O entendimento dos mecanismos de ação hormonal envolvidos com o crescimento do pêlo são de grande relevância na área médica e podem representar novas perspectivas no tratamento para distúrbios de crescimento de pêlos. A aromatase, enzima que converte androgênios em estrogênios, é uma das enzimas-chave relacionadas com o metabolismo intra-tecidual de hormônios sexuais. O objetivo desse estudo foi determinar a expressão gênica da enzima aromatase em folículos pilosos do vértice do escalpo de mulheres com ciclos regulares e ovulatórios e em pacientes com PCOS, verificando possíveis associações com variáveis hormonais e metabólicas dessas mulheres. Cinqüenta e quatro mulheres no menacme preencheram os critérios de inclusão (23 com PCOS e 31 com ciclos regulares e ovulatórios) e completaram avaliação antropométrica, hormonal e metabólica. Uma sub-amostra de 16 mulheres (11 com ciclos regulares e ovulatórios e 5 com PCOS) foi selecionada para coleta de folículos pilosos através da técnica do arrancamento. A expressão do gene da aromatase foi avaliada por PCR em tempo real, e os resultados foram normalizados em relação ao gene constitutivo b2-microglobulina. A expressão do gene da aromatase foi observada nos folículos pilosos da região do escalpo de mulheres dos dois grupos em estudo. A expressão deste gene foi de intensidade baixa e variável entre as amostras estudadas e não houve diferença estatisticamente significativa da relação dos genes aromatase/b2-microglobulina entre o grupo de mulheres com ciclos regulares [80 (35,31 – 138,25) e o grupo PCOS [52,11 (5,68 – 84,8), P = 0,157]. A expressão do gene da aromatase em folículos pilosos do escalpo de mulheres correlacionou-se negativamente e com significância estatística com os níveis séricos de LH (P = 0,008, r = -0,653) e esta correlação foi independente de testosterona ou SHBG. Esses resultados demonstram, pela primeira vez, que folículos pilosos da região do vértice do escalpo de mulheres expressam o gene da aromatase. A correlação negativa e independente de LH com a expressão gênica da aromatase pode estar refletindo o microambiente hormonal nos folículos pilosos e, em especial, o conjunto das alterações metabólicas e hormonais característico de pacientes com PCOS. É possível que a expressão gênica dessa enzima seja mais evidente na papila dérmica (porção dos folículos pilosos não analisada nesse estudo) e que a regulação do balanço estrogênico no metabolismo local não seja tão pronunciada na porção epitelial dos folículos pilosos que é obtida pela técnica do arrancamento. A análise da expressão protéica da enzima, a seleção de pacientes hirsutas de outras etiologias e de mulheres portadoras de alopecia, e a coleta de outras regiões pilosas hormônio-dependentes estão entre as perspectivas para a confirmação do padrão de expressão gênica da aromatase nos folículos pilosos. / The knowledge of hormonal mechanisms of action that are involved with hair growth is of great relevance on medical research and could represent new approaches on therapeutics for hair growth disturbs. Aromatase, the enzyme that converts androgens into estrogens, is one of the key enzymes related to sexual hormones metabolism and may act on different target tissues, like the hair follicle. The aim of this study was to determine the aromatase gene expression on hair follicles from the vertex portion of the scalp of women with regular and ovulatory cycles, and patients with PCOS. We were also interested on the possible association among the gene expression and hormonal/metabolic parameters of these women. Fifty-four women at reproductive age were included (23 with PCOS and 31 with regular and ovulatory cycles), and were submitted to anthropometric, hormonal, and metabolic evaluation. A minor group of 16 women (11 with regular and ovulatory cycles and 5 with PCOS) were selected for hair follicle’s molecular analysis, using the plucking technique. Aromatase gene expression was analyzed by using real time PCR, and the results were normalized with the housekeeping gene b2-microglobuline. Aromatase gene expression was observed at the scalp’s hair follicles from the two groups of women. The intensity of the gene expression was low and variable among the samples. There was not a statistically significant difference between the women with regular cycles [80 (35,31 – 138,25) and patients with PCOS [52,11 (5,68 – 84,8), P = 0,157]. Aromatase gene expression in the plucked hairs from the vertex portion of the scalp of women was negatively correlated with circulating LH levels (P = 0,008, r = -0,653), and was also independent of testosterone or SHBG levels. The present results show, for the first time, that plucked hairs from the vertex portion of the scalp of women express the gene of aromatase. The negative and independent correlation between LH and aromatase gene expression may reflect the hormonal microenvironment of the hair follicle, and also the hormonal and metabolic alterations characteristics of women with PCOS. Aromatase gene expression may be more evident at the dermal papilla (not analyzed in this study), and the local metabolism could not be so pronounced on the epithelial portion of hair follicles, when obtained by the plucking method. Aromatase protein expression, plucked hair from other hormone-dependent areas and from women with other clinical conditions like androgenetic alopecia, are some of the perspectives for the confirmation of the pattern of aromatase gene expression on hair follicles.

