by Lo Man-har. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 56-63). / LIST OF FIGURES --- p.5 / LIST OF TABLES --- p.6 / ACKNOWLEDGEMENTS --- p.8 / SUMMARY --- p.9 / Chapter 1. --- INTRODUCTION --- p.11 / Chapter 1.1 --- Lipid metabolism --- p.11 / Chapter 1.1.1 --- Chylomicron --- p.12 / Chapter 1.1.2 --- Very low density lipoprotein --- p.12 / Chapter 1.1.3 --- Low density lipoprotein --- p.13 / Chapter 1.1.4 --- High density lipoprotein --- p.14 / Chapter 1.2 --- Apolipoprotein B --- p.14 / Chapter 1.3 --- Apolipoprotein B gene --- p.15 / Chapter 1.4 --- Genetic variations in human apo B gene and their associations with abnormal lipid metabolism --- p.16 / Chapter 1.4.1 --- Abetalipoproteinemia --- p.16 / Chapter 1.4.2 --- Hypobetalipoproteinemia --- p.17 / Chapter 1.4.3 --- Familial hypercholesterolemia (FH) --- p.17 / Chapter 1.5 --- Polymorphisms of apo B gene --- p.17 / Chapter 1.6 --- Methods for detection of polymorphisms --- p.19 / Chapter 2. --- OBJECTIVES --- p.20 / Chapter 3. --- MATERIALS AND METHODS --- p.21 / Chapter 3.1 --- Materials and equipments --- p.21 / Chapter 3.1.1 --- Enzymes --- p.21 / Chapter 3.1.2 --- DNA markers --- p.21 / Chapter 3.1.3 --- General reagents --- p.21 / Chapter 3.1.4 --- Equipments --- p.22 / Chapter 3.2 --- Buffers --- p.22 / Chapter 3.3 --- Agarose gel electrophoresis --- p.22 / Chapter 3.4 --- Study subjects --- p.23 / Chapter 3.4.1 --- Cord blood samples --- p.23 / Chapter 3.4.2 --- Geriatric subjects --- p.23 / Chapter - --- Cases --- p.23 / Chapter - --- Controls --- p.24 / Chapter 3.5 --- Clinical Data --- p.24 / Chapter 3.6 --- Blood collection --- p.24 / Chapter 3.7 --- Biochemical analysis --- p.25 / Chapter 3.8 --- DNA extractions --- p.25 / Chapter 3.9 --- Polymerase chain reaction (PCR) --- p.26 / Chapter - --- Oligonucleotide primers --- p.26 / Chapter - --- Signal peptide insertion/deletion polymorphism --- p.26 / Chapter - --- Xba I polymorphism --- p.27 / Chapter - --- Eco RI polymorphism --- p.28 / Chapter 3.10 --- Data analysis --- p.29 / Chapter 4. --- RESULTS --- p.30 / Chapter 4.1 --- Optimization of PCR --- p.30 / Chapter 4.2 --- Clinical features of the case and control subjects --- p.30 / Chapter 4.3 --- Genotyping --- p.31 / Chapter 5. --- DISCUSSION --- p.33 / Chapter 5.1 --- Optimization of PCR protocols --- p.33 / Chapter 5.2 --- Clinical data --- p.34 / Chapter 5.3 --- Allelic frequencies of the three polymorphisms of apo B gene --- p.35 / Chapter 5.4 --- Association of polymorphisms of apo B gene with the case group --- p.36 / Chapter 5.5 --- Association of polymorphisms of apo B gene with hyperlipidaemia --- p.36 / Chapter - --- Signal peptide insertion/deletion polymorphism --- p.36 / Chapter - --- Xba I polymorphism --- p.38 / Chapter - --- Eco RI polymorphism --- p.38 / Chapter 5.6 --- Conclusion --- p.39 / APPENDIX I --- p.53 / APPENDIX II --- p.54 / Chapter 6. --- REFERENCES --- p.56

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Drug resistance is a major obstacle to management and control of malaria and currently progressing at a rapid rate across Africa. This thesis has examined factors influencing evolution of resistant P. falciparum at two sites in Africa, including parasite migration, cross mating and fitness cost of resistance. In Asar village, eastern Sudan, the frequencies of drug sensitive and resistant parasites were monitored throughout the dry season in the absence of anti-malarial drug usage to examine whether persistence of resistant parasites is reduced in the absence of drug pressure. Two cohorts of P. falciparum infected patients were treated with chloroquine in the transmission season (Oct-Dec), and followed monthly in the dry season into the next transmission season. A