Genetic Aspects in Shoulder Disorders / Aspectos genéticos nas afecções do ombro

Abstract The influence of genetic inheritance has been increasingly investigated in shoulder disorders, such as rotator cuff injury, instability and frozen shoulder. Although the initial findings are enlightening, it is necessary to progressively build a database of genetic markers to catalog genomic profiles that, later, may contribute for predicting the risk of the disease, as well as to the development of better diagnostic and treatment tools. The present article seeks to update what is evidence of genetic studies in the literature for these diseases, from polymorphism analyses, expression of candidate genes in tissues and broad genomic association studies (GWAS). However, it is necessary to point out that there is great difficulty in replicating and using the findings, mainly due to the lack of statistical power, the high rate of false-positive results and the large number of variables involved.

Resumo A influência da herança genética tem sido cada vez mais investigada nas afecções do ombro, como a lesão do manguito rotador, instabilidade e ombro congelado. Ainda que os achados iniciais sejam pouco esclarecedores, é necessário construir progressivamente um banco de marcadores genéticos para catalogar perfis genômicos que, mais adiante, poderão contribuir para a previsão do risco da doença, desenvolvimento de melhores ferramentas de diagnóstico e tratamento. O presente artigo busca atualizar o que há de evidências de estudos genéticos na literatura para essas doenças, desde análises de polimorfismos, expressão de genes candidatos em tecidos e estudos de associação genômica ampla (GWAS, na sigla em inglês). Porém, é necessário apontar que existe grande dificuldade na replicação e utilização dos achados, principalmente em razão da falta de poder estatístico, da alta taxa de resultados falso-positivos e da grande quantidade de variáveis envolvidas.

Association between Frozen Shoulder and Thyroid Diseases: Strengthening the Evidences / Associação entre ombro congelado e tireopatias: Reforçando as evidências

Abstract Objective To clarify the association of thyroid disorders and primary frozen shoulder by comparing this group with controls without shoulder disease and with patients with rotator cuff tears. Methods We evaluated 166 patients who presented frozen shoulder with treatment in progress or already treated, which were compared with 129 patients with diagnosis of rotator cuff tears and 251 control subjects. All of the participants answered the questionnaire on the following variables: age, gender, body mass index (BMI), occupation, physical activity, presence of thyroid disorders and other comorbidities, smoking and use of alcohol. Results When comparing the frozen shoulder group with the control and rotator cuff groups, there is a specific association between the presence of thyroid disorders and frozen shoulder. By calculating relative risk, it is possible to state that an individual with thyropathy has 2.69 more chance of developing frozen shoulder. Also, there was an association with gender, since women with frozen shoulder exceeded significantly the risk. Conclusions Thyroid disorders, especially hypothyroidism and the presence of benign thyroid nodules, are risk factors significantly associated with frozen shoulder, rising the chances to 2.69 times of developing frozen shoulder. This is the first study that uses, in addition to the control group, a second group with rotator cuff tears, so it was shown that there is a specific association of thyroid disorders and frozen shoulder, but not with shoulder disorders in general.

Resumo Objetivo Verificar a asssociação entre tireopatias e ombro congelado primário, comparando com grupo controle e com grupo de pacientes com lesão no manguito rotador. Métodos Foram avaliados 166 pacientes com diagnóstico de ombro congelado primário com tratamento em andamento ou já tratados. Este grupo foi comparado com 129 pacientes com diagnóstico de lesão de manguito rotador e com um terceiro grupo controle formado por 251 indivíduos sem acometimento dos ombros. Todos os participantes responderam questionário sobre as seguintes variáveis: idade, gênero, índice de massa corpórea (IMC), profissão, atividade física, presença de tireopatia e de outras comorbidades, hábito tabagista e etilismo. Resultados Quando comparamos o grupo de ombro congelado com os grupos controle e lesão de manguito rotador, percebemos que existe uma associação específica entre presença de doenças da tireoide (tireoidite, hipotireoidismo, hipertireoidismo, nódulos e câncer) e ombro congelado. Através do cálculo do risco relativo, é possível afirmar que um indivíduo com tireopatia tem probabilidade 2.69 maior de desenvolver ombro congelado. Também houve associação com gênero, já que as mulheres com ombro congelado elevam significativamente esse risco. Conclusão Os distúrbios da tireoide, especialmente o hipotireoidismo e a presença de nódulos tireoidianos benignos, são fatores de risco significativamente associados ao ombro congelado, aumentando as chances em 2,69 vezes de desenvolver a doença. Este é o primeiro estudo que utiliza, além do grupo controle, um segundo grupo com lesões do manguito rotador, de modo que foi demonstrada uma associação específica de distúrbios da tireoide e ombro congelado.

