No description available.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Cytochrome P450 2D6 (CYP2D6) is an important drug metabolizing enzyme that is involved in the metabolism of 20-25% of commonly prescribed drugs. There is interindividual variability in CYP2D6 enzyme activity and this leads to compromised metabolism of many drugs. Genetic and environmental factors explain only a part of the interindividual variability; the other factors that contribute to this variability are largely unknown. Hence, it becomes important to study CYP2D6 to understand the endogenous and exogenous factors that control its activity. The specific objective of this research was to determine the contribution of genetic and epigenetic factors in the regulation of CYP2D6 expression and activity. The specific aims were: (1) to identify the common CYP2D6 polymorphisms in Vietnamese and Filipino women with breast cancer and evaluate its association with plasma concentrations of endoxifen (an active metabolite of the breast cancer therapeutic drug, tamoxifen); (2) to identify the CYP2D6 copy number variations (CNVs) in these women and evaluate their association with endoxifen concentration; and (3) to identify microRNAs (miRNAs) that regulate the expression of CYP2D6 directly or indirectly. The results of this study indicated that: (1) in Vietnamese and Filipino women, the reduced function allele CYP2D6*10 was frequent (~55%) and it was significantly associated with reduced endoxifen concentration; (2) in these women, only 39% carried two copies of the CYP2D6 gene, the rest had a genomic imbalance for CYP2D6, primarily involving the CYP2D6(*36)n-*10 allele. However, carrying multiple copies of CYP2D6*36 allele did not significantly affect CYP2D6 activity, suggesting that multiple copies of a gene does not always translate to additive effects; and (3) microRNAs were identified to target HNF4A, a transcriptional factor that regulates CYP2D6 expression. These miRNAs are likely to play an important role in the indirect regulation of CYP2D6. Taken together, these results emphasize on the role of polymorphisms, CNVs and possibly miRNAs in the regulation of CYP2D6. These clinically important biomarkers will help to improve the efficacy and reduce the side effects of many CYP2D6 substrate drugs and thus contribute to personalization of drug therapy.

As a primary factor in human evolution, natural selection is an important component of genetic research. Studies of lactase persistence suggest that positive selection has played a powerful role in the adaptation to a lifelong consumption of fresh milk. Using multiple research studies of lactase persistence and suspected corresponding single nucleotide genetic polymorphisms, this study combines data sources to determine whether evidence exists for natural selection of a specific cytosine-to-thymine genetic mutation located 13,910 base pairs (T-13910) upstream from the lactase gene. This polymorphism has potential to be a causal element for lactase persistence, and data suggest that natural selection has played a role in the rising frequency and distribution of this allele, if only in some regions. European and neighboring regions appear to have the highest frequencies with little or no frequency in Asia, Africa and Indonesia; however the presence of lactase persistence in those areas suggests convergent evolution may be occurring on a phenotypic level. To examine this possibility several other identified polymorphisms in the same region as the T-13910 will be included in this study

No description available.

No / Hair diversity, its style, colour, shape and growth pattern is one of our most defining characteristics. The natural versus temporary style is influenced by what happens to our hair during our lifetime, such as genetic hair loss, sudden hair shedding, greying and pathological hair loss in the various forms of alopecia because of genetics, illness or medication. Despite the size and global value of the hair care market, our knowledge of what controls the innate and within-lifetime characteristics of hair diversity remains poorly understood. In the last decade, drivers of knowledge have moved into the arena of genetics where hair traits are obvious and measurable and genetic polymorphisms are being found that raise valuable questions about the biology of hair growth. The recent discovery that the gene for trichohyalin contributes to hair shape comes as no surprise to the hair biologists who have believed for 100 years that hair shape is linked to the structure and function of the inner root sheath. Further conundrums awaiting elucidation include the polymorphisms in the androgen receptor (AR) described in male pattern alopecia whose location on the X chromosome places this genetic contributor into the female line. The genetics of female hair loss is less clear with polymorphisms in the AR not associated with female pattern hair loss. Lifestyle choices are also implicated in hair diversity. Greying, which also has a strong genetic component, is often suggested to have a lifestyle (stress) influence and hair follicle melanocytes show declining antioxidant protection with age and lowered resistance to stress. It is likely that hair research will undergo a renaissance on the back of the rising information from genetic studies as well as the latest contributions from the field of epigenetics.

