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Since the arrest of the Golden State Killer in the US in April 2018, forensic geneticists have been increasingly interested in the investigative genetic genealogy (IGG) method. While this method has already been in practical use as a powerful tool for criminal investigation, we have yet to know well the limitations and potential risks. In this current study, we performed an evaluation study focusing on degraded DNA using the Affymetrix Genome-Wide Human SNP Array 6.0 platform (Thermo Fisher Scientific). We revealed one of the potential problems that occur during SNP genotype determination using a microarray-based platform. Our analysis results indicated that the SNP profiles derived from degraded DNA contained many false heterozygous SNPs. In addition, it was confirmed that the total amount of probe signal intensity on microarray chips derived from degraded DNA decreased significantly. Because the conventional analysis algorithm performs normalization during genotype determination, we concluded that noise signals could be genotype-called. To address this issue, we proposed a novel microarray data analysis method without normalization (nMAP). Although the nMAP algorithm resulted in a low call rate, it substantially improved genotyping accuracy. Finally, we confirmed the usefulness of the nMAP algorithm for kinship inferences. These findings and the nMAP algorithm will make a contribution to the advance of the IGG method.
Assuntos
DNA , Imunoglobulina G , Humanos , Genótipo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , DNA/genética , Imunoglobulina G/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The molecular pathophysiology underlying lumbar spondylosis development remains unclear. To identify genetic factors associated with lumbar spondylosis, we conducted a genome-wide association study using 83 severe lumbar spondylosis cases and 182 healthy controls and identified 65 candidate disease-associated single nucleotide polymorphisms (SNPs). Replication analysis in 510 case and 911 control subjects from five independent Japanese cohorts identified rs2054564, located in intron 7 of ADAMTS17, as a disease-associated SNP with a genome-wide significance threshold (P = 1.17 × 10-11, odds ratio = 1.92). This association was significant even after adjustment of age, sex, and body mass index (P = 7.52 × 10-11). A replication study in a Korean cohort, including 123 case and 319 control subjects, also verified the significant association of this SNP with severe lumbar spondylosis. Immunohistochemistry revealed that fibrillin-1 (FBN1) and ADAMTS17 were co-expressed in the annulus fibrosus of intervertebral discs (IVDs). ADAMTS17 overexpression in MG63 cells promoted extracellular microfibrils biogenesis, suggesting the potential role of ADAMTS17 in IVD function through interaction with fibrillin fibers. Finally, we provided evidence of FBN1 involvement in IVD function by showing that lumbar IVDs in patients with Marfan syndrome, caused by heterozygous FBN1 gene mutation, were significantly more degenerated. We identified a common SNP variant, located in ADAMTS17, associated with susceptibility to lumbar spondylosis and demonstrated the potential role of the ADAMTS17-fibrillin network in IVDs in lumbar spondylosis development.
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Disco Intervertebral , Osteoartrite da Coluna Vertebral , Espondilose , Humanos , Fibrilina-1 , Fibrilinas/análise , Estudo de Associação Genômica Ampla , Disco Intervertebral/química , Microfibrilas , Espondilose/genéticaRESUMO
Instead of traditional short tandem repeat (STR) profiling, the genetic genealogy method, which uses hundreds of thousands of single nucleotide polymorphisms (SNPs) spread across genome-wide, has emerged as a powerful kinship determination tool and recently attracted great attention in forensic genetics. In this study, we explored the tolerance and viability of kinship discrimination based on a high-density SNP profile for forensic DNA, especially focusing on low-quantity DNA. Using the Affymetrix Genome-Wide Human SNP Array 6.0 platform (Thermo Fisher Scientific), the influence of low-quantity DNA on SNP genotype determination was evaluated. The low-quantity DNA samples failed once every few samples, the generated SNP profile had low data quality. Our investigation revealed that the SNP profile with low data quality contained many genotyping errors in which the SNP genotype changed from homozygote to heterozygote. The kinship discrimination analysis using KING software was directly influenced by these genotyping errors, which was confirmed that some unrelated pairs were mis-specified as 4th-degree relatives. We confirmed that the false heterozygous SNPs resulted in an inflation of kinship coefficient and a decrease of non-shared allele between a tested pair. To eliminate the influence of these genotyping errors and acquire an accurate kinship discrimination result, we developed a novel method to select only the robust SNPs, which stably give the genotype determination with high accuracy even in SNP profiles with low data quality. The application of our novel method led to the improved results of kinship discrimination up to the same level as in the SNP profile with high data quality. In addition, this study demonstrated the advantage of kinship analysis using a high-density SNP profile in the forensic field. It is well known that likelihood ratio calculation based on autosomal STR profile, which is the most commonly applied approach, has difficulty in gaining true kinship analysis results, especially when the relationship between the tested two individuals is more biologically distant. We showed the kinship discrimination analysis with a high-density SNP profile is more suitable for the case without close relatives, using the real case data. Although further study with larger samples will be necessary, this study indicated that practical forensic use of kinship determination with a high-density SNP profile would bring benefits to the forensic field.
