP-Binding Cassette (ABC) transporters are involved in cholesterol metabolism and their dysfunctions could lead to obesity-associated complications. It was investigated whether SNPs in the ABCA1 (rs1800977 and rs2230806), ABCA7 (rs2279796) and ABCG1 (rs692383 and rs3827225) genes can modulate the responsiveness of 137 obese women to a weight-loss dietary intervention. Thus, anthropometric and lipid profiles were collected at baseline and after nine weeks of a calorie-restricted diet of 600kcal per day and participants were genotyped for the ABC genes SNPs. Regarding the transversal analysis, the ABCA7 rs2279796 GG genotype was associated with higher levels of total cholesterol and LDL-c at baseline (p = 0.044 for both). Association between ABCG1 rs692383 AA genotype and lower BMI were found in the post-diet moment, however, statistical significance was lost after multi-test correction. Regarding the longitudinal analysis, after multi-test correction, the association remained between ABCG1 rs692383 G allele and HDL-c levels: G allele carriers had a lower HDL-c reduction (p = 0.043). Results suggest the standard weight-loss diet applied in this study could attenuate the ABCA7 rs2279796 GG genotype effects found at baseline and non-dyslipidemic obese women with ABCG1 rs692383 G allele are benefitting from the diet with a lower reduction in HDL-c levels.

Abstract Genes can influence lipid profile and anthropometric variables related to obesity. The present study aimed to verify if variants of the APOE, APOB, ADIPOQ, HSD11β1, and PLIN4 genes are associated with lipid levels or anthropometric variables in a sample comprised of 393 Euro-Brazilian children and adolescents. DNA was genotyped by TaqMan allelic discrimination assay. The ε4 and ε2 alleles of the APOE gene were associated respectively with lower high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels (p=0.015 and p=0.012, respectively), while the ε3 allele was associated with higher abdominal circumference (p=0.0416) and excess weight (p=0.0001). The G allele (rs846910) of the HSD11β1 gene was also associated with excess weight (p=0.039). No other association was found. Our results indicate that the ε4 and ε2 alleles could contribute to lower HDL-C and LDL-C levels, respectively, furthermore, the ε3 allele and the G allele (rs846910) of HSD11β1 gene may be risk factors for excess of weight.These findings are very important because we observed that some genetic variants influence the lipid profile and anthropometric variables early in life.

Objective Butyrylcholinesterase (BChE) activity has been associated with obesity, lipid concentrations, and CHE2 locus phenotypes. This, the aim of this study was to evaluate the effects of an energetic restriction diet intervention on anthropometrical and biochemical variables and on absolute and relative BChE activity in CHE2 C5+ and CHE2 C5- individuals. Subjects and methods One hundred eleven premenopausal obese women from Southern Brazil participated in an energetic restriction diet intervention (deficit of 2500 kJ/day) for 8 weeks. Their anthropometric and biochemical parameters were evaluated before and after the intervention. Plasma BChE activity was measured, and BChE bands in plasma and CHE2 locus phenotypes were detected by electrophoresis. Results The dietetic intervention decreased anthropometric and biochemical parameters as well as absolute BChE activity and relative activity of the G4 band. The CHE2 C5+ phenotype presented a different effect when compared with the CHE2 C5- phenotype. The CHE2 C5+ phenotype showed an effect in absolute BChE activity and in the relative activity of the G4 form, maintaining higher BChE activity regardless of the metabolic changes. Conclusion In our study, 8 weeks was not sufficient time to lower the body mass index to normal, but it was enough to significantly reduce the absolute BChE activity, which became similar to the levels in nonobese individuals. CHE2 C5+ individuals were resistant to the decrease in BChE activity compared to CHE2 C5- individuals. This shows that the diet did not affect the CHE2 and G4 fraction complex and that the products of the CHE2 locus in association with BChE have a role in energy metabolism, maintaining high levels of enzymatic activity even after dietary intervention.

