Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 106-134.

Thesis (Dr. P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / "May 2007." Includes bibliographical references (leaves 111-120).

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 121-126).

Thesis (Ph.D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed on June 24, 2009). Includes bibliographical references (p. 108-133).

Orientador: Carmen Regina [UINESP] Marcati / Resumo: Estudos intraespecíficos com procedências replicadas em diferentes locais permitem distinguir o efeito do genótipo e do ambiente no crescimento e na estrutura anatômica das plantas. Diante das previsões de intensificação dos períodos seca e o aumento da temperatura em todo o mundo, entender como a predisposição genética e o ambiente influenciam o crescimento das plantas e as características do xilema secundário é importante para estabelecer futuros padrões na distribuição de espécies arbóreas. Assim, neste trabalho, avaliamos o efeito da procedência e das condições ambientais na variabilidade intraespecífica do crescimento das árvores e da estrutura anatômica do xilema secundário de Balfourodendron riedelianum (Engl.) Engl. (Rutaceae). Comparamos o crescimento (estimado por meio da altura e do diâmetro do caule), a densidade da madeira, a condutividade hidráulica potencial e as características anatômicas do xilema secundário de árvores adultas de três procedências de B. riedelianum crescidas em dois plantios homogêneos como testes de procedências. Selecionamos 72 árvores de 30 anos de idade de B. riedelianum crescidas em um plantio homogêneo localizado na Estação Experimental de Luís Antônio e outro na Estação Experimental de Pederneiras, ambos no estado de São Paulo. O solo do plantio de Luís Antônio é argiloso e neste local há maior precipitação anual do que no plantio de Pederneiras, onde o solo é arenoso. As procedências vêm de sementes coletadas em populações naturais lo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Intraspecific studies with provenances replicated at different sites allow to distinguish the effect of genotype and environment on the growth and anatomical structure of plants. Considering predictions of drought intensification and increased temperature in wordwilde, understanding how genetic predisposition and environment influence plant growth and secondary xylem features is important to establishing future patterns in the distribution of tree species. Thus, in this work, we evaluated the effect of the provenance and environmental conditions on the intraspecific variability of tree growth and the anatomical structure of the secondary xylem of Balfourodendron riedelianum (Engl.) Engl. (Rutaceae). We compared growth (estimated from stem height and diameter), wood density, potential hydraulic conductivity, and anatomical features of the secondary xylem of adult trees of three provenances of B. riedelianum from two homogeneous plantations as provenances tests. We selected 72 trees of 30 years old of B. riedelianum grown in a homogeneous plantation located in the Experimental Station of Luís Antônio and another in the Experimental Station of Pederneiras, in the state of São Paulo. The plantations of Luís Antônio have clay soil and highest annual precipitation than the plantations of Pederneiras, where the soil is sandy. The provenances came from seeds collected in natural populations located in the city of Alvorada do Sul, state of Paraná, and from Bauru and Gália, state of Sã... (Complete abstract click electronic access below) / Doutor

Abstract Approximately 5–10% of all breast cancer cases are estimated to result from a hereditary predisposition to the disease. Currently no more than 25–30% of these familial cases can be explained by mutations in the known susceptibility genes, BRCA1 and BRCA2 being the major ones. Additional predisposing genes are therefore likely to be discovered. This study evaluates whether germline alterations in three BRCA1-associated genes, BACH1 (i.e. BRIP1/FANCJ), BARD1 and TOPBP1, contribute to familial breast cancer. Altogether 214 Finnish patients having breast and/or ovarian cancer were analysed for germline mutations in the BACH1 gene. Nine alterations were observed, four of which located in the protein-encoding region. The previously unidentified Pro1034Leu was considered a possible cancer-associated alteration as it appeared with two-fold higher frequency among cancer cases compared to controls. All the other observed alterations were classified as harmless polymorphisms. Mutation analysis of the BARD1 gene among 126 Finnish patients having family history of breast and/or ovarian cancer revealed seven alterations in the protein-encoding region. The Cys557Ser alteration was seen at an elevated frequency among familial cancer cases compared to controls (p = 0.005, odds ratio [OR] 4.2, 95% confidence interval [CI] 1.7–10.7). The other alterations appeared to be harmless polymorphisms. To evaluate further the possible effect of Cys557Ser on cancer risk, a large case-control study was performed, consisting of 3,956 cancer patients from the Nordic countries. The highest prevalence of Cys557Ser was found among breast and ovarian cancer patients from BRCA1/BRCA2 mutation-negative families (p < 0.001, OR 2.6, 95% CI 1.7–4.0). In contrast, no significant association with male breast cancer, ovarian, colorectal or prostate cancer was observed. The current study is the first evaluating the role of TOPBP1 mutations in familial cancer predisposition. The analysis of 125 Finnish patients having breast and/or ovarian cancer revealed one putative pathogenic alteration. The commonly occurring Arg309Cys allele was observed at a significantly higher frequency among familial cancer cases compared to controls (p = 0.002, OR 2.4, 95% CI 1.3–4.2). The other 18 alterations observed were classified as harmless polymorphisms.