Assuntos
Impressões Digitais de DNA , Genética Forense , Humanos , Genética Forense/métodos , Genótipo , Polimorfismo de Nucleotídeo Único , DNA/genética , Repetições de MicrossatélitesRESUMO
The associations of single nucleotide polymorphisms (SNPs) in PLA2R1 and HLA-DQA1, as well as HLA-DRB1*15:01-DQB1*06:02 haplotype with idiopathic membranous nephropathy (IMN) is well known. However, the primary associations of these loci still need to be determined. We used Japanese-specific SNP genotyping array and imputation using 2,048 sequenced Japanese samples to fine-map PLA2R1 region in 98 patients and 413 controls. The most significant SNPs were replicated in a separate sample set of 130 patients and 288 controls. A two-SNP haplotype of intronic and missense SNPs showed the strongest association. The intronic SNP is strongly associated with PLA2R1 expression in the Genotype-Tissue Expression (GTEx) database, and the missense SNP is predicted to alter peptide binding with HLA-DRB1*15:01 by the Immune Epitope Database (IEDB). In HLA region, we performed relative predispositional effect (RPE) tests and identified additional risk alleles in both HLA-DRB1 and HLA-DQB1. We collapsed the risk alleles in each of HLA-DRB1 and HLA-DQB1 into single risk alleles. Reciprocal conditioning of these collapsed risk alleles showed more residual significance for HLA-DRB1 collapsed risk than HLA-DQB1 collapsed risk. These results indicate that changes in the expression levels of structurally different PLA2R protein confer risk for IMN in the presence of risk HLA-DRB1 alleles.
Assuntos
Glomerulonefrite Membranosa/genética , Cadeias HLA-DRB1/genética , Polimorfismo de Nucleotídeo Único , Receptores da Fosfolipase A2/genética , Haplótipos , Humanos , Receptores da Fosfolipase A2/metabolismoRESUMO
Although recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. We genotyped across the PLA2R1 gene and the HLA region, using 183 IMN patients and 811 healthy controls. Five SNPs around the PLA2R1 gene were significantly associated with IMN. In addition to the two SNPs previously reported to be strongly associated with IMN, rs3749119 and rs35771982 (OR 3.02 and 2.93, P = 3.24E-14 and 4.64E-14, respectively), two novel intronic SNPs (rs2715928 and rs16844715) were also identified as IMN-associated SNPs (OR = 2.30 and 2.51, P = 3.15E-10 and 5.66E-13, respectively). In the HLA gene analysis, DRB1*1501 and DQB1*0602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). The interaction was strongest between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the intronic SNP rs2715928 (OR = 17.53, P = 4.26E-26). Furthermore, positive interaction was also observed between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the missense SNP rs35771982 (OR = 15.91, P = 2.76E-29), which is in strong linkage disequilibrium with 5'UTR SNP rs3749119, and intronic SNP rs16844715 (OR = 15.91, P = 2.30E-26) for IMN. Neither HLA-DRB1*15:01 nor HLA-DQB1*06:02 was associated with steroid responsiveness, overall survival and renal survival during the observation period of mean 11 years though limited number of analysis.
Assuntos
Predisposição Genética para Doença , Glomerulonefrite Membranosa/genética , Antígenos HLA/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Receptores da Fosfolipase A2/genética , Idoso , Povo Asiático , Intervalo Livre de Doença , Feminino , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/mortalidade , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
[This corrects the article DOI: 10.1038/hgv.2015.24.][This corrects the article DOI: 10.1038/hgv.2015.24.].