O entendimento dos mecanismos de ação hormonal envolvidos com o crescimento do pêlo são de grande relevância na área médica e podem representar novas perspectivas no tratamento para distúrbios de crescimento de pêlos. A aromatase, enzima que converte androgênios em estrogênios, é uma das enzimas-chave relacionadas com o metabolismo intra-tecidual de hormônios sexuais. O objetivo desse estudo foi determinar a expressão gênica da enzima aromatase em folículos pilosos do vértice do escalpo de mulheres com ciclos regulares e ovulatórios e em pacientes com PCOS, verificando possíveis associações com variáveis hormonais e metabólicas dessas mulheres. Cinqüenta e quatro mulheres no menacme preencheram os critérios de inclusão (23 com PCOS e 31 com ciclos regulares e ovulatórios) e completaram avaliação antropométrica, hormonal e metabólica. Uma sub-amostra de 16 mulheres (11 com ciclos regulares e ovulatórios e 5 com PCOS) foi selecionada para coleta de folículos pilosos através da técnica do arrancamento. A expressão do gene da aromatase foi avaliada por PCR em tempo real, e os resultados foram normalizados em relação ao gene constitutivo b2-microglobulina. A expressão do gene da aromatase foi observada nos folículos pilosos da região do escalpo de mulheres dos dois grupos em estudo. A expressão deste gene foi de intensidade baixa e variável entre as amostras estudadas e não houve diferença estatisticamente significativa da relação dos genes aromatase/b2-microglobulina entre o grupo de mulheres com ciclos regulares [80 (35,31 – 138,25) e o grupo PCOS [52,11 (5,68 – 84,8), P = 0,157]. A expressão do gene da aromatase em folículos pilosos do escalpo de mulheres correlacionou-se negativamente e com significância estatística com os níveis séricos de LH (P = 0,008, r = -0,653) e esta correlação foi independente de testosterona ou SHBG. Esses resultados demonstram, pela primeira vez, que folículos pilosos da região do vértice do escalpo de mulheres expressam o gene da aromatase. A correlação negativa e independente de LH com a expressão gênica da aromatase pode estar refletindo o microambiente hormonal nos folículos pilosos e, em especial, o conjunto das alterações metabólicas e hormonais característico de pacientes com PCOS. É possível que a expressão gênica dessa enzima seja mais evidente na papila dérmica (porção dos folículos pilosos não analisada nesse estudo) e que a regulação do balanço estrogênico no metabolismo local não seja tão pronunciada na porção epitelial dos folículos pilosos que é obtida pela técnica do arrancamento. A análise da expressão protéica da enzima, a seleção de pacientes hirsutas de outras etiologias e de mulheres portadoras de alopecia, e a coleta de outras regiões pilosas hormônio-dependentes estão entre as perspectivas para a confirmação do padrão de expressão gênica da aromatase nos folículos pilosos. / The knowledge of hormonal mechanisms of action that are involved with hair growth is of great relevance on medical research and could represent new approaches on therapeutics for hair growth disturbs. Aromatase, the enzyme that converts androgens into estrogens, is one of the key enzymes related to sexual hormones metabolism and may act on different target tissues, like the hair follicle. The aim of this study was to determine the aromatase gene expression on hair follicles from the vertex portion of the scalp of women with regular and ovulatory cycles, and patients with PCOS. We were also interested on the possible association among the gene expression and hormonal/metabolic parameters of these women. Fifty-four women at reproductive age were included (23 with PCOS and 31 with regular and ovulatory cycles), and were submitted to anthropometric, hormonal, and metabolic evaluation. A minor group of 16 women (11 with regular and ovulatory cycles and 5 with PCOS) were selected for hair follicle’s molecular analysis, using the plucking technique. Aromatase gene expression was analyzed by using real time PCR, and the results were normalized with the housekeeping gene b2-microglobuline. Aromatase gene expression was observed at the scalp’s hair follicles from the two groups of women. The intensity of the gene expression was low and variable among the samples. There was not a statistically significant difference between the women with regular cycles [80 (35,31 – 138,25) and patients with PCOS [52,11 (5,68 – 84,8), P = 0,157]. Aromatase gene expression in the plucked hairs from the vertex portion of the scalp of women was negatively correlated with circulating LH levels (P = 0,008, r = -0,653), and was also independent of testosterone or SHBG levels. The present results show, for the first time, that plucked hairs from the vertex portion of the scalp of women express the gene of aromatase. The negative and independent correlation between LH and aromatase gene expression may reflect the hormonal microenvironment of the hair follicle, and also the hormonal and metabolic alterations characteristics of women with PCOS. Aromatase gene expression may be more evident at the dermal papilla (not analyzed in this study), and the local metabolism could not be so pronounced on the epithelial portion of hair follicles, when obtained by the plucking method. Aromatase protein expression, plucked hair from other hormone-dependent areas and from women with other clinical conditions like androgenetic alopecia, are some of the perspectives for the confirmation of the pattern of aromatase gene expression on hair follicles.

