RESUMO
Rotator cuff tears (RCT) is a multifactorial disease with genetic factors contributing for the disease etiology. We hypothesized that genetic variants in genes involved in extracellular matrix (ECM) homeostasis may alter susceptibility to RCT. We evaluated 20 polymorphisms of genes involved in ECM homeostasis in 211 cases of full-thickness tears of the supraspinatus (Nfemales = 130; Nmales = 81) and 567 age-matched controls (Nfemales = 317; Nmales = 250). Multivariate logistic regressions were carried out with age, gender, genetic ancestry (based on the analysis of 61 biallelic short insertion/deletion polymorphisms), and common co-morbidities (diabetes, dyslipidemia, and smoking habits) as covariates. We observed that carriers of the rare allele of both studied variants of TGFB1, as well as their G/A (rs1800470/rs1800469) haplotype, were less susceptible to RCT (p < 0.05). In contrast, carriers of the G allele of MMP9 rs17576 (p = 0.014) or G/G haplotype (rs17576/rs17577; p < 0.001) had an increased risk for tendon tears. The presence of the T allele of MMP2 rs2285053 (p = 0.033), the T allele of MMP3 rs679620 (p = 0.024), and the TT-genotype of TIMP2 rs2277698 (p = 0.01) was associated with susceptibility to tears, especially in females. In males, the A allele of COL5A1 rs3196378 (p = 0.032) and the G allele of TGFBR1 rs1590 (p = 0.039) were independent risk factors for RCT. The C/T COL5A1 (rs3196378/rs11103544) haplotype was associated with a reduced risk of tears in males (p = 0.03). In conclusion, we identified the genetic variants associated with RCT susceptibility, thereby reinforcing the role of genes involved in the structure and homeostasis of the ECM of tendons in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:192-201, 2020.
Assuntos
Matriz Extracelular/metabolismo , Predisposição Genética para Doença , Homeostase , Polimorfismo de Nucleotídeo Único , Lesões do Manguito Rotador/genética , Adulto , Idoso , Estudos de Casos e Controles , Colágeno Tipo V/genética , Feminino , Haplótipos , Humanos , Modelos Logísticos , Masculino , Metaloproteinase 2 da Matriz/genética , Pessoa de Meia-Idade , Caracteres Sexuais , Fator de Crescimento Transformador beta1/genéticaRESUMO
Frozen shoulder is a condition of loss of active and passive motion as result of inflammatory contracture and fibrosis of the joint capsule. We hypothesize that genetic variants in genes involved in these processes such as genes that play a role in extracellular matrix homeostasis (collagens, glycoproteins, genes involved in TGFß signaling, and metalloproteinases and its inhibitors) may contribute to the susceptibility to frozen shoulder. We evaluated eighteen SNPs of genes involved in extracellular matrix homeostasis in 186 cases (Nfemales = 114; Nmales = 72) of frozen shoulder and 600 age-matched controls (Nfemales = 308; Nmales = 292). Multivariate logistic regressions were carried out with age, gender, genetic ancestry, and common comorbidities as covariates. Carriers of the C allele of MMP13 rs2252070 and G/G MMP9 (rs17576 A>G/rs17577 G>A) haplotype may have an increased risk of frozen shoulder (p = 0.002, OR = 1.64, 95%CI = 1.20-2.26, and p = 0.046, OR = 1.40, 95%CI = 1.01-1.95, respectively), especially in females (p = 0.005, OR = 1.91, 95%CI = 1.22-2.99, and p = 0.046, OR = 1.59, 95%CI = 1.01-2.51, respectively). In females, the G allele of MMP9 rs17576 tended to contribute to the susceptibility to the studied disease (p = 0.05, OR = 1.51, 95%CI = 0.97-2.33). In contrast, the presence of the C allele of TGFB1 rs1800470 seems to be associated with a reduced risk (p = 0.04, OR = 0.47, 95%CI = 0.23-0.96) while the GG-genotype of TGFBR1 rs1590 was associated with increased risk (p = 0.027, OR = 4.11, 95%CI = 1.17-14.38) to frozen shoulder development in males. Thus, we identified genetic variants that were independent risk factors that can aid in the risk assessment of frozen shoulder reinforcing the involvement of MMP and TGFß signaling in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
Assuntos
Bursite/genética , Matriz Extracelular/genética , Metaloproteinases da Matriz/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Objective: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer’s disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results: Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Genótipo , Apolipoproteínas E/genética , Modelos Lineares , Transtornos Cerebrovasculares/fisiopatologia , Estudos Transversais , Idade de Início , Dosagem de Genes , Alelos , Proteínas de Transferência de Ésteres de Colesterol/genética , Estudos de Associação Genética , Doença de Alzheimer/fisiopatologia , Transtornos de Início Tardio , Receptores X do Fígado/genética , Lipoproteínas LDL/genética , Testes NeuropsicológicosRESUMO