Abstract Butyrylcholinesterase (BChE) activity and polymorphisms in its encoding gene had previously been associated with metabolic traits of obesity. This study investigated the association of three single nucleotide polymorphisms (SNPs) in the BCHE gene: -116G > A (rs1126680), 1615GA (rs1803274), 1914A < G (rs3495), with obesity and lipid metabolism markers, body mass index (BMI), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceride (TG) levels, and BChE enzymatic activity in obese (BMI≥30/n = 226) and non-obese women (BMI < 25/n = 81). BCHE SNPs genotyping was obtained by TaqMan allelic discrimination assay and by RFLP-PCR. Plasmatic BChE activity was measured using propionylthiocholine as substrate. Similar allele frequencies were found in obese and non-obese women for the three studied SNPs (p > 0.05). The dominant and recessive models were tested, and different effects were found. The -116A allele showed a dominant effect in BChE activity reduction in both non-obese and obese women (p = 0.045 and p < 0.001, respectively). The 1914A > G and 1615GA SNPs influenced the TG levels only in obese women. The 1914G and the 1615A alleles were associated with decreased plasma levels of TG. Thus, our results suggest that the obesity condition, characterized by loss of energy homeostasis, is modulated by BCHE polymorphisms.

ABSTRACT Aim To compare the anthropometric, metabolic, and inflammatory parameters of overweight adolescents after 12-weeks of resistance and aerobic training (CT), taking into account the Gln27Glu polymorphism of the β2 adrenergic receptor (ADRB2) gene. Methods Forty-seven adolescents (15.05±1.07y) were assigned to one of four groups, according to the presence or absence of the Glu27 allele: CT (CarrierT n=11; NoncarrierT n=11) or control (CarrierC n=13; NoncarrierC n=12). Body composition, abdominal fat, maturation, fitness, metabolic and lipid profile, inflammatory markers were assessed. The CT consisted of six resistance exercises, followed by 30 min of walking/running at 50-80% VO2max, totaling 60 min/session, three times a week. A mixed-model factorial ANOVA was used to compare variables at baseline and after 12-weeks. Results TC was effective in reducing total fat mass (NoncarrierT ES=.45, CarrierT ES=.27) and subcutaneous abdominal fat (NoncarrierT ES=.48, CarrierT ES=.46) and increasing lean mass (NoncarrierT ES=.58, CarrierT ES=.60) and fitness. CarrierT group showed a reduction in leptin (ES=.49). Conclusion The responses of body composition and physical fitness to TC were not influenced by the presence of the Gln27Glu polymorphism. However, only the Glu27 allele carriers showed reductions in leptin after 12-weeks. Besides, a lack of intervention caused obesogenic effects, especially in Glu27carriers.

Resumo Objetivo: Determinar a influência dos polimorfismos dos receptores adrenérgicos beta 2 (ADRB2) no desencadeamento de broncoespasmo induzido pelo exercício (BIE) em adolescentes. Métodos: Os sujeitos foram divididos em dois grupos: BIE presente (BIE+) (n=45) e BIE ausente (BIE−) (n=115). O teste de broncoprovocação com exercício foi feito com protocolo que consistiu em caminhar/correr durante no mínimo oito minutos em intensidade superior a 85% da frequência cardíaca máxima, considerando como BIE presente uma queda de 10% do volume expiratório forçado no primeiro segundo (VEF1). A genotipagem do gene ADRB2 foi feita pelo método Taqman por meio do aparelho Step One Plus. Para análise estatística usaram-se os testes t independente, U de Mann-Whitney, qui-quadrado e coeficiente de correlação de Spearman. Resultados: Idade, massa corporal, estatura, VEF1, CVF e relação VEF1/CVF foram menores no grupo BIE+ em comparação com o BIE− (p<0,05). Não houve diferenças significativas na proporção do alelo na posição 27 e dos genótipos Arg16Gly e Gln27Glu entre os grupos BIE+ e BIE− (p=0,26; p=0,97 e p=0,43, respectivamente). Entretanto, verificou-se uma tendência à significância estatística na maior proporção do alelo Gly16 para o grupo BIE+ comparado com o BIE− (p=0,08). Conclusões: A presença de polimorfismos associados ao alelo Glu27 e os genótipos Arg16Gly e Gln27Glu não influenciam no BIE. Porém, a tendência estatística observada para uma maior frequência do alelo Gly16 nos indivíduos com a presença de BIE pode ser considerado indício da influência de polimorfismos no gene ADBR2 no BIE em adolescentes.