large proportion of the cohort maintained sub-patent asymptomatic P. falciparum infections throughout the entire study period. Alleles of the chloroquine resistance transporter (Pfcrt) and multi-drug resistance protein (Pfmdr1) were examined. Mutant alleles of Pfcrt reached fixation following CQ treatment and remained high in the transmission season. However, at the start of the dry season, wild type alleles of both genes started to emerge and increased significantly in frequency as the season progressed. The mutant Pfcrt haplotype was invariably CVIET, indicating migration of CQ resistant parasites into an area; otherwise the CVMNK haplotype is normal. In addition, microsatellite haplotypes of dihydrofolate reductase (dhfr) gene and dihydropteroate synthase (dhps) genes, which control the parasite response to pyrimethamine and sulfadoxine respectively, were characterized. One major dhfr haplotype with double dhfr mutations and two major mutant dhps haplotypes were seen in eastern Sudan. These haplotypes are distinct from those prevailing in other African countries, suggesting the likely local origin of dhfr and dhps haplotypes conferring drug resistance. Transmission capacities of different P. falciparum clones within a single infection in The Gambia have a high ability to produce gametocytes and infect Anopheles mosquitoes even when they exist at levels not detectable by microscopy and PCR. These findings emphasize the crucial role of gametocyte complexity and infectivity in generating the remarkable diversity of P. falciparum genotypes seen in infected people. Parasites with different resistant dihydrofolate reductase (dhfr) haplotypes have the ability to infect Anopheles mosquitoes following drug treatment, and cross-mating between parasites with different dhfr haplotypes was detected. Our results showed that the major dhfr haplotype in the Gambia is similar to the common one seen in other African countries, suggesting that parasite migration plays a major role in spread of resistance. Indeed, the dominant resistant haplotype seen in infected patients was readily transmitted to infect mosquitoes.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A anemia falciforme (AF) Ã uma das alteraÃÃes genÃticas mais comuns em nosso paÃs. Os haplÃtipos da &#61538;s-globina estÃo associados com a heterogeneidade clÃnica apresentada pela doenÃa. Os portadores de AF sÃo submetidos a elevados nÃveis de estresse oxidativo. A hidroxiurÃia (HU) tem sido utilizada no tratamento por sua aÃÃo de elevar os nÃveis de hemoglobina fetal e aÃÃo antioxidante. O estudo teve como objetivo investigar o impacto do uso da HU e dos haplÃtipos no perfil oxidativo nos pacientes com AF. Foram analisadas amostras de 64 pacientes acompanhados no Hospital UniversitÃrio Walter CantÃdio - HUWC e do grupo controle de 20 indivÃduos sem hemoglobinopatias. Os pacientes foram estratificados em grupos: uso de HU > 1 ano, uso de HU &#8804; 1 ano e sem uso de HU (SHU). A confirmaÃÃo do diagnÃstico e a anÃlise dos haplÃtipos foram realizadas atravÃs de estudo molecular. As dosagens do nitrito (NO2-), malonaldeÃdo (MDA), glutationa peroxidase (GSH-Px), catalase (CAT), glutationas total (GSSG+GSH), oxidada (GSSG) e reduzida (GSH) e da relaÃÃo GSSG/GSH (glutationas oxidada/reduzida) foram realizadas por espectrofotometria. Os nÃveis mÃdios de NO2-, e MDA mostraram-se mais elevados no grupo SHU, sendo significante apenas para o MDA (p < 0,05). O grupo SHU apresentou atividade mÃdia das enzimas CAT (p = 0,031) e GSH-Px (p = 0,036) inferiores aos demais grupos e maior relaÃÃo GSSG/GSH (p < 0,05). A avaliaÃÃo do estresse oxidativo em relaÃÃo aos haplÃtipos demonstrou que na populaÃÃo sem uso de HU os nÃveis de NO2- e de MDA