The roles of Tenascin C and Fibronectin 1 in adhesive capsulitis: a pilot gene expression study

OBJECTIVES: We evaluated mRNA expression levels of genes that encode TGF-β1; the TGF-β1 receptor; the collagen-modifying enzymes LOX, PLOD1, and PLOD2; and the extracellular matrix proteins COMP, FN1, TNC and TNXB in synovial/capsule specimens from patients with idiopathic adhesive capsulitis. Possible associations between the measured mRNA levels and clinical parameters were also investigated. METHODS: We obtained glenohumeral joint synovium/capsule specimens from 9 patients with idiopathic adhesive capsulitis who had not shown improvement in symptoms after 5 months of physiotherapy. Adhesive capsulitis was confirmed in all patients by magnetic resonance imaging. We also obtained specimens from 8 control patients who had underwent surgery for acute acromioclavicular joint dislocation and who had radiological indication of glenohumeral capsule alteration based on arthroscopic evaluation. mRNA expression in the synovium/capsule specimens was analyzed by quantitative reverse transcription PCR. The B2M and HPRT1 genes were used as references to normalize target gene expression in the shoulder tissue samples. RESULTS: The synovium/capsule samples from the patients with adhesive capsulitis had significantly higher TNC and FN1 expression than those from the controls. Additionally, symptom duration directly correlated with expression of TGFβ1 receptor I. CONCLUSION: Elevated levels of TNC and FN1 expression may be a marker of capsule injury. Upregulation of TGFβ1 receptor I seems to be dependent on symptom duration; therefore, TGFβ signaling may be involved in adhesive capsulitis. As such, TNC, FN1 and TGFβ1 receptor I may also play roles in adhesive capsulitis by contributing to capsule inflammation and fibrosis.

Profile of collagen gene expression in the glenohumeral capsule of patients with traumatic anterior instability of the shoulder / Perfil de expressão de genes do colágeno na cápsula glenoumeral de pacientes com instabilidade traumática anterior do ombro

Objective: To evaluate the expression of the genes COL1A1, COL1A2, COL3A1 and COL5A1 in the glenohumeral capsule of patients with traumatic anterior instability of the shoulder. Methods: Samples from the glenohumeral capsule of 18 patients with traumatic anterior instability of the shoulder were evaluated. Male patients with a positive grip test and a Bankart lesion seen on magnetic resonance imaging were included. All the patients had suffered more than one episode of shoulder dislocation. Samples were collected from the injured glenohumeral capsule (anteroinferior region) and from the macroscopically unaffected region (anterosuperior region) of each patient. The expression of collagen genes was evaluated using the polymerase chain reaction after reverse transcription with quantitative analysis (qRT-PCR). Results: The expression of COL1A1, COL1A2 and COL3A1 did not differ between the two regions of the shoulder capsule. However, it was observed that the expression of COL5A1 was significantly lower in the anteroinferior region than in the anterosuperior region (median ± interquartile range: 0.057 ±0.052 vs. 0.155 ±0.398; p = 0.028) of the glenohumeral capsule. Conclusion: The affected region of the glenohumeral capsule in patients with shoulder instability presented reduced expression of COL5A1...

Objetivo: Avaliar a expressão dos genes COL1A1, COL1A2, COL3A1 e COL5A1 na cápsula glenoumeral de pacientes com instabilidade anterior traumática do ombro. Métodos: Foram avaliadas amostras de cápsula glenoumeral de 18 pacientes com instabilidade anterior traumática do ombro. Foram incluídos pacientes masculinos, com teste de apreensão positivo e lesão de Bankart no exame de ressonância magnética. Todos os pacientes sofreram mais de um episódio de luxação do ombro. Foram coletadas amostras da cápsula glenoumeral lesionada (região anteroinferior) e da região macroscopicamente não afetada (região anterossuperior) de cada paciente. A expressão dos genes de colágeno foi avaliada por reação em cadeia da polimerase após transcrição reversa com análise quantitativa (qRT-PCR). Resultados: A expressão de COL1A1, COL1A2 e COL3A1 não diferiu entre as duas regiões da cápsula do ombro. No entanto, foi observado que a expressão de COL5A1 estava significantemente reduzida na região anteroinferior em relação à região anterossuperior (mediana ± intervalo interquartílico: 0,057 ± 0,052 vs 0,155 ± 0,398; p = 0,028) da cápsula glenoumeral. Conclusão: A região afetada da cápsula glenoumeral de pacientes com instabilidade do ombro apresentou uma expressão reduzida de COL5A1...

Low frequency of human papillomavirus detection in prostate tissue from individuals from Northern Brazil

The presence of human papillomavirus (HPV) was evaluated in 65 samples of prostate tumours and six samples of prostates with benign prostatic hyperplasia from individuals from Northern Brazil. We used a highly sensitive test, the Linear Array HPV Genotyping Test, to detect 37 high and low-risk HPV types. In this study, only 3 percent of tumour samples showed HPV infection. Our findings support the conclusion that, despite the high incidence of HPV infection in the geographic regions studied, HPV was not associated with a higher risk of prostate cancer. To our knowledge, this is the first study evaluating the frequency of HPV detection in prostatic tissue of individuals from Brazil.