Abstract Objective: To determine the influence of polymorphisms of the beta-2 adrenergic receptor (ADRB2) in triggering exercise-induced bronchospasm (EIB) in adolescents. Methods: The subjects were divided into two groups: present EIB (EIB+) (n=45) and absent EIB (EIB−) (n=115). The bronchial provocation test with exercise was performed with a protocol that consisted of walking/running for at least eight minutes at high intensity, i.e., >85% of maximum heart rate, considering EIB+ as a 10% decrease in forced expiratory volume in one second (FEV1). The genotyping of the ADRB2 gene was performed by the Taqman method, using the Step One Plus system. Independent t-test, Mann–Whitney and Chi-square tests, as well as Spearman's correlation coefficient were used for the statistical analysis. Results: Age, body weight, height, FEV1, FVC and FEV1/FVC ratio were lower in the EIB+ group when compared to EIB− (p<0.05). There were no significant differences in the proportion of the allele at position 27 and Arg16Gly and Gln27Glu genotypes between the EIB+ and EIB− groups (p=0.26; p=0.97 and p=0.43, respectively). However, there was a trend toward statistical significance regarding the greater proportion of the Gly16 allele for the EIB+ when compared to the EIB− group (p=0.08). Conclusions: The presence of polymorphisms associated with the Glu27 allele and Arg16Gly and Gln27Glu genotypes had no influence on EIB. However, the statistical trend toward greater frequency of the Gly16 allele in individuals with EIB+ can be considered evidence of the influence of polymorphisms of the ADBR2 gene on EIB in adolescents.

Objetivo: Investigar a associação dos polimorfismos Arg16Gly e Gln27Glu do gene receptor β2-adrenérgico (ADRB2) com a ocorrência de asma e sobrepeso, bem como a influência do gene sobre variáveis antropométricas, clínicas, bioquímicas e de aptidão física em crianças e adolescentes. Métodos: Os indivíduos foram avaliados quanto à frequência alélica do gene ADRB2, estatura, peso, índice de massa corporal, IMC-escore Z, circunferência abdominal, estágio puberal, frequência cardíaca de repouso, pressão arterial, colesterol total, glicose, insulina, lipoproteína de alta densidade, lipoproteína de baixa densidade, triglicerídeos, Homeostasis Metabolic Assessment (HOMA2-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) e consumo máximo de oxigênio (VO2max). Os participantes foram divididos em quatro grupos: sobrepeso asmático (n=39), sobrepeso não asmático (n=115), peso normal asmático (n=12) e peso normal não asmático (n=40). Resultados: Com relação ao polimorfismo Gln27Glu, foi observado maior valor de colesterol total nos indivíduos do genótipo usual do que naqueles que carregam a variante (p=0,04). Não foi encontrada evidência de que os polimorfismos avaliados influenciem a aptidão física. O alelo Arg16 foi encontrado em maior frequência no grupo de peso normal asmático comparado com o grupo de peso normal não asmático (p=0,02) e o alelo Glu27 foi mais frequentemente encontrado no grupo de sobrepeso asmático comparado com o grupo de peso normal não asmático (p=0,03). Conclusões: A associação do alelo Arg16 com a ocorrência de asma e a associação do alelo Glu27 com adolescentes com sobrepeso asmáticos evidenciam a contribuição do gene ADBR2 para o desenvolvimento da obesidade e da asma.