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

Introdução: A artrite reumatóide (AR) é uma artropatia autoimune, de caráter inflamatório, com prevalência em torno de 1% da população. O tabagismo é considerado o principal fator de risco para o desenvolvimento da AR. O receptor de hidrocarbonetos de arila (AhR), um fator de transcrição intracelular ativado por hidrocarbonetos aromáticos componentes da fumaça do cigarro, foi identificado como alvo de regulação da diferenciação de células Th17. Objetivos: Avaliar se os polimorfismos genéticos do AhR estariam associados ao desenvolvimento da AR , e se este receptor estaria mais expresso em pacientes com AR. Pacientes e Métodos: Nós analisamos sete polimorfismos genéticos por mudança de única base (SNP) por PCR em tempo real utilizando sondas TaqMan em 138 pacientes com AR e 129 indivíduos saudáveis. A quantificação da expressão do mRNA do AhR em células mononucleares isoladas de pacientes com AR e indivíduos saudáveis foi realizada por PCR em tempo real. Resultados: Identificamos que haplótipos formados por SNPs no AhR estariam associados com desenvolvimento da AR, podendo ser fator protetor ou de risco para a doença. Em adição, os pacientes com haplótipos de risco apresentavam doença com índice de atividade elevado, principalmente quando o tabagismo estava presente. De fato, pacientes com AR apresentaram aumento na expressão de AhR (mRNA) em relação a indivíduos saudáveis. Conclusões: Em conjunto estes resultados sugerem que o AhR possui um papel importante para o desenvolvimento da artrite reumatóide. Possivelmente mutações neste receptor podem estar relacionadas com alterações na sua atividade e conseqüentemente na diferenciação de células Th17 e a susceptibilidade a AR. / Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune arthropaty with inflammatory characteristics and prevalence around 1% in the population. Tabagism is the main risk factor to RA development. The aryl hydrocarbon receptor (AhR) is an intracellular transcription factor activated by aromatic hydrocarbons present in smoking, whichwas identified to be a target of regulation of Th17 differentiation. Purpose: Study the relationship of genetic polymorphisms in AhR with RA development, and if this receptor expression is upregulated in RA patients. Patients and Methods: We analyzed seven genetic single nucleotide polymorphisms by Real-Time PCR using TaqMan probes in 138 patients with Rheumatoid Arthritis and 129 healthy controls. The AhR mRNA quantization in mononuclear cells isolated from AR patients and healthy controls has been done by Realt-Time PCR. Results: We identified that AhR haplotypes were associated with RA development and that they could be protector or risk factors to disease. In addition, patients with risk haplotypes showed higher disease activity index, mainly when smoking was present. Indeed, patients with RA showed upregulation in the AhR expression (mRNA) when compared with healthy controls. Conclusions: These results suggest that AhR has an important role in AR development. Probably, mutations in this receptor could be related with alterations in its activity and consequently in the differentiation of Th17 cells and RA susceptibility.