OBJECTIVE:: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. METHODS:: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. RESULTS:: Considering 201 patients, only APOE-É4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. CONCLUSION:: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/metabolismo , Genótipo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/genética , Transtornos Cerebrovasculares/fisiopatologia , Proteínas de Transferência de Ésteres de Colesterol/genética , Estudos Transversais , Feminino , Dosagem de Genes , Estudos de Associação Genética , Humanos , Transtornos de Início Tardio , Modelos Lineares , Lipoproteínas LDL/genética , Receptores X do Fígado/genética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Peptidil Dipeptidase A/genética , Escalas de Graduação Psiquiátrica , Valores de Referência , Fatores de RiscoRESUMO
Little is known on how risk factors for Alzheimer disease (AD) dementia affect disease progression, much less for populations with low mean schooling, whereas the transcription of APOE may be regulated by nongenetic factors. In this 44-month cohort study, 214 consecutive outpatients with late-onset AD were assessed for rates of cognitive and functional decline by way of Clinical Dementia Rating and Mini-Mental State Examination (MMSE) scores, keeping blinded assessment of APOE haplotypes. Subjects were evaluated for sex, schooling, age of dementia onset, and cerebrovascular risk factors (including Framingham risk scores). Of the 214 patients, there were 146 (68.2%) women and 113 (52.8%) APOE4+ carriers. The mean age of AD onset was 73.4±6.5 years-old, negatively correlated with time to Clinical Dementia Rating >1.0 (ß=-0.132; ρ<0.001), MMSE=20 (ß=-0.105; ρ<0.001), and MMSE=15 (ß=-0.124; ρ=0.003), more significantly for women and APOE4+ carriers. Mean schooling was 4.18±3.7 years, correlated with time to MMSE=20 and MMSE=15 for women and APOE4+ carriers. Body mass index was correlated with time to MMSE=20 only for men (ρ=0.006). The 10-year coronary heart disease risk was correlated with time to MMSE=20 only for APOE4+ carriers (ρ=0.015). These outcomes suggest interactions among genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes over mechanisms of neurodegeneration.
Assuntos
Atividades Cotidianas/psicologia , Doença de Alzheimer/psicologia , Disfunção Cognitiva/fisiopatologia , Progressão da Doença , Fatores Etários , Idade de Início , Idoso , Envelhecimento , Doença de Alzheimer/diagnóstico por imagem , Apolipoproteínas E/genética , Brasil , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Fatores de RiscoRESUMO
INTRODUCTION: Neuropsychiatric and epidemiological patterns may compensate for insufficient specificity of diagnostic criteria of Lewy body dementia (LBD) syndromes in differential analysis with Alzheimer disease (AD) dementia. We aimed to compare and distinguish demographic and neuropsychiatric features between LBD and APOE-ε3/ε3 late-onset AD. METHODS: A total of 39 consecutive patients with Parkinson disease dementia or dementia with Lewy bodies were matched with 39 APOE-ε3/ε3 patients with late-onset AD according to sex and Mini-Mental State Examination scores, and evaluated for education, age at disease onset, lifetime sanitary conditions, anthropometric measures, alcohol use, smoking, history of head trauma or bacterial infections, family history of neurodegenerative diseases, caregiver burden, functional independence, cognitive decline, neuropsychiatric symptoms, and pharmacological treatment. RESULTS: Family history of parkinsonism and worse motor performance were more prevalent in Parkinson disease dementia, also impacting sleep satisfaction and physical self-maintenance. Patients with AD had higher systolic blood pressure, were more independent, and had better performance in visuospatial tasks and calculations, whereas patients with LBD were more oriented and previously lived longer in rural areas without sanitation. Among neuropsychiatric symptoms, hallucinations, apathy, dysphoria, anxiety, and aberrant motor behavior were the most significant for discrimination amidst dementia diagnoses. CONCLUSIONS: Functional performance, visuospatial skills, and behavioral symptoms are helpful for differential diagnoses between LBD and AD. Cerebrovascular risk might be more important for AD pathogenesis, whereas environmental factors might impact development of LBD.