Objective: To investigate the association of Arg16Gly and Gln27Glu polymorphisms of β2-adrenergic receptor gene (ADRB2) with the occurrence of asthma and overweight and the gene's influence on anthropometric, clinic, biochemical and physical fitness variables in children and adolescents. Methods: Subjects were evaluated for allelic frequencies of the β2-adrenergic receptor gene, height, weight, body mass index (BMI), BMI Z-score, waist circumference (WC), pubertal stage, resting heart rate (HRres), blood pressure (BP), total cholesterol (TC), glucose, insulin, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), triglyceride (TG), Homeostasis Metabolic Assessment (HOMA2-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) and maximal oxygen uptake (VO2max). The participants were divided in four groups: overweight asthmatic (n=39), overweight non-asthmatic (n=115), normal weight asthmatic (n=12), and normal weight non-asthmatic (n=40). Results: Regarding the Gln27Glu polymorphism, higher total cholesterol was observed in usual genotype individuals than in genetic variant carriers (p=0.04). No evidence was found that the evaluated polymorphisms are influencing the physical fitness. The Arg16 allele was found more frequently among the normal weight asthmatic group when compared to the normal weight non-asthmatic group (p=0.02), and the Glu27 allele was more frequently found in the overweight asthmatics group when compared to the normal weight non-asthmatic group (p=0.03). Conclusions: The association of Arg16 allele with the occurrence of asthma and of the Glu27 allele with overweight asthmatic adolescents evidenced the contribution of the β2-adrenergic receptor gene to the development of obesity and asthma.

O objetivo desta revisão foi apresentar os genes APOE e MAPT e as proteínas ApoE e tau como marcadores genéticos que vêm sendo estudados na demência frontotemporal com inclusões tau-positivas, os quais poderão, futuramente, auxiliar no diagnóstico diferencial. A demência frontotemporal é um transtorno neurocognitivo marcado por disfunção dos lobos frontais e temporais, geralmente associada à atrofia dessas estruturas e relativa preservação das regiões cerebrais posteriores. Clinicamente, manifesta-se por volta dos 57 anos de idade, com igual incidência entre homens e mulheres. A demência frontotemporal tem início insidioso e caráter progressivo, com discreto comprometimento da memória episódica, mas com importantes alterações comportamentais, de personalidade e na linguagem. Devido às semelhanças possíveis entre as manifestações clínicas das demências inclusive a doença de Alzheimer, há grande dificuldade no diagnóstico diferencial, sendo necessário um exame clínico e neuropsicológico detalhado do indivíduo acometido, além de exames bioquímicos e de neuroimagem. O gene MAPT codifica a proteína tau e sua função principal é estabilizar os microtúbulos. Em células nervosas sadias, a proteína tau é normalmente encontrada nos axônios, ao contrário dos achados descritos nos transtornos neurocognitivos, em que a proteína se encontra distribuída no corpo celular e nos dendritos. A apolipoproteína E ApoE é uma glicoproteína polimórfica, codificada pelo gene APOE, que tem importante papel na absorção, transporte e redistribuição de colesterol, necessário ao reparo e manutenção do tecido nervoso. Com o aumento da expectativa de vida e controle da natalidade, o envelhecimento populacional tornou-se fato, trazendo consigo maior prevalência de doenças crônico-degenerativas, de modo que é de extrema importância conhecer melhor essas doenças, no sentido de buscar novas formas de tratamento, visto que as demências não dispõem ainda de cura. Sabe-se que o diagnóstico definitivo da maioria das síndromes demenciais depende do exame neuropatológico, mas conclui-se que, com o avanço tecnológico, bem como técnicas de biologia e genética molecular, novas perspectivas têm surgido para o diagnóstico diferencial e precoce das demências.