O entendimento dos mecanismos de ação hormonal envolvidos com o crescimento do pêlo são de grande relevância na área médica e podem representar novas perspectivas no tratamento para distúrbios de crescimento de pêlos. A aromatase, enzima que converte androgênios em estrogênios, é uma das enzimas-chave relacionadas com o metabolismo intra-tecidual de hormônios sexuais. O objetivo desse estudo foi determinar a expressão gênica da enzima aromatase em folículos pilosos do vértice do escalpo de mulheres com ciclos regulares e ovulatórios e em pacientes com PCOS, verificando possíveis associações com variáveis hormonais e metabólicas dessas mulheres. Cinqüenta e quatro mulheres no menacme preencheram os critérios de inclusão (23 com PCOS e 31 com ciclos regulares e ovulatórios) e completaram avaliação antropométrica, hormonal e metabólica. Uma sub-amostra de 16 mulheres (11 com ciclos regulares e ovulatórios e 5 com PCOS) foi selecionada para coleta de folículos pilosos através da técnica do arrancamento. A expressão do gene da aromatase foi avaliada por PCR em tempo real, e os resultados foram normalizados em relação ao gene constitutivo b2-microglobulina. A expressão do gene da aromatase foi observada nos folículos pilosos da região do escalpo de mulheres dos dois grupos em estudo. A expressão deste gene foi de intensidade baixa e variável entre as amostras estudadas e não houve diferença estatisticamente significativa da relação dos genes aromatase/b2-microglobulina entre o grupo de mulheres com ciclos regulares [80 (35,31 – 138,25) e o grupo PCOS [52,11 (5,68 – 84,8), P = 0,157]. A expressão do gene da aromatase em folículos pilosos do escalpo de mulheres correlacionou-se negativamente e com significância estatística com os níveis séricos de LH (P = 0,008, r = -0,653) e esta correlação foi independente de testosterona ou SHBG. Esses resultados demonstram, pela primeira vez, que folículos pilosos da região do vértice do escalpo de mulheres expressam o gene da aromatase. A correlação negativa e independente de LH com a expressão gênica da aromatase pode estar refletindo o microambiente hormonal nos folículos pilosos e, em especial, o conjunto das alterações metabólicas e hormonais característico de pacientes com PCOS. É possível que a expressão gênica dessa enzima seja mais evidente na papila dérmica (porção dos folículos pilosos não analisada nesse estudo) e que a regulação do balanço estrogênico no metabolismo local não seja tão pronunciada na porção epitelial dos folículos pilosos que é obtida pela técnica do arrancamento. A análise da expressão protéica da enzima, a seleção de pacientes hirsutas de outras etiologias e de mulheres portadoras de alopecia, e a coleta de outras regiões pilosas hormônio-dependentes estão entre as perspectivas para a confirmação do padrão de expressão gênica da aromatase nos folículos pilosos. / The knowledge of hormonal mechanisms of action that are involved with hair growth is of great relevance on medical research and could represent new approaches on therapeutics for hair growth disturbs. Aromatase, the enzyme that converts androgens into estrogens, is one of the key enzymes related to sexual hormones metabolism and may act on different target tissues, like the hair follicle. The aim of this study was to determine the aromatase gene expression on hair follicles from the vertex portion of the scalp of women with regular and ovulatory cycles, and patients with PCOS. We were also interested on the possible association among the gene expression and hormonal/metabolic parameters of these women. Fifty-four women at reproductive age were included (23 with PCOS and 31 with regular and ovulatory cycles), and were submitted to anthropometric, hormonal, and metabolic evaluation. A minor group of 16 women (11 with regular and ovulatory cycles and 5 with PCOS) were selected for hair follicle’s molecular analysis, using the plucking technique. Aromatase gene expression was analyzed by using real time PCR, and the results were normalized with the housekeeping gene b2-microglobuline. Aromatase gene expression was observed at the scalp’s hair follicles from the two groups of women. The intensity of the gene expression was low and variable among the samples. There was not a statistically significant difference between the women with regular cycles [80 (35,31 – 138,25) and patients with PCOS [52,11 (5,68 – 84,8), P = 0,157]. Aromatase gene expression in the plucked hairs from the vertex portion of the scalp of women was negatively correlated with circulating LH levels (P = 0,008, r = -0,653), and was also independent of testosterone or SHBG levels. The present results show, for the first time, that plucked hairs from the vertex portion of the scalp of women express the gene of aromatase. The negative and independent correlation between LH and aromatase gene expression may reflect the hormonal microenvironment of the hair follicle, and also the hormonal and metabolic alterations characteristics of women with PCOS. Aromatase gene expression may be more evident at the dermal papilla (not analyzed in this study), and the local metabolism could not be so pronounced on the epithelial portion of hair follicles, when obtained by the plucking method. Aromatase protein expression, plucked hair from other hormone-dependent areas and from women with other clinical conditions like androgenetic alopecia, are some of the perspectives for the confirmation of the pattern of aromatase gene expression on hair follicles.

