Abstract Mycophenolic acid (MPA) inhibits IMPDH, involved in the guanosine nucleotides synthesis, and prevents DNA replication in immune cells. The repression of cell and humoral immunity by MPA induces allograft tolerance preventing acute rejection in solid organ transplantation. MPA is an effective and safe drug, but genetic and non-genetic factors have been implicated in the interindividual variability of drug response. Several studies have shown the impact of variants of pharmacokinetics or pharmacodynamics-related genes on MPA response in kidney transplantation. This review explored further the influence of genes involved in the immune response on clinical outcomes of kidney recipients on short- or long-term MPA treatment. Variants in genes related to T cell activation (CD28, CTL4, ICOS, PDPC1), pro-inflammatory cytokines (IL2, IL6, IL12A, IL12B, TNF, IFNG), immunomodulatory cytokines (IL4, IL10, TGFB1), and innate immune response (CD14, TLR2, TLR4) were shown to be associated with increased risk of acute rejection, graft function or survival, chronic graft nephropathy, viral infections or MPA-induced myelotoxicity. Some of the significant pharmacogenetic associations were confirmed by meta-analyses of kidney transplantation. These findings are suggestive that variants in immune response-related genes contribute to the variability of MPA response, and have potential application as biomarkers of acute rejection in kidney transplantation.

Background: Childhood and adolescent obesity is a major public health problem in Chile. Aim: To characterize cardiometabolic risk factors in a population of schoolchildren from Carahue, Chile. Material and Methods: Cross-sectional assessment of 208 children aged 10.4 ± 1.0 years (106 women). A clinical evaluation was carried out including pubertal development according to Tanner and anthropometric parameters. A fasting blood sample was obtained to measure glucose, insulin and lipid profile. HOMA-IR and Quicki indices were calculated. Insulin resistance (IR) was established according to Burrows criteria and Barja criteria, previously proposed for the Chilean pediatric population. The metabolic syndrome (MetS) was established using the modified Cook criteria. Results: Thirty eight percent of children had overweight and 33.1% obesity. MetS was only observed in obese subjects and the frequency in this subgroup was 38%. The prevalence of IR was 51% according to the Burrows criteria and 19% according to Barja criteria. It was more common in participants who were overweight, obese or had abdominal obesity. Children with insulin resistance according to Barja criteria, had worse anthropometric measures than their counterparts without resistance. When Burrows criteria was used, no differences in anthropometric measures were observed between participants with or without resistance. The frequency of MetS was 26 and 18% in children with insulin resistance according to Barja and Burrows criteria, respectively. Insulin levels and insulin sensitivity indexes were positively correlated with anthropometric parameters. Conclusions: There was a high prevalence of overweight, obesity and MetS in these participants. Our results suggest that the IR criteria according to Barja allows to identify cases with higher metabolic risk.

Dyslipidemia, diabetes, obesity and hypertension are common metabolic diseases. In the last decades, unhealthy lifestyle and aging have leads to an increased incidence of these diseases, increasing morbidity and mortality by cardiovascular causes. The treatment of metabolic diseases includes life-style interventions as healthy diet and physical exercise, as well as pharmacological interventions. Several drugs are available for the management of metabolic diseases including among others lipid-lowering antidiabetics and antihypertensive drugs. Variability in response to these drugs is influenced by both genetic and non-genetic factors. Polymorphisms in genes related to drug pharmacokinetics and pharmacodynamics have been shown to influence drug efficacy and safety. This review is focused on pharmacogenetic studies related to the management of metabolic diseases in samples of the Brazilian population. Associations of variants in drug metabolizing enzymes and transporters, drug target and metabolism-related genes with the efficacy and safety of lipid-lowering, antidiabetic and antihypertensive drugs are described. Most pharmacogenetic studies in Brazil have focused in pharmacological response to a small group of drugs, as statins and some antihypertensives, while there are almost no studies on antidiabetic and antiobesity drugs. Some studies reported significant associations of gene polymorphisms with drug response confirming previous data from other populations, whereas other works did not replicate, which may relay on the genetic admixture of our population. In conclusion, further studies are necessary considering larger sample sizes, new unexplored drugs and more genetic variants to obtain stronger conclusions to explore clinical applications of pharmacogenetic studies in our population.