This review aimed to present the APOE and MAPT gene and ApoE and tau proteins as genetic markers that have been studied in frontotemporal dementia, which may in future help in the differential diagnosis. Frontotemporal dementia is a neurocognitive disorder characterized by frontal and temporal lobes dysfunction, often associated with atrophy of these structures and relative preservation of posterior brain regions. Clinically, it manifests around 57 years-old, with same incidence in men and women. Frontotemporal dementia has an insidious and progressive onset, with a mild impairment of episodic memory, but with significant behavioral, personality and language changes. Due to possible similarities between the clinical manifestations of dementia including Alzheimer's disease there is a great difficulty in the differential diagnosis, which needs detailed clinical and neuropsychological examination of individuals affected, further biochemical and neuroimaging exams. MAPT gene encodes tau protein, its main function is to stabilize microtubules. In healthy nerve cells, tau protein is usually found in the axons, in contrast to the findings described in neurocognitive disorders in which protein is distributed in the cell body and dendrites. The apolipoprotein E ApoE is a polymorphic glycoprotein, encoded by the APOE gene, which plays an important role in absorption, transport and redistribution of cholesterol, necessary for the repair and maintenance of nervous tissue. Because of increasing life expectancy and birth control, population aging has become fact, bringing a higher prevalence of chronic diseases, so it is extremely important to know more about these dis eases, in order to seek new ways of treating dementias seen that do not have a cure. It is known that the definitive diagnosis of most dementia depends on neuropathological examination, however, with technological advances and techniques of molecular biology and genetics, new opportunities have emerged for the early and differential diagnosis of dementias.

Many conditions interfere with butyrylcholinesterase (BChE) activity, e.g., pregnancy or presence of the BCHE gene variant -116A can decrease activity whereas obesity and types I and II diabetes mellitus can increase activity. In this study, we examined BChE activity, -116A and 1615A BCHE gene variants, and anthropometric and biochemical variables associated with diabetes in patients with gestational diabetes mellitus (GDM) and in healthy pregnant women. BChE activity was measured spectrophotometrically using propionylthiocholine as substrate and genotyping of the -116 and 1615 sites of the BCHE gene was done with a TaqMan SNP genotyping assay. Three groups were studied: 150 patients with GDM, 295 healthy pregnant women and 156 non-pregnant healthy women. Mean BChE activity was significantly lower in healthy pregnant women than in women from the general population and was further reduced in GDM patients. BChE activity was significantly reduced in carriers of -116A in GDM patients and healthy pregnant women. Although GDM patients had a significantly higher mean body mass index (BMI) and triglycerides than healthy pregnant women, they had lower mean BChE activity, suggesting that the lowering effect of GDM on BChE activity was stronger than the characteristic enhancing effect of increased BMI and triglycerides.

The individual response to diet may be influenced by gene polymorphisms. This study hypothesized that ADRB2 (Gln27Glu, rs1042714 and Arg16Gly, rs1042713), ADRB3 (Trp64Arg, rs4994) and GHRL (Leu72Met, rs696217) polymorphisms moderate weight loss. The study was a seven weeks dietary weight loss intervention with Brazilian adult obese women (n = 109). The body mass index (BMI) was calculated and polymorphisms in these genes were assessed by real-time PCR assays. Two-way repeated-measures ANOVA (2 x 2) were used to analyze the intervention effect between polymorphisms and BMI over the period and after stratification for age and socioeconomic status (SES). The weight loss intervention resulted in decreased BMI over the seven-week period (p < 0.001), for high and low SES (p < 0.05) and mainly for participants with 30-49 y. The intervention did not result in a statistically significant difference in weight loss between polymorphism carriers and non-carriers, and although, the ADRB2, ADRB3 and GHRL polymorphisms did not moderate weight loss, the Gln27Glu polymorphism carriers showed a lower BMI compared to non-carriers in the low SES (p = 0.018) and the 30-39 y (p = 0.036) groups, suggesting a role for this polymorphism related to BMI control.