Jiang, Jieying. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 170-186). / Abstract also in Chinese. / ACKNOWLEDGEMENT --- p.II / ABBREVIATIONS --- p.III / ABSTRACT OF THESIS ENTITLED: --- p.VI / 摘要 --- p.IX / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Individual variations of blood sex steroid levels and their determinants --- p.1 / Chapter 1.1.1 --- Introduction to Sex steroids --- p.1 / Chapter 1.1.2 --- Androgens --- p.1 / Chapter 1.1.2.1 --- Types of androgens --- p.1 / Chapter 1.1.2.2 --- Androgens plasma concentration and relative biological potencies --- p.2 / Chapter 1.1.2.3 --- Androgen biosynthesis and metabolism --- p.3 / Chapter 1.1.2.4 --- Testosterone transportation in plasma --- p.6 / Chapter 1.1.2.5 --- Measurement of free testosterone --- p.7 / Chapter 1.1.2.6 --- The hypothalamus-pituitary-testicular axis and testosterone secretion --- p.8 / Chapter 1.1.2.7 --- Androgen action --- p.10 / Chapter 1.1.2.8 --- Androgen biological function and diseases in men --- p.11 / Chapter 1.1.3 --- Estrogen biological function and diseases in men --- p.12 / Chapter 1.1.4 --- Factors influencing circulating sex steroid levels --- p.13 / Chapter 1.1.4.1 --- Genetic determinants affecting sex steroid levels --- p.15 / Chapter 1.2 --- Genetic variants in sex steroid metabolic pathway and hepatocellular carcinoma (HCC) --- p.18 / Chapter 1.2.1 --- Epidemiology of HCC --- p.18 / Chapter 1.2.2 --- Etiological factors of HCC --- p.22 / Chapter 1.2.3 --- The male predominance in HCC --- p.24 / Chapter 1.2.4 --- Genetic predisposition to HCC --- p.26 / Chapter CHAPTER 2 --- PART A STUDY: GENETIC VARIATIONS IN SEX STEROID METABOLIC PATHWAY AND ASSOCIATION WITH SEX STEROID LEVELS --- p.28 / Chapter 2.1 --- Introduction --- p.28 / Chapter 2.1.1 --- Candidate genes association with sex steroid levels --- p.28 / Chapter 2.1.2 --- Genes involved in androgen metabolism --- p.29 / Chapter 2.1.2.1 --- SRD5A --- p.29 / Chapter 2.1.2.2 --- HSD3B1 --- p.30 / Chapter 2.1.2.3 --- HSD17B2 --- p.31 / Chapter 2.1.2.4 --- AKR1C3 and AKRlC4 --- p.31 / Chapter 2.1.2.5 --- AKR1D1 --- p.32 / Chapter 2.1.3 --- Genes involved in estrogen metabolism --- p.32 / Chapter 2.1.3.1 --- CYP19A1 --- p.32 / Chapter 2.1.3.2 --- Other genes involved in estrogen metabolism --- p.33 / Chapter 2.1.4 --- Association of sex steroid related genes and blood concentrations of sex steroid levels --- p.33 / Chapter 2.1.4.1 --- Genes involved in androgen metabolic pathway and association with sex steroid levels --- p.33 / Chapter 2.1.4.2 --- Genes involved in estrogen metabolic pathway and association with sex steroid levels --- p.36 / Chapter 2.1.5 --- Aims of the study (Part A) --- p.37 / Chapter 2.2 --- Materials and methods --- p.38 / Chapter 2.2.1 --- Study subjects and biological samples --- p.38 / Chapter 2.2.2 --- TagSNP selection --- p.39 / Chapter 2.2.3 --- Genotyping of tagging SNPs --- p.41 / Chapter 2.2.4 --- Genotyping methods comparison --- p.52 / Chapter 2.2.5 --- Statistics --- p.53 / Chapter 2.3 --- Results --- p.54 / Chapter 2.3.1 --- Characteristics of study population --- p.54 / Chapter 2.3.2 --- Replication study for the association of CYP19A1 --- p.55 / Chapter 2.3.2.1 --- Association of the SNP rs2470152 and rs2899470 with serum estrogen and testosterone levels --- p.55 / Chapter 2.3.2.2 --- Halotype analysis and haplotype association in the tertile groups --- p.61 / Chapter 2.3.2.3 --- Haplotype construction of 3 SNPs --- p.63 / Chapter 2.3.3 --- SRD5A1 --- p.65 / Chapter 2.3.3.1 --- Association of SRD5A1 and sex steroid levels --- p.65 / Chapter 2.3.3.2 --- Haplotype analysis and haplotype association in the tertile groups --- p.71 / Chapter 2.3.4 --- SRD5A2 --- p.72 / Chapter 2.3.4.1 --- Association of SRD5A2 and sex steroid levels --- p.72 / Chapter 2.3.4.2 --- Haplotype association analysis of SRD5A2 in tertile groups --- p.76 / Chapter 2.3.5 --- HSD3B1 --- p.77 / Chapter 2.3.5.1 --- Association of HSD3B1 and sex steroid levels --- p.77 / Chapter 2.3.6 --- HSD17B2 --- p.80 / Chapter 2.3.6.1 --- Association of HSD17B2 and sex steroid levels --- p.80 / Chapter 2.3.6.2 --- Halotype association analysis of HSD17B2 