Study of Methylation Pattern of de Novo DNA Methyltransferase Genes and its Correlation with DNA Methylation Pattern of RUNX3 in Individuals with Gastric Cancer from Northern Region of Brazil / Estudio del Estado de Metilación de Novo de Genes Metiltransferasas y su Correlación con el Patrón de Metilación de RUNX3 en Individuos con Cáncer Gástrico de la Región Norte del Brasil

Gastric cancer is the forth malignancy in frequency in the world. In the northern Brazil is the second neoplasia most frequent in males and the third most frequent in females. Genetic and epigenetic alterations are evolved on gastric carcinogenesis and DNA methylation is the epigenetic alteration better studied. We analyzed de novo DNA methyltransferases methylation pattern and its association with RUNX3 gene methylation pattern in Brazilian samples of intestinal-type and diffuse-type of gastric cancer. PCR methylation specific was used to evaluate DNA methylation pattern. Sixty-six samples were studied in this work. Only the gene RUNX3 presented altered methylation pattern, being methylated in 38.5% of gastric cancer intestinal-type samples and in 70% of gastric cancer diffuse-type samples and, by this reason, it should be evolved in the genesis of this neoplasia. There was a statistically significant difference among diffuse-type and intestinal-type samples (p=0.0418) and among normal and tumour tissues (p<0.0001) for RUNX3 gene but not to DNMT3A, DNMT3B e DNMT3 genes on CpG islands analyzed. Alteration of RUNX3 methylation pattern is not associated to de novo alteration of DNA methyltransferases methylation pattern on studied regionsTherefore, it becomes necessary a better comprehension of this phenomenon on gastric carcinogenesis.

El cáncer gástrico es la cuarta patología más frecuente en el mundo. En el norte del Brasil, es la segunda neoplasia más frecuente en hombres y la tercera en mujeres. Alteraciones genéticas y epigenéticas relacionadas con la carcinogénesis gástrica y la metilación del DNA son las alteraciones epigenéticas mejor estudiadas. En este trabajo, analizamos el estado de novo de metilación de genes DNA metiltransferases y su asociación con el estado de metilación del gen RUNX3 en muestras de individuos brasileños con cáncer gástrico de los tipos intestinal y difuso. Fue usada la Reacción en Cadena de la Polimerasa (PCR), metilación específica, para analizar el estado de metilación del DNA. Fueron estudiados 66 tejidos tumorales. Solamente el gen RUNX3 presentó un estado de metilación alterado, estuvo metilado en 38,5% de las muestras de cáncer gástrico tipo intestinal y en 70% de muestras de cáncer gástrico tipo difuso, lo que sugiere que estaría relacionado con la génesis de esta neoplasia. Hubo una diferencia estadística significativa entre muestras de los tipos difuso e intestinal (p=0.0418) y entre tejidos normal y tumoral (p<0.0001)parael gen RUNX3. Esta asociación no fue encontrada para los genes DNMT3A, DNMT3B y DNMT3 en las islas CpG analizadas. Alteraciones del estado de metilación de RUNX3 no están asociadas con alteraciones de novo de genes DNA metiltransferases. De esta forma se hace necesaria una mejor comprensión de este fenómeno en la carcinogénesis gástrica.

Chromosome instability in carcinomas / Inestabilidad Cromosómica en Carcinomas

Los modelos actuales de carcinogénesis consideran la ocurrencia de mutaciones crecientes y mecanismos selectivos, favoreciendo la sobrevivencia y proliferación celular aumentada. Mecanismos epigenéticos también participan en la oncogénesis, destacando la metilación del DNA. La característica de las células tumorales que permite el aumento de la ocurrencia de mutaciones es denominada inestabilidad genética, donde son identificados dos mecanismos: inestabilidad de microsatélites, caracterizada por alteraciones nucleotídicas con errores en los sistemas de reparación del DNA; inestabilidad cromosómica, en la cual las aberraciones suceden en grandes segmentos cromosómicos. Los carcinomas son caracterizados por alteraciones citogenéticas complejas y grandes mezclas génicas. Alteraciones teloméricas, quiebres de DNA reparados inadecuadamente y deficiencia en los sistemas de chequeo del huso mitótico, son eventos capaces de generar inestabilidad cromosómica y aneuploidía que caracterizan estas neoplasias más agresivas. El conocimiento de los mecanismos que provocan la inestabilidad cromosómica puede permitir la utilización clínica de información en el desarrollo de estrategias terapéuticas más adecuadas, dirigidas a puntos específicos involucrados en procesos de malignización.

In the current carcinogenesis models, the occurrence of increasing mutations and selection mechanisms favoring cell survival and higher proliferation rates are taken into account. Epigenetic mechanisms, among which DNA methylation stands out, also take part in oncogenesis. The characteristic of tumor cells that allows the increase of mutations is named genetic instability, encompassing two mechanisms: microsatellite instability, characterized by nucleotide alterations with errors in the DNA repair systems; and chromosomal instability, represented by aberrations occurring in large chromosome segments. Carcinomas are characterized by complex cytogenetic alterations and large gene amalgamations. Telomeric alterations, inadequately repaired DNA breaks, and deficiencies in the mitotic spindle checking systems are events capable of generating the chromosomal instability and aneuploidy which characterize more aggressive neoplasias. A better understanding of the chromosomal instability mechanisms can show the way towards a clinical utilization of such information, like developing more adequate therapeutic strategies, targeted at specific sites involved in the malignization process.