Fundamento: O óxido nítrico (NO) tem sido amplamente associado com proteção cardiovascular através de melhoria da função endotelial. Recentemente, novas evidências sobre a modulação do NO na liberação de microRNAs (miRs) têm sido relatadas, o que poderia estar envolvido com efeitos pleiotrópicos dependentes de estatinas, incluindo propriedades anti-inflamatórias relacionadas com a função do endotélio vascular. Objetivo: Avaliar os efeitos dos medicamentos redutores de colesterol, incluindo os inibidores da síntese de colesterol, atorvastatina e sinvastatina, e o inibidor da absorção de colesterol, ezetimiba, na liberação de NO, expressão do mRNA do NOS3 e miRs potencialmente envolvidos na biodisponibilidade do NO. Métodos: Células endoteliais da veia umbilical humana (HUVEC) foram expostas à atorvastatina, sinvastatina ou ezetimiba (0 a 5,0 μM). As células foram submetidas à extração do RNA total e quantificação relativa de mRNA do NOS3 e dos miRs-221,-222 e -1303 por qPCR. A liberação de NO foi medida em sobrenadantes por ozônio-quimioluminescência. Resultados: Ambas as estatinas aumentaram os níveis de NO e a expressão do mRNA do NOS3, mas nenhum efeito foi observado em relação ao tratamento com ezetimiba. A atorvastatina, sinvastatina e ezetimiba regularam negativamente a expressão do miR-221, enquanto que o miR-222 reduziu somente após o tratamento com atorvastatina. A magnitude da redução de miR-221 e miR-222 após tratamento com estatinas correlacionou com o incremento nos níveis de mRNA do NOS3. Nenhuma influência foi observada sobre a expressão do miR-1303 após os tratamentos. Conclusão: A liberação de NO pelas células endoteliais é aumentada por estatinas, mas não pelo inibidor da absorção de colesterol ezetimiba. Nossos resultados fornecem novas evidências sobre a participação dos miRs regulatórios 221/222 na liberação de NO mediada por estatinas. Embora a ezetimiba não tenha modulado os níveis de NO, a regulação negativa do miR-221 poderia envolver efeitos potenciais sobre a função endotelial.

Background: Nitric oxide (NO) has been largely associated with cardiovascular protection through improvement of endothelial function. Recently, new evidence about modulation of NO release by microRNAs (miRs) has been reported, which could be involved with statin-dependent pleiotropic effects, including anti-inflammatory properties related to vascular endothelium function. Objective: To evaluate the effects of cholesterol-lowering drugs including the inhibitors of cholesterol synthesis, atorvastatin and simvastatin, and the inhibitor of cholesterol absorption ezetimibe on NO release, NOS3 mRNA expression and miRs potentially involved in NO bioavailability. Methods: Human umbilical vein endothelial cells (HUVEC) were exposed to atorvastatin, simvastatin or ezetimibe (0 to 5.0 μM). Cells were submitted to total RNA extraction and relative quantification of NOS3 mRNA and miRs -221, -222 and -1303 by qPCR. NO release was measured in supernatants by ozone-chemiluminescence. Results: Both statins increased NO levels and NOS3 mRNA expression but no influence was observed for ezetimibe treatment. Atorvastatin, simvastatin and ezetimibe down-regulated the expression of miR-221, whereas miR-222 was reduced only after the atorvastatin treatment. The magnitude of the reduction of miR-221 and miR-222 after treatment with statins correlated with the increment in NOS3 mRNA levels. No influence was observed on the miR-1303 expression after treatments. Conclusion: NO release in endothelial cells is increased by statins but not by the inhibitor of cholesterol absorption, ezetimibe. Our results provide new evidence about the participation of regulatory miRs 221/222 on NO release induction mediated by statins. Although ezetimibe did not modulate NO levels, the down-regulation of miR-221 could involve potential effects on endothelial function.