Introduction: Type 2 diabetes mellitus (T2DM) is a worldwide spread disease of affluence which prevalence has been growing. Although, the probability of its manifestation is being linked above all with environmental factors, genetic susceptibility plays an important role too. The aim of this thesis was to find out the association of four polymorphisms with the risk of T2DM manifestation in Czech population. Polymorphisms rs10203174 THADA, rs6819243 MAEA, rs849135 JAZF1 and rs1552224 ARAP1 (CENTD2) were chosen based on their risk in British population. Methodology: We studied groups of 712 Czech patients with T2DM and 752 healthy controls selected as a random sample of Czech population in the post-MONICA study. For a genotypisation rs10203174 and rs6819243 we used the PCR-RFLP method. For an analysis of genotypes rs849135 and rs1552224 was used the real-time PCR method. The results were analysed via odds ratio (OR) a chi-square test. Results: In case of the rs1552224 variant, the risk was proved with statistical significance (P = 0,01). The value of OR for the risk allele T is 1,37 (95% CI 1,07-1,75). In case of the polymorphisms rs10203174, rs6819243 and rs849135 no significant association with the disease was proved. For rs10203174 the value of OR of the allele C is 1,20 (95% CI 0,91-1,56, P = 0,20), OR of...

Muitos estudos têm sido conduzidos em diferentes populações visando a identificação da proporção da variância fenotípica total atribuída a efeitos genéticos. A herdabilidade de fatores de risco relacionados à Síndrome Metabólica apresenta variações entre populações, tanto por causa da diferente distribuição de fatores de risco ambientais quanto pela variação genética presente em populações distintas. O objetivo desta análise foi avaliar as influências genéticas e ambientais dos componentes da Síndrome Metabólica, usando uma análise de componentes de variância, estimando a herdabilidade destes fatores em uma amostra de extensas famílias. Nós examinamos 1.712 indivíduos de 119 famílias selecionadas randomicamente da população geral de uma cidade do Brasil. Um total de 1.666 indivíduos de 81 famílias foi usado para análises. O tamanho das famílias variou de 3 a 156 indivíduos com uma média de 21 indivíduos por família. Antes de ajustes, as herdabilidades poligênicas da pressão sistólica (PAS) e diastólica (PAD) foram de 15 e 16,4%, circunferência abdominal de 26,1%, glicemia de 32,8%, triglicérides de 25,7% e HDL-c de 31,2%. Ajuste para idade, sexo, idade2 e interação sexo x idade aumentou as estimativas de herdabilidade para todos os traços: PAS (25,9%), PAD (26,2%), circunferência abdominal (40,1%), glicemia de jejum (34,5%), triglicérides (28,8%) e HDL-c (32,0%). Quando os fatores de risco para Síndrome Metabólica foram tratados como traços discretos, utilizando pontos de corte segundo critérios do ATPIII, as estimativas de herdabilidade, após ajuste para covariáveis, foram: 24,5% para SM, 37,5% para pressão arterial, 40,6% para circunferência abdominal, 54,5% para glicemia, 25,5% para triglicérides e 37,8% para HDL-c. Em conclusão, as estimativas de herdabilidade para os traços da síndrome metabólica em uma amostra da população brasileira são altas e não significativamente diferente de outros estudos em populações mundiais / Many studies have been conducted in different populations aiming at the identification of the proportion of total phenotypic variance that is attributable to genetic effects. The heritability of Metabolic Syndrome (MS) factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations. The purpose of this analysis was to evaluate genetic and environmental influences on metabolic syndrome traits, using a variance component analysis, by estimating the heritability of these traits in a sample of extended pedigrees. We examined 1,712 individuals of 119 randomly selected families from the general population of a city of Brazil. A total of 1,666 individuals of 81 families were used for analysis. Family size varied from 3 to 156 individuals with a mean of 21 subjects per family. Before adjustment, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15% and 16.4%, waist circumference 26.1%, fasting glucose 32.8%, triglycerides 25.7%, and HDL-c 31.2%. Adjustment for age, sex, age2, age and sex interaction increased polygenic heritability estimates for all traits: SBP (25.9%), DBP (26.2%), waist circumference (40.1%), fasting glucose (34.5%), triglycerides (28.8%), and HDL-c (32,0%). When the Metabolic Syndrome factors were treated as discrete traits, using ATPIII cut off, the estimates of heritability after adjusting for covariates were: 24.5% for MS, 37.5% for blood pressure, 40.6% for abdominal circumference, 54.5% for fasting glucose, 25.5% for triglycerides, and 37.8% for HDL-cholesterol. In conclusion, heritability estimates for metabolic syndrome traits in a sample of Brazilian population are high and not significantly different from other studied worldwide populations

Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates preventive management for carriers of mutations in OC-susceptibility genes. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We analyzed 219 genes in 1333 Czech OC patients and 2278 population-matched controls (PMC) using next-generation sequencing. Altogether, 427/1333 (32%) patients and 58 /2278 (2,5%) PMC carried pathogenic mutations in 18 known/anticipated OC predisposition genes. Mutations in BRCA1, BRCA2, RAD51C, RAD51D, BARD1 and mismatch repair genes conferred a high OC risk (with OR>5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR ≥2 - <5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Results of this study demonstrate the high proportion...

Introdução: A investigação de genes associados a doenças complexas em estudos caso-controle, baseada na frequência de variantes polimórficas, pode não ser adequada na presença de estratificação populacional advinda da mistura étnica, que é uma das características da população brasileira. Torna-se, portanto, difícil utilizar esta metodologia, pelo risco de associações espúrias devido às diferenças no background genético dos indivíduos casos e controles. Marcadores informativos de ancestralidade (AIMs) podem ser aplicados para estimar ancestralidade e corrigir estas distorções. As mesmas variantes genéticas de susceptibilidade para o diabetes tipo 1 autoimune (DM1A) como os alelos HLADR3- DR4 e os polimorfismos do PTPN22, CTLA4 e VNTR-INS presentes em caucasianos não foram sempre encontradas com a mesma frequência na nossa população com DM1A, ou conferiram risco menor quando presentes. Tais diferenças podem advir da nossa miscigenação. Portanto, no presente estudo, objetivou-se: 1) Analisar uma amostra de portadores de DM1A da cidade de São Paulo e controles não diabéticos, utilizando marcadores genéticos autossômicos de ancestralidade, identificando os componentes ancestrais individuais e os da população, permitindo assim, maior compreensão da sua potencial estratificação; 2) Verificar o papel dos alelos do sistema HLA-DR e DQ, dos polimorfismos dos genes PTPN22, CTLA4 e INS-VNTR, na predisposição à doença, corrigindo para o viés introduzido pela estratificação da nossa população. Materiais e métodos: 915 pacientes com DM1A, idade de 24,6±13,0 anos, 81,7% autorreferidos brancos e 789 controles, idade 28,5 ± 11,5 anos, 65,6% autorreferidos brancos participaram do estudo. A genotipagem dos 93 marcadores informativos de ancestralidade foi realizada por meio da plataforma BeadXpress (Illumina, EUA). A composição ancestral dos indivíduos foi caracterizada pelo programa Structure 2.3, e os alelos e variantes dos genes candidatos, testados por meio de análise structured association, utilizando o programa STRAT. Resultados: A ancestralidade européia prevaleceu no grupo de pacientes com DM1A e nos controles, (77% e 71%, respectivamente), seguida pela africana e ameríndia. Os alelos - DRB1*0301, -DR4 (subtipos -*0401, -*0402, -*0405) e - DR*09, e os alelos DQB1*0201 e -*0302 foram confirmados como predisponentes, mesmo após a correção para a estrutura de nossa população, assim como os alelos protetores- DRB1 (*0302, -*07, -*10, -*11, -*13, -*14 e -*15) e -DQB1 (*0402, -*0503, -*0602 e -*0603). Os haplótipos DRB1*0301/DQB1*0201, - *0401/0302, -*0402/0302, -*0405/0302, -*09/0202 predominaram no grupo DM1A, enquanto -*0302/0402, -*07/0202, -*10/0501, -*11/0301, -*11/0602, - *13/0603, -*14/0503 e -*15/0602 conferiram proteção. A correção para estratificação evidenciou o alelo DRB1*16 e o haplótipo -*07/0201 como de proteção e o DQB1*0501, que inicialmente era de proteção, como neutro. Também confirmou o haplótipo -*09/0202, como de risco e o -*0302/0402, de proteção, à semelhança do observado em afro-americanos. Os haplótipos - *10/0501, -*11/0602 e -*13/0603, protetores na nossa população e em afroamericanos, foram neutros nos caucasianos. A susceptibilidade determinada pelos genótipos I/I do INS VNTR e CT + TT do gene PTPN22 foram confirmadas após correção para estrutura