foram semelhantes entre os grupos, com um aumento nÃo significante da GSH-Px no grupo Bantu/n em relaÃÃo ao Benin/n e do Ãndice GSSG/GSH no grupo Benin/n em relaÃÃo ao Bantu/n. Na populaÃÃo em uso de HU verificou-se um aumento nÃo significante dos nÃveis de NO2- no grupo Bantu/n em relaÃÃo ao Benin/n com resultados semelhantes de MDA entre os grupos e um aumento significante da GSH-Px (p<0,03) no grupo Benin/n em relaÃÃo ao Bantu/n. Os resultados da CAT foram semelhantes entre os grupos. A relaÃÃo GSSG/GSH foi maior, porÃm nÃo significante no grupo Bantu/n em relaÃÃo ao Benin/n. Os resultados do presente estudo reforÃam a hipÃtese de que os pacientes com AF apresentam um estado hiperoxidativo com nÃveis elevados dos produtos do estresse oxidativo e diminuÃdos do perfil antioxidante e que a hidroxiurÃia teve um impacto sobre o perfil oxidativo. No entanto, em relaÃÃo ao impacto dos haplÃtipos no estresse oxidativo, estudos posteriores com uma maior amostragem devem ser recomendados para confirmar nossos resultados, considerando que o grupo de pacientes nÃo tratados com HU foi menor que o grupo de pacientes em uso de HU, o que pode ter interferido na anÃlise estatÃstica dos resultados. / The sickle cell anemia is one of the most common genetic disorders in our country. The &#61538;-globin haplotypes are associated with the clinical heterogeneity of the disease. Individuals with sickle cell disease are subjected to high levels of oxidative stress. Hydroxyurea (HU) has been used as treatment and it increases the levels of fetal hemoglobin having an action antioxidant. The study aimed to investigate the impact of the use of HU and haplotypes in the oxidative status in patients with sickle cell anemia. Samples from 64 patients treated at the University Hospital Walter CantÃdio - HUWC and the control group of 20 individuals without hemoglobinopathies. Patients were stratified into groups: the first one using HU > 1 year, the second using HU &#8804; 1 year and the third using of HU (SHU). Confirmation of the diagnosis and analysis of haplotypes were performed by molecular study. The measurements of nitrite (NO2-), malonaldehyde (MDA), glutathione peroxidase (GSH-Px), catalase (CAT), glutathione total (GSSG+GSH), oxidized (GSSG) and reduced (GSH) and the ratio GSSG/GSH (glutathione oxidized/reduced) were performed by spectrophotometry. Mean levels of NO2- and MDA were shown to be higher in SHU group, being significant only for MDA (p < 0,05). The assessment of oxidative stress in relation to haplotypes showed that the population without the use of HU levels of NO2- and MDA were similar between groups, with an insignificant increase of GSH-Px in the Bantu/n compared with Benin/n and index GSSG/GSH in the Benin/n compared with Bantu/n. In the population using the HU there was a nonsignificant increase in the levels of NO2- in the Bantu/n compared with Benin/n with similar results between groups of MDA and a significant increase in GSH-Px (p <0.03) in the Benin/n compared with Bantu/n. The results of CAT were similar between groups. The ratio of GSSG/GSH was higher but not significant in the Bantu/n compared to Benin/n. The results of this study support the hypothesis that patients with the sickle cell anemia have a state hiperoxidativo products with high levels of oxidative stress and decreased antioxidant status and that of hydroxyurea had an impact on oxidative stress. However, regarding the impact of the haplotypes in oxidative stress, further studies with a larger sample should be recommended to confirm our results, considering that the group of patients not treated with HU was lower than the group of patients using HU, the which may have interfered in the statistical analysis of results.