Os transtornos alimentares (TA) são quadros psiquiátricos graves, de etiologia multifatorial e a influência genética parece exercer importante papel. Três genes são candidatos em potencial para o desenvolvimento desses quadros e são investigados: o gene do receptor 5-hidroxitriptamina (5-HT2A), o do Fator Neurotrófico Derivado do Cérebro (BDNF) e do receptor ? do estrogênio (ER?). O objetivo deste estudo foi identificar a presença de polimorfismos (SNPs) desses genes em pacientes e ex-pacientes com TA (grupo de pacientes-GP) e em mulheres jovens saudáveis (grupo controle-GC) e foi realizado junto ao Grupo de Assistência em Transtornos Alimentares do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto-USP. Coletaram-se os dados: idade, peso e altura para cálculo do índice de massa corporal (IMC) e aplicou-se o Eating Atitudes Test (EAT-26) para excluir possível caso de doença no GC (<21pontos). Os SNPs foram determinados pela técnica de reação em cadeia da polimerase (PCR). Para análises estatísticas, utilizou-se o Statistical Package for Social Sciences (SPSS, 20.0), nas variáveis contínuas (IMC e idade) usou-se o teste ANOVA, na variável dicotômica (presença ou não de SNPs), teste qui-quadrado e regressão logística binária (pa ). Como resultados, foram coletados dados de 29 indivíduos do GP e 78 do GC. A idade foi de 26,37±7,00 anos no GP e 28,65±6,67 anos no GC (p=0,274), o IMC foi de 20,83±4,47kg/m2 no GP e 21,56±1,67kg/m2 no GC (p=0,294), e o EAT-26 foi de 30,34±18,83 pontos no GP e 7,83±4,94 pontos no GC (p=0,000). Calcularam-se as frequências alélicas e genotípicas dos genes e foi feita análise que unia genótipos que possuíam alelos de risco para cada gene. No gene 5HT2A 75,8% do GP e 38,4% do GC apresentaram-se os genótipos com o alelo de risco (GA e AA) (pX2 =0,253; OR=1,964; IC95%=0,748-5,156 e pa =0,552). No do BDNF, encontraram-se frequências de 96,5% no GP e 96,1% no GC com os genótipos com alelo de risco, MM e MV (pX2 =1,00; OR=1,120; IC95%=0,112-11,221 e pa =0,362 ). No gene do ER?, para o SNP presente no éxon 5 (1082 G->A), as frequências dos genótipos de risco GA e AA foram de 6,8% no GP e 8,9% no GC (pX2 =1,00; OR=0,751; IC95%=0,147-3,841 e pa =0,883), e o SNP situado no éxon 8 (1730 A->G), as frequências dos genótipos de risco AG e AA foram de 65,5% no GP e 83,3% no GC (pX2 =0,064; OR=0,380; IC95%=0,144-1,002 e pa =0,399). Todas as análises não apresentaram diferença estatística significativa para a presença dos alelos de risco que podem contribuir para o desenvolvimento de TA. Concluiu-se que a heterogeneidade da população brasileira, a baixa incidência da doença e a amostra limitada do GP podem ter influenciado para as semelhanças entre os grupos. Futuros estudos, utilizando marcadores genéticos de etnias e amostras maiores, devem prosseguir na linha promissora da investigação etiológica. / Eating disorders (ED) are serious psychiatric conditions with multifactorial etiology, it seems genetic influence has an important role. Three genes were investigated: the receptor 5-hydroxitriptamine (5-HT2A), the Brain-Derived Neurotrophic Factor (BDNF) and the Estrogen Receptor ? (ER?). This study aims at identifying the presence of polymorphisms (SNPs) in patients or in ex-patients with ED (Group of patients - GP) and in wealthy women (Control Group - CG). The study was conducted with the Eating Disorders Assistence Group at Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto-USP. To calculate the Body Mass Index (BMI), we collected data referring to age, weight and height, we applied the Eating Attitudes Test (EAT-26) to exclude a possible occurrence of disease in the CG (<21 points). The polymerase chain reaction (PCR) was used to determine SNPs. For the statistical analysis we used the Statistical Package for Social Sciences (SPSS, 20.0): for the continuous variables (BMI and age), the ANOVA and for the dichotomous variable (presence or not of SNPs), Chi-square test and Binary logistic regression (pa ). There were 29 individuals of the