Made available in DSpace on 2015-07-22T20:49:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-07-28 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: Estudos epidemiológicos demonstram uma redução de até 13 anos na expectativa de vida das portadoras de Síndrome de Turner (ST) em relação às mulheres normais, sendo a principal causa de mortalidade a Doença Cardiovascular (DCV). Hipertensão arterial sistêmica, Diabetes mellitus, alterações lipídicas e níveis elevados de Homocisteína são importantes fatores de risco para DCV. Os genes TAP1, ENPP1, APOE e MTHFR estão associados ao risco cardiovascular por, estarem envolvidos na patogênese da HAS, do DM, da hipercolesterolemia e da elevação dos níveis plasmáticos de He, respectivamente. O objetivo do presente estudo foi analisar a frequência de polimorfismo destes genes nas portadoras de ST e correlacioná-las como fatores de risco para DCV. Material e métodos: A amostra deste estudo compreende 78 portadoras de ST e 372 indivíduos saudáveis sem a presença e história pessoal e familiar de DCV. Os polimorfismo dos genes TAP1, ENPP1 e C677T MTHFR foram analisado por RFLP – Análise do polimorfismo dos fragmentos de restrição, e as isoformas do gene APOE e polimorfismo A1298C do gene MTHFR foram genotipados através de ensaio TaqMan® SNP Genotyping Assays provenientes da Applied Biosystems®. As frequências dos alelos e dos genótipos foram comparadas às respectivas frequências do grupo controle. Os resultados foram analisados estatisticamente através do teste qui-quadrado (X2) no programa SPSS para Windows 9.0 (SPSS, Inc., Chicago, IL). O nível de significância considerado foi menor que 0,05 (<0,05). Resultados: Na análise do polimorfismo A637G do gene TAP1 as frequências dos genótipos A637A, A637G e G637G nas pacientes com ST foi, respectivamente, 7,7%, 52,6% e 39,7%, enquanto que no grupo controle 11,0%, 55,0% e 34,0%, respectivamente. A frequência dos genótipos para o polimorfismo A121C do gene ENPP1 nas pacientes ST foram: AA 42,3,0%, AC 48,7% e CC 9,0%. Em relação xxi ao grupo controle os genótipos AA, AC e CC se distribuíram da seguinte maneira, 45,0%, 42,0% e 12,0%, respectivamente. A frequência dos genótipos do gene da APOE nas pacientes com ST e nos controles, foi respectivamente: E3E3 68,3% e 61,5%, E2E3 6,3% e 12,4,0%, E3E4 24,1% e 22,6%, E2E2 0% e 1,0%, E4E4 0% e 1,3% e E2E4 1,3% e 1,1%. A frequência dos genótipos MTHFR 677CC, 677CT e 677TT nas 78 pacientes portadoras de ST foi, respectivamente, de 47,4%, 42,3% e 10,3%, enquanto que nos 372 indivíduos do grupo controle os genótipos 677CC, 677CT e 677TT foram encontrados nas seguintes frequências: 59,0%, 29,0% e 12,0% , respectivamente. As frequências dos genótipos para o polimorfismo A1298C no gene MTHFR nas pacientes com ST e grupo controle, foram, respectivamente: AA 46,2% e 64%, AC 35,9% e 31% e CC 17,9% e 5%. Conclusão: Não foi observada associação entre os polimorfismos dos genes TAP1, ENPP1, APOE e C677T MTHFR e o risco para DCV nas portadoras de ST. Entretanto o polimorfismo A1298C do gene MTHFR apresenta-se com frequência estatisticamente elevada nas pacientes (p<.0001), sendo considerado um fator de risco para a DCV nas portadoras / Background: Epidemiological studies showed a reduction of up to 13 years in life expectancy of Turner Syndrome (TS) patients compared to normal women, being the main cause of cardiovascular disease (CVD) mortality. Hypertension (SAH) diabetes mellitus (DM) and dislipidemy are important risk factors for CVD that are highly prevalent in this syndrome. TAP1, ENPP1 and APOE genes are associated with cardiovascular risk for being involved in the pathogenesis of hypertension, DM and hypercholesterolemia, respectively. The aim of this study was to analyze the frequency of polymorphism of these genes in TS patients. Methods: Seventy eight TS patients and 372 healthy individuals with no personal and familial history of CVD were assessed for polymorphisms of genes TAP1 and ENPP1 by Restriction fragment length polymorphism (RFLP). Isoforms of APOE gene were genotyped by qPCR. Results: Analysis of AA, GG and AG genotypes frequencies of A637G TAP1 polymorphism in TS patients were, respectively, 7.7%, 52.6% and 39.7%, while the control group presented 11.0%, 55.0% and 34.0% (p=0.4584). The frequency of genotypes for ENPP1 A121C polymorphism in the ST patients were: AA 42,3,0%, AC 48.7% and CC 9.0% and 45.0%, 42.0% and 12.0% in controls (p=0.5169). The frequency of genotypes of APOE gene in TS patients and controls were, respectively: E3E3 68.3% and 61.5%, E2E3 6.3% and 12,4%, E3E4 24.1% and 22,6%, E2E2 0% and 1.0%, E4E4 0% and 1.3% and E2E4 1.3% and 1.1%, (p=0,864). Conclusion: There were no correlations between the frequencies of TAP1, ENPP1 and APOE polymorphisms and CVD risk in women with TS. / TEDE / BV UNIFESP: Teses e dissertações