Orientador: Margareth Castro Ozelo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T17:29:43Z (GMT). No. of bitstreams: 1 Santos_Andreydos_D.pdf: 4770033 bytes, checksum: 92cd7a4adf25e169140e6fbbb68fe9d2 (MD5) Previous issue date: 2010 / Resumo: Uma complicação decorrente do tratamento da hemofilia é a formação de anticorpos neutralizadores da atividade coagulante do fator VIII ou IX (inibidores). Diversos fatores estão relacionados com o desenvolvimento desses inibidores em indivíduos com hemofilia, incluindo fatores genéticos e ambientais. Entre os fatores genéticos, a mutação associada ao diagnóstico da hemofilia é um fator de risco bem documentado. Recentemente foi observada a maior ocorrência de inibidores em indivíduos da etnia negra. O objetivo deste trabalho foi analisar os aspectos genéticos e não genéticos envolvidos no desenvolvimento de inibidores. Foram incluídos nesse estudo 411 pacientes hemofílicos, sendo 321 com hemofilia A (HA) (238 famílias) e 99 com hemofilia B (HB) (59 famílias). A presença de inibidores foi constatada apenas entre os pacientes HA graves. Do total de 220 HA graves desse estudo, 46 (20,9%) apresentaram inibidor detectado em pelo menos uma ocasião após sua inclusão no estudo. Mutações consideradas de alto-risco para o desenvolvimento de inibidores foram identificadas em 125/220 pacientes HA graves (58,8%), e 33 deles desenvolveram inibidores (26,4%). Considerando o grupo étnico de acordo com traços físicos e ancestralidade, 38% dos pacientes HA graves foram classificados como negros. A incidência de inibidores foi maior nesse grupo de pacientes (31% do total de pacientes HA graves classificados como negros) quando comparada aos pacientes caucasóides (20% do total de pacientes HA graves classificados como caucasóides). Recentemente, foi observado que a maior incidência de inibidores em uma população norte-americana de pacientes com HA, estava relacionada com a presença de determinados haplótipos no gene do fator VIII. Esta observação poderia ser explicada pelo fato dos as proteínas expressas pelos haplótipos que aparecem exclusivamente entre a população negra (denominados H3 e H4), estarem ausentes nos concentrados de fator VIII recombinantes utilizados rotineiramente no tratamento desses pacientes. Em nossa análise a presença desses haplótipos não está relacionada com a maior freqüência de inibidor na população negra desse estudo. Além disso, a distribuição dos diferentes haplótipos do gene do fator VIII, classificados de H1 a H6, foi distinta entre todos os grupos étnicos brasileiros e norte-americanos. Essa observação pode ser explicada pela origem distinta entre os negros que imigraram da África para o Brasil e para a América do Norte, assim como o alto índice de miscigenação de nossa população. Em outra fase desse estudo, foi realizada a análise comparativa da expressão gênica a partir de amostras de RNA mensageiro (RNAm) extraídas em pool leucocitário de pacientes com HA grave, com ou sem a presença de inibidores. Na avaliação que incluiu numa primeira análise pacientes de uma mesma família discordante para a presença de inibidor e, em uma segunda fase, indivíduos não relacionados, foram observados 50 genes mais expressos e 16 genes menos expressos em pacientes com inibidor em comparação aos sem inibidor. Dentre esses genes foram selecionados dez, levando-se em conta sua participação na resposta imune ou sua correlação prévia com o desenvolvimento de inibidores em outros estudos. Pela técnica de PCR em tempo real, observou-se que os genes da interleucina 8 (IL-8) e da cistatina F (CST7) demonstraram ser mais expressos em pacientes com inibidor, enquanto que o gene da interleucina 10 (IL-10) foi menos expresso nesse grupo de pacientes. Dessa forma, nossos resultados fortalecem a idéia de que o mecanismo de desenvolvimento de inibidores em hemofilia é complexo e ainda não totalmente esclarecido e que existe um grande envolvimento de diversos genes relacionados com sistema imune na formação desses inibidores. O estudo em diferentes populações é uma importante etapa para o entendimento dos fatores de risco para o desenvolvimento de inibidores. Esse foi o primeiro trabalho realizado no Brasil incluindo pacientes de diversas regiões e analisando simultaneamente diferentes fatores e seu envolvimento com o desenvolvimento de inibidores. A determinação desses fatores