GP and 78 of the CG. The age was 26,37±7,00 in the GP and 28,65±6,67 in the CG (p=0,274), the BMI was 20,83±4,47Kg/m2 in the GP and 21,56±1,67Kg/m2 in the CG (p=0,294), and the EAT-26 was 30,34±18,83 points in the GP e 7,83±4,94 points in the CG (p=0,000). We calculated the allelic and genotypic frequencies in the genes of the studied groups and afterwards we did an analysis that joined genotypes with risk alleles for each gene. The genes 5HT2A 75,8% of GP and 38,4% of the CG presented the genotype with risk allele (GA and AA) (pX2 =0,253; OR=1,964; IC95%=0,748-5,156 e pa =0,552). In the BDNF we found frequencies of 96,5% in the GP and 96,1% in the CG with genotypes with risk allele, MM and MV (pX2 =1,00); OR=1,120; IC95%=0,112-11,221 e pa =0,362). Regarding the gene ER?, for the SNP present in the exon 5 (1082 G->A), the frequency of risk genotypes GA and AA were of 6,8% in the GP and of 8,9% in the CG (pX2 =1,00; OR=0,751; IC95%=0,147-3,841 and pa =0,883), and for the SNP located in the exon 8 (1730 A->G), the frequency of risk genotypes AG and AA were of 65,5% in the GP and 83,3% in the CG (pX2 =0,064; OR=0,380; IC95%=0,144-1,002 e pa =0,399). There were no significant differences between the studied groups for the presence of risk alleles that may contribute to the development of ED. We concluded that heterogeneity of Brazilian population, the low incidence of the disease in it and the limited sample of GP may have influenced the similarities between the groups. Future studies using genetic markers of ethnicity and a wider sampling may contribute to the promising trend of etiologic investigation.

Aborto espontâneo recorrente (AER) é definido pela presença de três ou mais abortos espontâneos e consecutivos que ocorreram até a 20ª semana de gestação. O AER possui origem multifatorial. Dentre os diversos fatores associados ao AER, alterações na hemostasia podem comprometer o fluxo sanguíneo na placenta e com isso pode aumentar o risco de complicações obstétricas, como o aborto. O objetivo geral deste estudo foi investigar se existe associação entre polimorfismos genéticos (no gene do fibrinogênio (FGB -455G>A e -148C>T), da trombomodulina (THBD 1418C>T), do fator V (F5 1691G>A), da protrombina (F2 20210 G>A), do PAI-1 (SERPINE1 4G/5G) e do TAFI (CPB2<i/> c.505G>A)) e os abortos espontâneos recorrentes (primários e secundários). Os objetivos específicos desse estudo foram: 1- avaliar se existe associação entre os sete polimorfismos e o período em que ocorreram as perdas fetais (precoce ou tardia) e o número de abortos recorrentes; 2- determinar se os haplótipos dos polimorfismos FGB -455G>A e FGB -148C>T estão ou não associados aos abortos primários e secundários. Foram incluídas 256 mulheres com história de abortos espontâneos recorrentes, provenientes do Ambulatório de Obstetrícia da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da USP e 264 mulheres saudáveis, sem história de aborto espontâneo e que tiveram pelo menos duas gestações normais (grupo controle), pareadas segundo as idades. Amostras de sangue foram obtidas para realização das genotipagens dos polimorfismos por meio de PCR em tempo real (FGB -148C>T, FGB -455G>A, THBD 1418C>T e CBP2 c.505G>A), e PCR-RFLP (SERPINE14G/5G, F5 1691G>A e F2 20210 G>A). As frequências dos genótipos e de alelos para os sete polimorfismos foram semelhantes entre os grupos aborto primário, aborto secundário e grupo controle. Entretanto, quando foi realizada um modelo de regressão logística multivariada saturada, que incluiu as variáveis independentes: F5 1691G>A (referência GG vs GA), F2 20210G>A (referência GG vs GA), CBP2 c.505G>A (referência GG + GA vs AA), THBD 1418C>T (referência CC + CT vs TT), SERPINE1 4G/5G (referência 5G/5G vs 4G/4G + 4G/5G) FGB -455G>A (referência GG vs GA vs AA) e FGB -148C>T (referência CC vs CT vs TT), apenas o polimorfismo FGB -148C>T foi associado ao maior risco de ter aborto primário (OR: 2,91, IC 95% 1,02 - 8,29, p=0,045). Quando os haplótipos para os polimorfismos FGB -455G>A e