OBJETIVO: O estudo teve por objetivo investigar a influência de polimorfismos nos genes da leptina (LEP) e do receptor de leptina (LEPR) na adiposidade e em marcadores metabólicos, como leptina, glicose e lipídeos, em uma amostra de nossa população. SUJEITOS E MÉTODOS: Um grupo de 326 indivíduos com idade de 30 a 80 anos, 87 homens e 239 mulheres, 148 obesos e 178 não obesos, e de etnia branca foi selecionado aleatoriamente em dois hospitais clínicos da cidade de São Paulo, Brasil. Medidas antropométricas, índice de massa corporal (IMC) e gordura corporal foram avaliados. Amostras de sangue foram obtidas para extração de DNA e determinações de leptina, receptor de leptina solúvel, glicose e lipídeos. Os polimorfismos LEP -2548G>A e LEPR Lys109Arg (c.326A>G), Gln233Arg (c.668A>G) e Lys656Asn (c.1968G>C) foram detectados por PCR-RFLP. RESULTADOS: Leptina e lipídeos séricos aumentados e LEPR Arg223Arg (genótipo GG) foram associados com maior risco de obesidade (p < 0,05), enquanto foi encontrado risco reduzido de obesidade, em portadores de LEPR Arg109Arg (genótipo GG) (OR: 0,38, 95%CI: 0,19-0,77, p = 0,007). A análise de regressão linear múltipla mostrou relação entre o alelo LEPR 223Arg e circunferência abdominal e leptinemia aumentadas (p < 0,05), enquanto o alelo LEPR 109Arg foi associado com aumento de colesterol total e triglicerídeos (p < 0,05). Os portadores do haplotipo 3 do LEPR (AGG: 109Lys/233Arg/656Lys) tiveram maior risco aumentado para obesidade (OR: 2.56, 95% CI: 1.19-5.49, p = 0,017). Além disso, esse haplótipo foi associado com IMC, circunferência abdominal e leptinemia aumentados (p < 0,05). CONCLUSÕES: Polimorfismos de LEPR são associados com obesidade, hiperleptinemia e perfil lipídico aterogênico sugerindo seu papel potencial para a resistência à leptina e risco cardiovascular.

OBJECTIVE: The aim of the study was to investigate whether adiposity and metabolic markers, such as leptin, glucose, and lipids, are influenced by leptin (LEP) and leptin receptor (LEPR) gene polymorphisms in a sample of our population. SUBJECTS AND METHODS: A group of 326 individuals of Caucasian-European descent, aged 30 to 80 years, 87 men and 239 women, 148 obese and 178 non-obese, was randomly selected at two clinical hospitals in the city of Sao Paulo, Brazil. All individuals declared their ethnic group as white during the initial interview. Anthropometric measurements, body mass index (BMI), and fat mass were evaluated. Blood samples were drawn for DNA extraction and measurements of leptin, soluble leptin receptor, glucose, and lipids. LEP -2548G>A and LEPR Lys109Arg (c.326A>G), Gln233Arg (c.668A>G) and Lys656Asn (c.1968G>C) polymorphisms were detected by PCR-RFLP. RESULTS: Increased leptin and serum lipids, and LEPR Arg223Arg (GG genotype) were associated with higher risk for obesity (p < 0.05), while reduced risk was found in LEPR Arg109Arg (GG genotype) carriers (OR: 0.38, 95%CI: 0.19-0.77, p = 0.007). Multiple linear regression analysis showed a relationship between LEPR 223Arg, increased waist circumference, and leptinemia (p < 0.05), while LEPR 109Arg was associated with high total cholesterol and triglycerides (p < 0.05). LEPR haplotype 3 (AGG: 109Lys/233Arg/656Lys) carriers have increased risk for obesity (OR: 2.56, 95% CI: 1.19-5.49, p = 0.017). Moreover, this haplotype was associated with increased BMI, waist circumference, and leptinemia (p < 0.05). CONCLUSIONS: LEPR polymorphisms are associated with obesity, hyperleptinemia, and atherogenic lipid profile, suggesting their potential role for leptin resistance and cardiovascular risk. Moreover, LEPR haplotype 3 confers susceptibility to adiposity and hyperleptinemia in our population.