de risco ajudará no futuro a determinar um tratamento diferenciado para o controle e sobretudo prevenção do desenvolvimento de inibidores / Abstract: The most serious complication of the treatment of hemophilia is the development of neutralizing antibodies to coagulation activity of factor VIII or IX (inhibitors). Several risk factors are related to the development of these inhibitors in patients with hemophilia, including genetic and environmental factors. Among genetic factors, the mutation associated with the diagnosis of hemophilia is a risk factor well documented. Recently, it was observed a higher incidence of inhibitors in African ancestry patients. The aim of this study was to analyze the genetic and non-genetic factors involved in the development of inhibitors. The study included 411 hemophilia patients, of which 321 with hemophilia A (HA) and 99 with hemophilia B (HB), belonging to a total of 238 and 59 families, respectively. The inhibitors were observed only in severe HA patients. From the 220 severe HA, 46 (20.9%) had inhibitor. The high risk mutation for the development of inhibitors were identified in 125 / 220 (58.8 %) severe HA patients, and 33 (26.4 %) of them developed inhibitors. Considering the ethnic group according to physical traits and ancestry, 38 % of severe HA patients were classified as black. The incidence of inhibitors is higher in this group of patients (31%) when compared to Caucasian patients (20%). The higher risk of inhibitor among African-Brazilians, could not be explained by the presence of the distinct factor VIII haplotypes, such as H3 and H4, as suggested in previous study. In fact, the prevalence rates of these haplotypes were distinct between Brazilians and North Americans, probably due to the fact that migrations of blacks to Brazil and to North America were originated from different geographic areas of Africa. In another phase of this study, we performed a comparative analysis of gene expression in samples of messenger RNA (mRNA) extracted from leukocytes of inhibitor and non-inhibitor patients with severe HA was performed. The evaluation consisted of an initial analysis of severe HA patients siblings, or from the same family, discordant for inhibitor development and in a second phase a group of unrelated individuals. Using the bioarrays technology 50 genes were upregulated and 16 were downregulated in inhibitor patients compared with non-inhibitor patients. Ten genes were selected among them, which are involved in immune response and were related to inhibitors development in other studies. It was observed by real time PCR that the genes for interleukin 8 (IL-8) and cystatin F (CST7) were upregulated and for interleukin 10 (IL-10) was downregulated in inhibitor patients. In conclusion, our results strengthen the idea that the mechanism of inhibitor development in hemophilia is complex, not clear and there is a large involvement of several genes related to the immune system in the development of these inhibitors. The study in different populations is important to understand the risk factors for the development of inhibitors. This is the first work in Brazil, to study patients from various regions and to performe analysis of different factors and their involvement in the development of inhibitors. The determination of these risk factors will help in the future to determine differential treatment for the control and in particular, for preventing the development of inhibitors / Doutorado / Clinica Medica / Doutor em Clínica Médica

Orientador: Heron Fernando de Sousa Gonzaga / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-10T16:40:54Z (GMT). No. of bitstreams: 1 Rodrigues_Marcelo_D.pdf: 760160 bytes, checksum: 48a5a2282ffba53fa69fd0f990fa8ed0 (MD5) Previous issue date: 2008 / Resumo: A hialinose cutâneo-mucosa (HCM) é uma dermatose autossômica recessiva rara, congênita, de aparecimento precoce na infância. Caracteriza-se por deposição de material hialino, que se acumula na pele e mucosas. Foram descritos 258 casos na literatura mundial e no Brasil, doze casos. A HCM apresenta aumento da expressão do colágeno tipo IV e V e redução da expressão do colágeno I e III. Esta doença foi mapeada no locus do cromossomo 1q21. Mutações patogênicas foram identificadas no gene ECM1. A doença é caracterizada por voz rouca, pápulas cutâneas amareladas, cicatrizes