The aim of the present study was to evaluate the effect of a 12 week program of physical exercise (PE) on butyrylcholinesterase (BChE) in obese adolescents. This study compared obese adolescents (N = 54) before and after PE, regarding the relative intensity (RI) and activity of different molecular forms (G1, G2, G4 and G1-ALB) of BChE found in plasma. Waist circumference (WC) and lipid profile were also assessed before and after PE. It was shown that before PE, mean plasma BChE activity was significantly higher in obese than in non-obese adolescents and that it was significantly reduced after PE, becoming similar to that found in non-obese adolescents. Lipid profile and WC also changed in response to PE. These results are consistent with studies that found a correlation between BChE and lipid metabolism and suggest that PE may have led to a physiological regularization of plasma BChE activity. Although mean BChE activity of each isoform was significantly reduced by PE, their RI did not change. This is in accordance with a previous suggestion that this proportion is maintained under factors such as obesity, and may therefore be important for BChE functions.

Ghrelin coded by the GHRL gene is related to weight-gain, its deactivation possibly depending on its hydrolyzation by butyrylcholinesterase (BChE) encoded by the BCHE gene, an enzyme already associated with the body mass index (BMI). The aim was to search for relationships between SNPs of the GHRL and BCHE genes with BChE activity, BMI and obesity in 144 obese and 153 nonobese Euro-Brazilian male blood donors. In the obese individuals, a significant association with higher BChE activity, in the 72LM+72MM; -116GG genotype class (GHRL and BCHE genes, respectively) was noted. No significant differences were found otherwise, through comparisons between obese and control individuals, of genotype and allele frequencies in SNPs of the GHRL gene (Arg51Gln and Leu72Met), or mean BMI between 72LL and 72LM+72MM genotypes. Although there appears to be no direct relationship between the examined GHRL SNPs and BMI, the association of the 72M SNP with higher BChE activity in obese subjects probably points to a regulatory mechanism, thereby implying the influence of the GHRL gene on BChE expression, and a consequential metabolic role in the complex process of fat utilization.

This study compared obese (N = 134) and unobese (N = 92) male blood donors, regarding the relative intensity (RI) and activity of different molecular forms (G1, G2, G4 and G1-ALB) of butyrylcholinesterase (BChE, EC 3.1.1.8) found in plasma, thereby searching for an association between these variables with obesity and SNPs of exons 1 and 4 of the BCHE gene. It was shown that obese and unobese individuals do not differ in the RI of each BChE band, even when classifying the sample into three genotypes of exons 1 and 4 of the BCHE gene (-116GG/539AA, -116GG/539AT, -116GA/539AT). Although the mean BChE activity of each band was significantly higher in obese than in unobese blood donors, the proportions of BChE bands were maintained, even under the metabolic stress associated to obesity, thereby leading to infer that this proportion is somehow regulated, and may therefore be important for BChE functions.

Butyrylcholinesterase (BChE; EC 3.1.1.8; Online Mendelian Inheritance in Man (OMIM) number 177400) is an enzyme found in many human tissues and encoded by the BCHE gene, of which 65 variants have been identified. In a recent study we found that the -116A variant of exon 1 of the BCHE gene was associated with lower mean BChE activity. The present study analyzed the -116 single nucleotide polymorphism (SNP) in 253 Guarani Amerindian Brazilians from the state of Mato Grosso do Sul (148 Guarani-Kaiowá, 83 Guarani-Ñandeva and 22 Kaiowá-Ñandeva descendants) and verified that they were all homozygotic for the -116G variant. A comparative analysis of the -116 site in nine vertebrate species indicated the -116A variant as the ancestral type. This is the first study of the -116 SNP in Amerindians and it is therefore difficult to infer whether or not the -116A variant was always absent from southern paleo-Amerindians or was present and then subsequently lost due to evolutionary factors.