RESUMO
Tuberculosis (TB) is a complex disease, and both genetic and environmental factors contribute to disease progression. A previous genome-wide linkage study in Thailand determined that chromosome 20p13-12.3 may contain risk factors for young-onset disease. The present study aimed to identify novel susceptibility genes for young-onset TB within a 1-Mbp target region adjacent to the top-ranking risk marker in Chr.20p13-12.3. We performed next-generation sequencing (NGS) of the region in 13 young patients from multi-case families in Thailand. We then selected the functionally interesting single-nucleotide polymorphisms as candidates for subsequent analyses. The detected candidates rs13830 and rs1127354 in ITPA showed an association with young (<45 years old) TB patients. However, there was no association in old (⩾45 years old) patients. These findings confirm that stratifying patients based on age of TB onset can be important for identifying genetic risk factors for TB susceptibility. In addition, in silico expression quantitative trait loci analyses indicated that ITPA expression was associated with rs13830 genotype. This is the first study to use NGS resequencing to gain insight into host genetic factors associated with TB and to report a significant association for ITPA with host susceptibility in young-onset TB. The study also demonstrated the effectiveness of NGS in identifying susceptibility genes in common diseases.
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The toxicity of arsenic differs markedly between individuals and populations, which might be related to the metabolism (methylation) of inorganic arsenic (As), as well as the selenium (Se) nutritional status. Urinary excretion of As (u-As) and Se (u-Se) was examined in an adult population (n=128) living in an As-contaminated area in Bangladesh. Although there was a significant negative correlation between u-Se and u-As (median 137; range 49-927 µg/g creatinine), closer examination revealed a non-monotonous relationship between them. A quadratic curve with an axis of As at 155 µg/g Cre gave a better fit, and u-As and u-Se were positively or negatively correlated depending on whether the As concentration was lower or higher than 155 µg As/g Cre, respectively. Likewise, the relationships between the As methylation pattern and glutathione-S-transferase (GST) polymorphism, body mass index (BMI), and u-Se differed depending on the u-As range; i.e., higher or lower than 155 µg/g Cre. Although we did not determine the causal mechanism for these observations, the non-monotonic relationship between As exposure and the variables examined suggested the existence of a threshold at which the handling of As by human body is qualitatively changed. The possible importance of Se nutrition for As toxicity is also discussed.
Assuntos
Arsênio/urina , Selênio/urina , Adulto , Bangladesh , Índice de Massa Corporal , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Masculino , Metilação , Pessoa de Meia-IdadeRESUMO
The oxytocin receptor (OXTR) gene has been implicated as a risk gene for autism spectrum disorder (ASD)-a neurodevelopmental disorder with essential features of impairments in social communication and reciprocal interaction. The genetic associations between common variations in OXTR and ASD have been reported in multiple ethnic populations. However, little is known about the distribution of rare variations within OXTR in ASD patients. In this study, we resequenced the full length of OXTR in 105 ASD individuals using an approach that combined the power of next-generation sequencing technology, long-range PCR and DNA pooling. We demonstrated that rare variants with minor allele frequency as low as 0.05% could be reliably detected by our method. We identified 28 novel variants including potential functional variants in the intron region and one rare missense variant (R150S). We subsequently performed Sanger sequencing and validated five novel variants located in previously suggested candidate regions in ASD individuals. Further sequencing of 312 healthy subjects showed that the burden of rare variants is significantly higher in ASDs compared with healthy individuals. Our results support that the rare variation in OXTR gene might be involved in ASD.
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Although intraocular pressure (IOP) is the most definitive cause of glaucoma, a subtype of open angle glaucoma (OAG) termed normal tension glaucoma (NTG), which occurs in spite of normal IOP, accounts for a large part of glaucoma cases, especially in Japan. To find common genetic variants contributing to NTG in Japanese patients, we conducted a genome-wide association study (GWAS). We performed the first screening for 531,009 autosomal SNPs with a discovery cohort of 286 cases and 557 controls, and then a second screening for the top 30 suggestive loci in an independent cohort of 183 cases and 514 controls. Our findings identified a significantly associated SNP; rs523096 [combined p-valueâ=â7.40× 10(-8), odds ratio (OR)=â2.00 with 95% confidence interval (CI) 1.55-2.58] located 10 kbp upstream of CDKN2B on chromosome 9p21. Moreover, analysis of another independent case-control set successfully replicated the results of the screening studies (combined values of all 3 stages pâ=â4.96 × 10(-11), OR=â2.13 with 95% CI 1.69-2.68). The SNPs near rs523096 were recently reported to be associated with OAG associated with elevated IOP in primary open-angle glaucoma (POAG), the predominant subtype of glaucoma in Caucasian populations. Our results revealed that the 9p21 locus is also associated with NTG in Japanese. In addition, we identified SNPs more strongly associated with NTG.