in the tertile groups --- p.87 / Chapter 2.3.7 --- AKR1C4 --- p.89 / Chapter 2.3.7.1 --- Association of AKR1C4 and sex steroid levels --- p.89 / Chapter 2.3.7.2 --- Halotype association analysis of AKR1C4 in the tertile groups --- p.93 / Chapter 2.3.8 --- AKR1D1 --- p.94 / Chapter 2.3.8.1 --- Association of AKR1D1 and sex steroid levels --- p.94 / Chapter 2.3.8.2 --- Haplotype association analysis of AKR1D1 in the tertile groups --- p.99 / Chapter 2.3.9 --- AKR1C3 --- p.100 / Chapter 2.3.9.1 --- Association of AKR1C3 and sex steroid levels --- p.100 / Chapter 2.3.9.2 --- Haplotype association analysis of AKR1C3 in the tertile groups --- p.104 / Chapter 2.3.10 --- Overall association of polymorphisms in sex steroid metabolism genes and metabolites levels in blood --- p.105 / Chapter 2.4 --- Discussion --- p.106 / Chapter 2.4.1 --- SRD5A and sex steroid levels --- p.106 / Chapter 2.4.2 --- HSD17B2 and sex steroid levels --- p.110 / Chapter 2.4.3 --- "AKR1D1, AKR1C4, AKR1C3 and catabolic intermediates of sex steroids" --- p.112 / Chapter 2.4.4 --- HSD3B1 and sex steroid levels --- p.114 / Chapter 2.4.4 --- CYP19A1 and sex steroid levels --- p.114 / Chapter CHAPTER 3 --- PART B STUDY: GENETIC VARIATIONS IN SEX STEROID METABOLIC PATHWAY AND ASSOCIATION WITH HCC --- p.119 / Chapter 3.1 --- Introduction --- p.119 / Chapter 3.1.1 --- Previous genetic association studies of HCC on sex steroid metabolic pathways --- p.119 / Chapter 3.1.2 --- Previous genetic association studies of HCC in other pathways --- p.120 / Chapter 3.1.3 --- "Association of sex steroid related genes and other cancers, like prostate cancer" --- p.121 / Chapter 3.1.4 --- Aims of the study (Part B) --- p.123 / Chapter 3.2 --- Materials and method --- p.125 / Chapter 3.2.1 --- "Study subjects, Genomic DNA extraction" --- p.125 / Chapter 3.2.2 --- Tissue specimen and cell lines --- p.125 / Chapter 3.2.3 --- TagSNP selection --- p.126 / Chapter 3.2.4 --- Genotyping of tagging SNPs --- p.126 / Chapter 3.2.5 --- Statistics --- p.127 / Chapter 3.2.6 --- Extraction of RNA and Reverse-Transcription-PCR --- p.128 / Chapter 3.3 --- Results --- p.130 / Chapter 3.3.1 --- SRD5A1 --- p.130 / Chapter 3.3.1.1 --- SRD5A1 polymorphisms and risk of HCC --- p.130 / Chapter 3.3.2 --- SRD5A2 --- p.134 / Chapter 3.3.2.1 --- SRD5A2 polymorphisms and risk of HCC --- p.134 / Chapter 3.3.2.2 --- Haplotype analysis --- p.136 / Chapter 3.3.3 --- HSD3B1 --- p.137 / Chapter 3.3.3.1 --- HSD3B1 polymorphisms and risk of HCC --- p.137 / Chapter 3.3.3.2 --- Haplotype analysis --- p.139 / Chapter 3.3.4 --- HSD17B2 --- p.140 / Chapter 3.3.4.1 --- HSD17B2 polymorphisms and risk of HCC --- p.140 / Chapter 3.3.4.2 --- Haplotype analysis --- p.143 / Chapter 3.3.5 --- CYP19A1 --- p.144 / Chapter 3.3.5.1 --- CYP19A1 polymorphisms and risk of HCC --- p.144 / Chapter 3.3.5.2 --- Haplotype analysis --- p.146 / Chapter 3.3.6 --- AKR1C4 --- p.147 / Chapter 3.3.6.1 --- AKR1C4 polymorphisms and risk of HCC --- p.147 / Chapter 3.3.6.2 --- Haplotype analysis --- p.148 / Chapter 3.3.7 --- AKR1D1 --- p.149 / Chapter 3.3.7.1 --- AKR1D1 polymorphisms and risk of HCC --- p.149 / Chapter 3.3.7.2 --- Haplotype analysis --- p.150 / Chapter 3.3.8 --- AKR1C3 --- p.151 / Chapter 3.3.8.1 --- AKR1C3 polymorphisms and risk of HCC --- p.151 / Chapter 3.3.8.2 --- Haplotype analysis --- p.152 / Chapter 3.3.9 --- mRNA expression study of the 5 α -reductase isoforms --- p.153 / Chapter 3.3.9.1 --- Expression of SRD5A1 and SRD5A2 mRNAin HCC patients --- p.153 / Chapter 3.3.9.2 --- Expression of SRD5A1 and SRD5A2 mRNAin prostate and HCC cell lines --- p.154 / Chapter 3.3.10 --- Overall association of polymorphisms in sex steroid metabolism genes and risk of HCC --- p.154 / Chapter 3.3.11 --- GMDR analysis --- p.156 / Chapter 3.4 --- Discussion --- p.159 / Chapter 3.4.1 --- 5 α-reductase and risk of HCC --- p.159 / Chapter 3.4.1.1 --- SRD5A2 --- p.160 / Chapter 3.4.1.2 --- SRD5A1 --- p.161 / Chapter 3.4.2 --- Other genes and association with HCC --- p.162 / Chapter 3.4.2.1 --- HSD17B2 and risk of HCC --- p.162 / Chapter 3.4.2.2 --- "HSD3B1, AKR1C3, AKR1C4, AKR1D1 and risk of HCC" --- p.163 / Chapter 3.4.2.3 --- CYP19A1 and risk of HCC --- p.164 / Chapter 3.4.3 --- Gene-Gene interactions associated with HCC --- p.165 / Chapter CHAPTER 4 --- CONCLUSIONS AND PROSPECT FOR FUTURE WORK --- p.166 / Chapter 4.1 --- Conclusion --- p.166 / Chapter 4.2 --- Future works and prospect --- p.169 / REFERENCES --- p.170