atróficas, lesões ulceradas cutâneas, blefarose moniliforme e conjuntivite pseudo-membranosa. Manifesta multiplicidade de sintomas, afetando vários órgãos. A revisão da literatura sobre HLA e HCM não mostrou nenhum trabalho. Realizou-se o estudo clínico e das especificidades HLA na família de uma afetada por HCM. Foram submetidos a exames clínicos e complementares. A tipificação HLA foi realizada através da análise de DNA genômico pela técnica de PCR-SSP. A afetada era branca, com 14 anos. Referia choro rouco desde o nascimento e eritema na região subescapular e cervical há 13 anos, que evoluiu para vesículas e posteriormente, micropápulas, que se rompiam, evoluindo para lesões ulceradas. Nesses locais, apareciam verrucosidades nos ângulos da boca, joelhos, cotovelos e regiões palmares. Concomitantemente, evoluiu para micropápulas hipocrômicas no dorso das mãos e axilas. Referia disfagia. Negava história familiar. Ao exame dermatológico, pápulas amareladas nas pálpebras e linearmente na borda livre; cicatrizes atróficas varioliformes nas regiões antecubitais; placas verrucosas nos cotovelos, regiões palmares, joelhos; pápulas amareladas em dorso das mãos e região cervical posterior. Apresentava alopecia parieto-occipital. Ao exame bucal, abertura limitada, endurecimento labial, lesões vegetantes no ângulo da boca, placas branco-amareladas em regiões de mucosa jugal, vestibular, orofaringe, dorso e ventre da língua. Ulcerações linguais e no palato duro e mole. Xerostomia discreta foi observada. Ao exame dentário, placa bacteriana, cálculos e agenesia do dente 22. A gengiva era friável, hipertrófica com bolsas periodontais. Ao exame oftalmológico, obstrução das vias lacrimais, mucosa espessada nos pontos lacrimais e prurido periocular. Diagnóstico psiquiátrico de Distimia foi estabelecido. Na avaliação neurológica, cefaléia. O exame clínico nos outros membros da família não mostrou nenhum traço da doença. Na fibronasofaringolaringoscopia, espessamento epidérmico em epiglote e hipertrofia de falsas cordas, pregueamento mucoso em prega interaritenóidea. O EEG não mostrou anormalidades. A tomografia computadorizada apresentou calcificações parenquimatosas hipocampais bilaterais. O exame histopatológico confirmou o diagnóstico de HCM. Constatou-se que sendo a doença autossômica recessiva, a ausência de manifestações clínicas nos pais da afetada, mostrou serem os mesmos heterozigotos. As manifestações clínicas são importantes para o diagnóstico. A primeira manifestação clínica mais freqüente na literatura, apresentada pela afetada, é a rouquidão. As manifestações clínicas mais exuberantes na doença são as cutâneas e mucosas. O estudo das especificidades HLA determinou os seguintes haplótipos na afetada: A31-B39-Cw7-DR4-DQ8 e A74-B7-Cw7-DR8-DQ-. A paciente era haploidêntica a um dos seus dois meioirmãos. Este foi o primeiro trabalho em que se investigou especificidades HLA em portador de HCM / Abstract: Cutaneous-mucous hyalinosis (CMH) is a rare congenital autosomal recessive dermatose, which is presented precociously in early childhood. It is characterized by disposition of hyaline material that accumulates in the skin and cutaneous mucous. 258 cases were described in the world and 12 cases in Brazil. The CMH presents an increase of the expression of the collagen types IV and V and reduction of the expression of the collagen I and II. The disorder was mapped in a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene. The disease is characterized by hoarse voice, yellowed cutaneous papules, atrophic scars, ulcerated cutaneous lesions, moniliform blepharosis, and pseudomembranous conjunctivitis. It manifests multiple symptoms affecting several organs. The review of literature about HLA as well as CMH has not presented any work so far. The clinical study as well as of the HLA antigens in the family of an individual affected by CMH was performed. They were submitted to clinical and auxiliary tests. The HLA type was accomplished through the analysis of genome DNA by the technique of PCR-SSP. The proband was a 14 year old white female. It referred hoarse crying from the birth and erythema in the sub-omoplate and cervical area 13 years ago which developed for vesicles and later on, micropapules that broke up, developing for ulcerated lesions, verrucous lesions in the angles of the mouth, knees, elbows and palm areas