FGB 148C>T foram considerados, foi observada maior frequência de haplótipo 455G/148T em mulheres com AER primário (3,4%) do que no grupo controle (1,1%), (p=0,030); porém esse efeito não foi observado no AER secundário. Em relação ao número de abortos consecutivos, houve uma tendência (p=0,060) a maior frequência de genótipo TT para o polimorfismo FGB -148C>T no grupo de aborto primário com até três perdas quando comparado com as mulheres do mesmo grupo, porém com número maior de perdas (>3). Em conclusão, os sete polimorfismos quando analisados separadamente, não foram associados ao AER; no entanto, em modelo multivariado de regressão logística, o genótipo TT do polimorfismo FGB 148C>T foi associado com o aumento do risco de ter AER primário. Além disso, foi encontrado maior frequência do haplótipo 455G/148T para os polimorfismos FGB -455G>A e FGB -148C>T em mulheres com aborto primário. / Recurrent pregnancy loss (RPL) is defined by the presence of three or more consecutive losses prior to 20 weeks of gestation. The RPL has multifactorial origin. Among several factors associated with RPL, changes in hemostasis may impair the blood flow in the placenta and thus may increase the risk of obstetric complications, such as pregnancy loss. The general aim of this study was to investigate the association between genetic polymorphisms (in the genes of fibrinogen (FGB -455G>A and -148C>T), thrombomodulin (THBD 1418C>T), factor V (F5 1691G>A), prothrombin (F2 20210 G>A), PAI-1 (SERPINE1 4G/5G) and TAFI (CPB2 c.505G>A)) and recurrent pregnant losses (primary and secondary). The specific aims of this study were: 1 - to evaluate the association between the seven polymorphisms and the period in which the fetal losses occurred (early or late) and the number of recurrent losses; 2 - to determine if the haplotypes of polymorphisms FGB -455G>A and FGB -148C>T present association with primary and secondary pregnant losses. We included 256 women with a RPL history, from the Ambulatory of Obstetrics from Clinical Hospital of the Medical School of USP and 264 healthy women without losses history that have had at least two normal pregnancies (control group), matched according to age. Blood samples were obtained to perform the genotyping of polymorphisms by real-time PCR (FGB -148C>T, FGB -455G>A, THBD 1418C>T and CBP2 c.505G>A), and PCR-RFLP (SERPINE1 4G/5G, F5 1691G>A and F2 20210G>A). The frequencies of genotypes and alleles for the seven genetic polymorphisms were similar in 3 groups. However, when it was performed a model of multivariate logistic regression, which included the independent variables: F5 1691G>A (GG vs GA reference), F2 20210G>A (GG vs GA reference), CBP2 c.505G>A (GG + GA reference vs AA), THBD 1418C>T (reference CC + CT vs TT), SERPINE1 4G/5G (reference 5G/5G + 4G/5G vs 4G/4G), FGB -455G>A (GG reference vs GA vs AA) and FGB - 148C>T (reference CC vs CT vs TT), only the polymorphism FGB 148C>T polymorphism was associated with a higher risk of having primary losses (OR: 2.91, 95% CI 1.02 to 8.29, p = 0.045). When the haplotypes for the polymorphisms FGB -455G>A and FGB -148C>T were considered, had a higher frequency of the haplotype 455G/148T in women with primary RPL (3.4%) than in the control group (1.1%) (p = 0.030); but this effect was not observed in secondary RPL. Regarding the number of successive pregnant losses, there was a trend (p = 0.060) to higher frequency of the TT genotype for FGB -148C>T polymorphism in the group with primary RPL up to three losses when compared with women of the same group, but with loss number higher than three. In conclusion, when the seven genetic polymorphisms were evaluated separately, they do not show association with RPL, however, in multivariate logistic regression analysis, the TT genotype of the FGB -148C>T polymorphism was associated with increased risk for primary RPL. Furthermore, it was found higher frequency of the haplotype 455G/148T for the FGB -455G>A and FGB -148 C>T polymorphisms in women with primary RPL.