INTRODUÇÃO: O Infarto agudo do miocárdio (IAM) é infrequente em indivíduos jovens (<45 anos) e está associado à história familiar precoce de doença cardiovascular.OBJETIVO: O presente estudo descreveu o perfil sócio-demográfico e os fatores de risco cardiovascular de indivíduos com diagnóstico de IAM < 45 anos de idade e seus familiares de primeiro grau. Avaliou-se também a relação de parâmetros clínico-laboratoriais de acordo com a extensão angiográfica da doença arterial coronária (DAC) dos casos índices (doença uniarterial vs. multiarterial) e dos seus respectivos familiares.MÉTODOS: Estudo transversal realizado de novembro de 2010 a janeiro de 2015 em hospital terciário em Fortaleza, Ceará. Foram incluídos 103 casos índices e 166 familiares de primeiro grau que não apresentavam suspeita de hipercolesterolemia familiar. Estes foram comparados com 111 indivíduos assintomáticos e sem história familiar de DAC pareados para sexo e idade. Foram avaliados os parâmetros clínicos e laboratoriais dos 3 grupos. Os dados foram estudados por análises uni e multivariadas. RESULTADOS:O grupo casos apresentou maior prevalência de tabagismo (57,3 vs. 28,6%, p < 0,001), diabete melito tipo 2 - DM2 (43,4 vs. 19,5%, p < 0,001) e hipertensão arterial sistêmica - HAS (42,7 vs. 19%, p < 0,001) quando comparado aos familiares pareados para sexo e idade. Da mesma forma, os casos, quando comparados ao grupo controle, apresentaram, além destes fatores, concentrações mais elevadas de triglicerídeos (192 ± 75 vs. 140±74mg/dL, p < 0,001), menores concentrações de HDL-c (36 ± 12 vs. 48 ± 14mg/dL, p < 0,001) e uma maior prevalência de síndrome metabólica -SM (82,2 vs. 36%, p<0,001). Observou-se que 50,5% dos casos tinham acometimento multiarterial. Após análise multivariada, a HAS (p=0,030) e o DM2 (p=0,028) associaram-se de forma independente à DAC multiarterial. Quando comparados ao grupo controle, os familiares apresentaram maior prevalência de tabagismo (29,5 vs. 6,3%, p < 0,001), DM2 (19,9 vs. 1,8%, p < 0,001), pré-diabetes (40,4 vs. 27%, p < 0,024) e SM (64,7 vs. 36% p < 0,001). Foram observadas aindaconcentrações mais baixas de HDL-c (39±10 vs. 48 ± 14mg/dL, p < 0,001), valores mais elevados de triglicerídeos (179 ± 71 vs. 140 ± 74mg/dL, p = 0,002), LDL-c (122±37 vs. 113±36mg/dL, p = 0,031) e colesterol não-HDL (157 ± 43 vs. 141 ± 41mg/dL, p = 0,004) nos familiares. Não houve diferenças entre familiares e controles quanto ao IMC (p=0,051). Os familiares também apresentaram maior prevalência do risco calculado como alto/intermediário de acordo com o escore de Framingham (82,7 vs. 2,6%, p < 0,001) em relação aos controles. Os valores de TSH foram maiores, mesmo dentro do valor de referência do método, no grupo de casos (2,6 ± 1,6 vs. 1,9 ± 1,0 mUI/L, p < 0,001) e familiare (2,4±1,6 vs. 1,9 ± 1,0 mUI/L, p=0,002) em relação aos controles. CONCLUSÃO: Evidenciou-seelevada prevalência de fatores de risco cardiovascular, principalmente a SM, dislipidemia aterogênica, DM2, HAS e tabagismo em casos e familiares de primeiro grau de indivíduos com IAM < 45 anos. A HAS e o DM2 associaram-se à maior extensão angiográfica da DAC / BACKGROUND: The acute myocardial infarction (AMI) is uncommon in young individuals ( < 45 years), and is associated with premature family history of cardiovascular disease. OBJECTIVE: This study described the socio-demographic and cardiovascular risk factors of both subjects with AMI < 45 years of age and their first-degree relatives. The association of clinical and laboratory parameters with the angiographic extension of coronary artery disease (CAD) of index cases (single-vessel vs. multivessel disease) and in their respective relatives was also evaluated. METHODS: Cross-sectional study conducted from November 2010 to January 2015 in a tertiary hospital in Fortaleza, Ceara. One hundred and three index cases and 166 