appeared. Concomitantly it developed for hypochromic micropapules in the back of the hands and armpits. It referred dysphagia. There was no history family. During the dermatological examination she presented yellowed papules in the eyelids and lineally in the free border; atrophic varioliform scars in the ante-cubital areas; verrucous plates in the elbows, palm areas and knees: yellowed papules in the back of the hands and posterior cervical area. She showed Parietal-occipital alopecia. During the oral examination she Presented limited opening, labial hardening, vegetative lesions in the angle of the mouth, white yellowed plaques in the areas of buccal, vestibular, oro-pharynx, dorsal and ventral tongue mucous membranes. Tongue ulcerations and also in the hard and soft palate. Discreet xerostomia was observed. During the dental examination, bacterial plaque, calculous and agenesis of the tooth 22. The gengive was friable, hypertrophic with periodontal depressions. During the ophthalmic examination, obstruction of the lacrimal via, thickened mucous in the lacrimal vias and perio-ocular pruritis. Psychiatric diagnosis of Dysthymia was estableshed. In the neurological evaluation, migraine. The clinical examination in the other members of the family did not show any line of the disease. Epidermal thickening in the epiglottis and hypertrophy of false strings, mucous pleatment in interarytenoide pleat were found. EEG did not show abnormalities. Computed tomography presented bilateral parenchymatosis hippocampus calcifications. The histopathology examination confirmed the diagnosis of CMH. It was verified because of the disease was recessive autosomal, the absence of clinical manifestations in the parents of the affected individual who were heterozygote. The clinical manifestations are important for the diagnosis. The most frequent clinical manifestation in the literature, presented by the affected girl, is the hoarse voice. The most exuberant clinical manifestations in the disease are the cutaneous and the mucous ones. The study of the HLA antigens determined the following haplotypes in the affected girl: A31-B39-Cw7-DR4-DQ8 and A74-B7-Cw7DR8-DQ- . She is haplo-identical to one of two her middle-siblings. This was the first work in which HLA antigens were investigated in carrier of CMH / Doutorado / Estomatologia / Doutor em Estomatopatologia

Les technologies actuelles permettent d’explorer le génome entier pour y découvrir des variants génétiques associés aux maladies. Cela implique des outils bioinformatiques adaptés à l’interface de l’informatique, des statistiques et de la biologie. Ma thèse a porté sur l’exploitation bioinformatique des données génomiques issues de la cohorte GRIV du SIDA et du projet international IHAC (International HIV Acquisition Consortium). Posant les prémices de l'imputation, j’ai d’abord développé le logiciel SUBHAP. Notre équipe a montré que la région HLA était essentielle dans la non progression et le contrôle de la charge virale et cela m’a conduit à étudier le phénotype non-progresseur non « elite ». J’ai ainsi révélé un variant du gène CXCR6 qui, en dehors du HLA, est le seul résultat identifié par approche génome-entier et répliqué. L’imputation des données du projet IHAC (10000 patients infectés et 15000 contrôles) a été réalisée et des premières associations sont en cours d’exploration. / Nowadays with the newest technologies, the entire genome can be explored to uncover genetic variants which may be linked to diseases. This requires bioinformatics tools which are adequate for studies which are at the border between computing, statistics and biology. My thesis work focused on the bioinformatical analysis of genomic data from the GRIV AIDS cohort and from the IHAC (International HIV Acquisition Consortium) project. I first laid the foundation for imputation work by developing the SUBHAP software. Our team showed that the HLA region was essential in non-progression and viral charge control. This led me to study the non progressor non elite phenotype. Thus, I uncovered a variant of the CXCR6 gene which is, apart from HLA, the only result identified with a GWAS approach so far and which has been reproduced. The imputation of data from the IHAC project (10000 infected patients and 15000 control subjects) was also performed and the first associations are now being studied.