Craniofacial asymmetry is a dentofacial deformity with genetic influences. The genes PITX2, ENPP1 and ESR1 have multiple genetic associations with functional properties in muscle and bone. The objectives of this study are to investigate how PITX2, ENPP1 and ESR1 gene expression associates with four subclassifications of craniofacial asymmetry, temporomandibular disorders and fiber type differences compared between right and left masseter muscles. We developed an asymmetry classification that diagnosed four types of asymmetry with distinctive growth patterns: Group 1 – menton deviation without ramal difference (“mandibular body asymmetry”); Group 2 –menton deviation with shorter ramal height on the deviated side (“typical asymmetry”); Group 3 – shorter ramal height on the opposite side of menton deviation (“atypical asymmetry”); Group 4 – menton deviation with shorter ramal height and maxillary canting on the deviated side (“C-shaped asymmetry”). Some of these patients are at high risk for TMD; therefore, temporomandibular joint functioning is assessed as a routine part of the pre-surgical evaluation. TMD was diagnosed using the Diagnostic Criteria for TMD (DC/TMD). The clinical examination includes mandibular range of motion, palpation for pain, joint noise and bruxism. In addition, the Jaw Pain and Function (JPF) questionnaire was used to assess patient reported symptoms as an indication of perceived severity before and one year after orthognathic surgery. Masseter muscle samples were collected from 174 subjects undergoing surgical treatment for correction of malocclusion. Muscle serial cross-sections were mounted for immunostaining with five antibodies specific for myosin heavy chain (MyHC) isoform. We classified masseter fibers into 4 fiber type groups: type I, type I/II hybrid, type IIA and/or IIX, neonatal and atrial. With the remaining muscle samples, total RNA was isolated and PITX2, ENPP1, and ESR1 expression was quantified using TaqMan qRT-PCR. Average relative quantity gene expression values and percent differences between left and right masseter samples were calculated. In this population, there is a high prevalence of facial asymmetry (48%). Pre-surgical mean JPF scores are significantly different between symmetric (JPF=1.97) and asymmetric (JPF=6.9; p&lt;0.001) patients; with scores ≥ 6 diagnostic for presence of TMD. ENPP1 and ESR1 expression is differentially expressed between right and left masseter muscle in patients with asymmetry. ENPP1 is differentially expressed in asymmetry group 4 (p=0.01) and ESR1 is differentially expressed in asymmetry group 1 (p=0.048), group 2 (p=0.004) and group 4 (p=0.02). Masseter fiber type properties of type I, type I/II hybrid and type II fibers associate with facial asymmetry and specific subclassifications, suggesting functional differences between type I, type I/II and type II fibers may be important factors in the development of symmetry between facial sides. There are significant differences in the left-right percent differences of fiber area of type I fibers in asymmetry group 3 (p=0.05), type I/II hybrid fibers in group 3 (p=0.02), and type II fibers in asymmetric patients (p=0.03), asymmetry group 2 (p=0.05) and group 4 (p=0.005). Additionally, there are significant differences in the left-right percent differences of percent occupancy of type I fibers in asymmetric patients (p=0.04), asymmetry group 2 (p=0.01) and group 3 (p=0.05) and type II fibers in asymmetry group 2 (p=0.04). By comparing gene expression with masseter muscle fiber type properties, we found significant results for PITX2 and ENPP1 suggesting their roles as genetic factors influencing jaw bone length and masticatory muscle strength in malocclusion. There are significant positive correlations between left-right percent differences of PITX2 and type I fiber area (r=0.86; p=0.03), type I/II hybrid fiber area (r=0.94; p=0.006), and type I/II hybrid fiber percent occupancy (r=0.90; p=0.01). Also, there are positive correlations approaching significance between left-right percent differences of ENPP1 and type I fiber area (r=0.80; p=0.06) and type I/II hybrid fiber area (r=0.75; p=0.09). Given the high prevalence of TMD in a population of patients with facial asymmetry, we compared differences in gene expression in masseter muscle of patients with specific TMD diagnostic conditions. Average PITX2 expression is significantly increased (p=0.0375) and average ENPP1 is increased, but not significantly, in all TMD patients diagnosed by the clinician. Average ESR1 is slightly increased compared to JPF scores and may be an essential factor for patient reported TMD symptoms. With these results, PITX2, ENPP1, and ESR1 should be considered biomarkers for asymmetry and TMD; however, further studies are needed to provide a more thorough understanding of the genetic influences on the craniofacial complex. / Oral Biology

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