first-degree relatives without suspicion of familial hypercholesterolemia were included. These were compared with 111 asymptomatic individuals without family history of CAD matched for sex and age. Clinical and laboratory parameters of the 3 groups were evaluated. Associations were tested by univariate and multivariate analysis. RESULTS: AMI cases presented a higher prevalence of smoking (57.3% vs. 28.6%, p < 0.001), type 2 diabetes mellitus -DM2 (43.4 vs. 19.5%, p < 0.001), and hypertension (42.7 vs. 19%, p < 0.001) when compared to relatives matched for sex and age. Likewise cases, when compared to controls showed in addition higher triglycerides (192 ± 75mg/dL vs. 140 ± 74mg/dL, p < 0.001), lower HDL-C (36 ± 12mg/dL vs. 48±14mg/dL, p < 0.001), and a greater prevalence of the metabolic syndrome-MS (82.2% vs. 36%, p < 0.001). Multivessel disease was found in 50.5% of cases. After multivariate analysis, hypertension (p=0.030), and DM2 (p=0.028) were independently associated with multivessel disease. First-degree relatives showed a greater prevalence of smoking (29.5% vs. 6.3%, p < 0.001), DM2 (19.9% vs. 1.8%, p < 0.001), pre-diabetes (40.4 % vs. 27%, p < 0.024) and MS (64.7% vs. 36%, p < 0.001), when compared to controls. Lower HDL-c (39±10mg/dL vs. 48 ± 14mg/dL, p < 0.001), higher triglycerides (179±71mg/dL vs. 140±74mg/dL, p=0.002), higher LDL-C (122 ± 37mg/dL vs. 113 ± 36mg/dL, p=0.031) and non-HDL cholesterol (157 ± 43 vs. 141±41mg/dL, p=0.004) were found in relatives than controls. There was no difference in BMI (p=0.051) between the groups. Relatives also showed a higher prevalence of high/intermediate calculated coronary heart disease risk according to the Framingham risk score (82.7% vs. 2.6%, p < 0.001). TSH levels even within the reference value method were higher in AMI patients (2.6 ± 1.6mUI/mL, p < 0.001) and relatives (2.4 ± 1.6mUI/mL, p=0.002) in comparison with controls 1.9±1.0mUI/mL). CONCLUSION: A high prevalence of risk factors mainly MS, atherogenic dyslipidemia, type 2 DM, hypertension and smoking were encountered in cases and first-degree relatives of individuals with AMI < 45 years. Hypertension and DM2 were associated with greater angiographic extent of coronary artery disease

INTRODUÇÃO: O Infarto agudo do miocárdio (IAM) é infrequente em indivíduos jovens (<45 anos) e está associado à história familiar precoce de doença cardiovascular.OBJETIVO: O presente estudo descreveu o perfil sócio-demográfico e os fatores de risco cardiovascular de indivíduos com diagnóstico de IAM < 45 anos de idade e seus familiares de primeiro grau. Avaliou-se também a relação de parâmetros clínico-laboratoriais de acordo com a extensão angiográfica da doença arterial coronária (DAC) dos casos índices (doença uniarterial vs. multiarterial) e dos seus respectivos familiares.MÉTODOS: Estudo transversal realizado de novembro de 2010 a janeiro de 2015 em hospital terciário em Fortaleza, Ceará. Foram incluídos 103 casos índices e 166 familiares de primeiro grau que não apresentavam suspeita de hipercolesterolemia familiar. Estes foram comparados com 111 indivíduos assintomáticos e sem história familiar de DAC pareados para sexo e idade. Foram avaliados os parâmetros clínicos e laboratoriais dos 3 grupos. Os dados foram estudados por análises uni e multivariadas. RESULTADOS:O grupo casos apresentou maior prevalência de tabagismo (57,3 vs. 28,6%, p < 0,001), diabete melito tipo 2 - DM2 (43,4 vs. 19,5%, p < 0,001) e hipertensão arterial sistêmica - HAS (42,7 vs. 19%, p < 0,001) quando comparado aos familiares pareados para sexo e idade. Da mesma forma, os casos, quando comparados ao grupo controle, apresentaram, além destes fatores, concentrações mais elevadas de triglicerídeos (192 ± 75 vs. 140±74mg/dL, p < 0,001), menores concentrações de HDL-c (36 ± 12 vs. 48 ± 14mg/dL, p < 0,001) e uma maior prevalência de síndrome metabólica -SM (82,2 vs. 36%, p<0,001). Observou-se que 50,5% dos casos tinham acometimento multiarterial. Após análise multivariada, a HAS (p=0,030) e o DM2 (p=0,028) associaram-se de forma independente à DAC multiarterial. Quando comparados ao grupo controle, os familiares apresentaram maior