populacional. O polimorfismo CTLA4 rs231775A > G não pôde ser avaliado. Conclusão: Evidenciamos diferenças nas variantes genéticas de susceptibilidade e proteção ao DM1A na nossa população em relação às caucasianas e afroamericanas, possivelmente decorrentes da mistura étnica. A correção para a estrutura populacional foi importante para confirmar a característica de proteção conferidas pelo alelo -DRB1*16 e haplótipo -*07/0201 / Introduction: The investigation of genes associated with complex diseases in case-control studies, based on the frequency of polymorphic variants, may not be appropriate in the presence of population stratification arising from the ethnic admixture, which is characteristic of the Brazilian population. It is therefore difficult to apply this method, due to the risk of spurious associations related to differences in the genetic background of individual cases and controls. Ancestry informative markers (AIMs) can be used to estimate ancestry and correct these distortions. The same genetic variants of susceptibility to type 1 autoimmune diabetes (T1AD) like HLA- DR3 -DR4 alleles and polymorphisms in PTPN22, CTLA4 and VNTR-INS genes usually present in caucasians were not always found at the same frequency in our population with T1AD, or conferred lower risk when present. These discrepancies may result from our miscigenation. Therefore, in this study, we aimed to: 1) analyze a sample of patients with T1AD and health controls, mostly living in São Paulo, using genetic autosomal markers of ancestry, to identify the ancestry of individual components and of the population, that could identify its potential stratification; 2) Evaluate the role of HLA-DR and -DQ alleles and polymorphisms of PTPN22, CTLA4 and INSVNTR genes in the predisposition to disease, correcting for the bias introduced by the stratification of our population. Methods: 915 patients with T1D, aged 24.6±13.0 years, 81.7% self-reported as white and 789 controls, aged 28.5±11.5 years, 65.6% self-reported as white participated of the study. Genotyping of 93 informative markers was performed by BeadXpress platform (Illumina, USA). The ancestry composition of individuals was characterized by Structure 2.3 program, and variants and alleles of candidate genes were tested using structured association analysis with the STRAT program. Results: The european ancestry prevailed in T1AD and control groups (77% and 71%, respectively), followed by african and amerindian. The -DRB1*0301, -DR4 (subtypes -*0401, -*0402, -*0405) and -DR*09 alleles as well as -DQB1 *0201 and -*0302 alleles were confirmed as predisposing to T1AD, even after correcting for the structure of our population. The same was observed for the protective alleles: -DRB1 (-*0302, - *07, -*10, -*11, -*13, -*14 and -*15) and - DQB1 (-*0402, -* 0503, -*0602 and -*0603). HLA-DRB1*0301/DQB1*0201, - *0401/0302, -*0402/0302, -*0405/0302, -*09/0202 haplotypes predominated in T1AD group, while -*0302/0402, -*07/0202, -*10/0501, -*11/0301, -*11/0602, - *13/0603, -*14/0503 and -*15/0602 conferred protection. The correction for stratification evidenced DRB1*16 allele and -*07/0201 haplotype as protective and DQB1*0501, initially associated with protection, as neutral. This analysis also confirmed the -*09/0202, as a risk haplotype and -*0302/0402, -*10/0501, - *11/0602 and -*13/0603 as protective in our population, similar to reported in african-americans, although neutral in caucasians.The susceptibility to T1AD determined by INS VNTR I/I and PTPN22 CT+TT haplotypes were confirmed after correcting for population structure. The CTLA4 rs231775 A > G polymorphism could not be evaluated. Conclusion: We demonstrated differences in genetic variants associated with susceptibility and protection to T1AD in our population when compared to caucasian and african-american Abstract populations, possibly due to the ethnic admixture. The correction for the population structure was important to confirm the protection conferred by - DRB1*16 allele and -*07/0201 haplotype