prevalência de tabagismo (29,5 vs. 6,3%, p < 0,001), DM2 (19,9 vs. 1,8%, p < 0,001), pré-diabetes (40,4 vs. 27%, p < 0,024) e SM (64,7 vs. 36% p < 0,001). Foram observadas aindaconcentrações mais baixas de HDL-c (39±10 vs. 48 ± 14mg/dL, p < 0,001), valores mais elevados de triglicerídeos (179 ± 71 vs. 140 ± 74mg/dL, p = 0,002), LDL-c (122±37 vs. 113±36mg/dL, p = 0,031) e colesterol não-HDL (157 ± 43 vs. 141 ± 41mg/dL, p = 0,004) nos familiares. Não houve diferenças entre familiares e controles quanto ao IMC (p=0,051). Os familiares também apresentaram maior prevalência do risco calculado como alto/intermediário de acordo com o escore de Framingham (82,7 vs. 2,6%, p < 0,001) em relação aos controles. Os valores de TSH foram maiores, mesmo dentro do valor de referência do método, no grupo de casos (2,6 ± 1,6 vs. 1,9 ± 1,0 mUI/L, p < 0,001) e familiare (2,4±1,6 vs. 1,9 ± 1,0 mUI/L, p=0,002) em relação aos controles. CONCLUSÃO: Evidenciou-seelevada prevalência de fatores de risco cardiovascular, principalmente a SM, dislipidemia aterogênica, DM2, HAS e tabagismo em casos e familiares de primeiro grau de indivíduos com IAM < 45 anos. A HAS e o DM2 associaram-se à maior extensão angiográfica da DAC / BACKGROUND: The acute myocardial infarction (AMI) is uncommon in young individuals ( < 45 years), and is associated with premature family history of cardiovascular disease. OBJECTIVE: This study described the socio-demographic and cardiovascular risk factors of both subjects with AMI < 45 years of age and their first-degree relatives. The association of clinical and laboratory parameters with the angiographic extension of coronary artery disease (CAD) of index cases (single-vessel vs. multivessel disease) and in their respective relatives was also evaluated. METHODS: Cross-sectional study conducted from November 2010 to January 2015 in a tertiary hospital in Fortaleza, Ceara. One hundred and three index cases and 166 first-degree relatives without suspicion of familial hypercholesterolemia were included. These were compared with 111 asymptomatic individuals without family history of CAD matched for sex and age. Clinical and laboratory parameters of the 3 groups were evaluated. Associations were tested by univariate and multivariate analysis. RESULTS: AMI cases presented a higher prevalence of smoking (57.3% vs. 28.6%, p < 0.001), type 2 diabetes mellitus -DM2 (43.4 vs. 19.5%, p < 0.001), and hypertension (42.7 vs. 19%, p < 0.001) when compared to relatives matched for sex and age. Likewise cases, when compared to controls showed in addition higher triglycerides (192 ± 75mg/dL vs. 140 ± 74mg/dL, p < 0.001), lower HDL-C (36 ± 12mg/dL vs. 48±14mg/dL, p < 0.001), and a greater prevalence of the metabolic syndrome-MS (82.2% vs. 36%, p < 0.001). Multivessel disease was found in 50.5% of cases. After multivariate analysis, hypertension (p=0.030), and DM2 (p=0.028) were independently associated with multivessel disease. First-degree relatives showed a greater prevalence of smoking (29.5% vs. 6.3%, p < 0.001), DM2 (19.9% vs. 1.8%, p < 0.001), pre-diabetes (40.4 % vs. 27%, p < 0.024) and MS (64.7% vs. 36%, p < 0.001), when compared to controls. Lower HDL-c (39±10mg/dL vs. 48 ± 14mg/dL, p < 0.001), higher triglycerides (179±71mg/dL vs. 140±74mg/dL, p=0.002), higher LDL-C (122 ± 37mg/dL vs. 113 ± 36mg/dL, p=0.031) and non-HDL cholesterol (157 ± 43 vs. 141±41mg/dL, p=0.004) were found in relatives than controls. There was no difference in BMI (p=0.051) between the groups. Relatives also showed a higher prevalence of high/intermediate calculated coronary heart disease risk according to the Framingham risk score (82.7% vs. 2.6%, p < 0.001). TSH levels even within the reference value method were higher in AMI patients (2.6 ± 1.6mUI/mL, p < 0.001) and relatives (2.4 ± 1.6mUI/mL, p=0.002) in comparison with controls 1.9±1.0mUI/mL). CONCLUSION: A high prevalence of risk factors mainly MS, atherogenic dyslipidemia, type 2 DM, hypertension and smoking were encountered in cases and first-degree relatives of individuals with AMI < 45 years. Hypertension and DM2 were associated with greater angiographic extent of coronary artery disease