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Cromossomos Humanos Par 9 , Glaucoma de Baixa Tensão/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Japão , Desequilíbrio de Ligação , Pessoa de Meia-IdadeRESUMO
To elucidate the molecular mechanism underlying the endochondral ossification process during the skeletal growth and osteoarthritis (OA) development, we examined the signal network around CCAAT/enhancer-binding protein-ß (C/EBPß, encoded by CEBPB), a potent regulator of this process. Computational predictions and a C/EBP motif-reporter assay identified RUNX2 as the most potent transcriptional partner of C/EBPß in chondrocytes. C/EBPß and RUNX2 were induced and co-localized in highly differentiated chondrocytes during the skeletal growth and OA development of mice and humans. The compound knockout of Cebpb and Runx2 in mice caused growth retardation and resistance to OA with decreases in cartilage degradation and matrix metalloproteinase-13 (Mmp-13) expression. C/EBPß and RUNX2 cooperatively enhanced promoter activity of MMP13 through specific binding to a C/EBP-binding motif and an osteoblast-specific cis-acting element 2 motif as a protein complex. Human genetic studies failed to show the association of human CEBPB gene polymorphisms with knee OA, nor was there a genetic variation around the identified responsive region in the human MMP13 promoter. However, hypoxia-inducible factor-2α (HIF-2α), a functional and genetic regulator of knee OA through promoting endochondral ossification, was identified as a potent and functional inducer of C/EBPß expression in chondrocytes by the CEBPB promoter assay. Hence, C/EBPß and RUNX2, with MMP-13 as the target and HIF-2α as the inducer, control cartilage degradation. This molecular network in chondrocytes may represent a therapeutic target for OA.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Cartilagem/metabolismo , Condrócitos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Desenvolvimento Ósseo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Humanos , Metaloproteinase 13 da Matriz/genética , Camundongos , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite do Joelho/genética , Regiões Promotoras Genéticas , Transcrição Gênica , Ativação TranscricionalRESUMO
Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P(rec)) = 6.0 × 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.
Assuntos
Glipicanas/genética , Síndrome Nefrótica/genética , Adulto , Idoso , Animais , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA/genética , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Glipicanas/antagonistas & inibidores , Glipicanas/deficiência , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Genéticos , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Podócitos/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genéticaRESUMO
OBJECTIVES: Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. METHODS: A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. RESULTS: With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10â»9), thereby confirming its role as a susceptibility locus for OA. CONCLUSION: The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, ß), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
Assuntos
Cromossomos Humanos Par 7/genética , Predisposição Genética para Doença , Osteoartrite do Joelho/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Genetic studies of pulmonary tuberculosis (PTB), including those of human leukocyte antigen (HLA) genes, have been reported in several populations. Some studies also have reported these genes to have a stronger role in severe tuberculosis. We investigated HLA class I and II alleles and haplotypes to ascertain their role in susceptibility and resistance to new and recurrent PTB in 257 PTB patients (216 new and 41 recurrent PTB patients) and 236 healthy controls in Western Javanese (Indonesia). HLA-B*4006 was associated with new PTB (p = 0.044, p(adj) = ns), whereas HLA-B*1802, HLA-B*4001 and HLA-DRB1*1101 were associated with recurrent PTB (p = 0.013, p(adj) = 0.016; p = 0.015, p(adj) = 0.028; and p = 0.008, p(adj) = 0.027 for new PTB vs recurrent PTB, respectively). Except for HLA-B*4006, those associations remained significant after adjustment for age and gender by logistic regression analysis, although they disappeared after correction for multiple testing. Haplotype HLA-B*1802-DRB1*1202 was associated with susceptibility to recurrent PTB (p = 0.014, odds ratio = 3.8, 95% confidence interval = 1.18-12.27). In contrast, HLA-DRB1*1202 in the absence of HLA-B*1802 showed a significant association with resistance to recurrent PTB (p = 8.2 x 10(-4), odds ratio = 0.32, 95% confidence interval = 0.16-0.64), suggesting that stronger susceptibility effect of HLA-B*1802 masked the protective effect of HLA-DRB1*1202. Further studies using larger number of patients with recurrent PTB will be needed to confirm our findings.
Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Tuberculose Pulmonar/genética , Adulto , Feminino , Frequência do Gene/genética , Cadeias HLA-DRB1 , Humanos , Indonésia , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto JovemRESUMO
Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Desenvolvimento Ósseo/genética , Condrócitos/fisiologia , Osteoartrite/genética , Transativadores/genética , Transcrição Gênica/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Desenvolvimento Ósseo/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Colágeno Tipo X/genética , Colágeno Tipo X/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Camundongos Mutantes , Pessoa de Meia-Idade , Osteoartrite/fisiopatologia , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/fisiopatologia , Osteogênese/genética , Osteogênese/fisiologia , Transativadores/fisiologia , Transcrição Gênica/fisiologiaRESUMO
Musculoskeletal diseases, especially osteoarthritis (OA) and osteoporosis (OP), impair activities of daily life (ADL) and quality of life (QOL) in the elderly. Although preventive strategies for these diseases are urgently required in an aging society, epidemiological data on these diseases are scant. To clarify the prevalence of knee osteoarthritis (KOA), lumbar spondylosis (LS), and osteoporosis (OP) in Japan, and estimate the number of people with these diseases, we started a large-scale population-based cohort study entitled research on osteoarthritis/osteoporosis against disability (ROAD) in 2005. This study involved the collection of clinical information from three cohorts composed of participants located in urban, mountainous, and coastal areas. KOA and LS were radiographically defined as a grade of > or =2 by the Kellgren-Lawrence scale; OP was defined by the criteria of the Japanese Society for Bone and Mineral Research. The 3,040 participants in total were divided into six groups based on their age: < or =39, 40-49, 50-59, 60-69, 70-79, and > or =80 years. The prevalence of KOA in the age groups < or =39, 40-49, 50-59, 60-69, 70-79, and > or =80 years 0, 9.1, 24.3, 35.2, 48.2, and 51.6%, respectively, in men, and the prevalence in women of the same age groups was 3.2, 11.4, 30.3, 57.1, 71.9, and 80.7%, respectively. With respect to the age groups, the prevalence of LS was 14.3, 45.5, 72.9, 74.6, 85.3, and 90.1% in men, and 9.7, 28.6, 41.7, 55.4, 75.1, and 78.2% in women, respectively. Data of the prevalence of OP at the lumbar spine and femoral neck were also obtained. The estimated number of patients with KOA, LS, and L2-L4 and femoral neck OP in Japan was approximately 25, 38, 6.4, and 11 million, respectively. In summary, we estimated the prevalence of OA and OP, and the number of people affected with these diseases in Japan. The ROAD study will elucidate epidemiological evidence concerning determinants of bone and joint disease.
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Povo Asiático/estatística & dados numéricos , Pessoas com Deficiência/estatística & dados numéricos , Vértebras Lombares/patologia , Osteoartrite do Joelho/epidemiologia , Osteoporose/epidemiologia , Caracteres Sexuais , Espondilose/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/fisiologia , Estudos de Coortes , Feminino , Geografia , Humanos , Vértebras Lombares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/fisiopatologia , Osteoporose/fisiopatologia , Prevalência , Espondilose/fisiopatologiaRESUMO
OBJECTIVE: To investigate the risk of radiographic knee osteoarthritis (OA) and lumbar spondylosis associated with occupational activity in elderly Japanese subjects using the large-scale population-based cohort of the Research on Osteoarthritis Against Disability (ROAD) study. METHODS: From the baseline survey of the ROAD study, 1,471 participants age > or =50 years (531 men and 940 women) living in mountainous and seacoast communities were analyzed. Information collected included a lifetime occupational history and details of specific work place physical activities. Radiographic severity at the knee and lumbar spine was determined by the Kellgren/Lawrence (K/L) grading system. RESULTS: The prevalence of K/L grade > or =2 knee OA and lumbar spondylosis among agricultural, forestry, and fishery workers was significantly higher than among clerical workers and technical experts in the overall population. For occupational activities, sitting on a chair had a significant inverse association with K/L grade > or =2 knee OA and lumbar spondylosis. Standing, walking, climbing, and heavy lifting were associated with K/L grade > or =2 knee OA, but were not associated with K/L grade > or =2 lumbar spondylosis. Kneeling and squatting were associated with K/L grade > or =3 knee OA. CONCLUSION: This cross-sectional study using a population-based cohort suggests that sitting on a chair is a significant protective factor against both radiographic knee OA and lumbar spondylosis in Japanese subjects. An occupational activity that includes heavy lifting appears to have a greater effect on knee OA than on lumbar spondylosis.
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Doenças Profissionais/epidemiologia , Osteoartrite do Joelho/epidemiologia , Espondilite/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Avaliação da Deficiência , Emprego , Feminino , Humanos , Japão/epidemiologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/diagnóstico por imagem , Doenças Profissionais/fisiopatologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/fisiopatologia , Prevalência , Radiografia , Fatores de Risco , Espondilite/diagnóstico por imagem , Espondilite/fisiopatologia , Adulto JovemRESUMO
Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.
Assuntos
Regiões 5' não Traduzidas , Proteínas Morfogenéticas Ósseas/genética , Predisposição Genética para Doença , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Proteínas Morfogenéticas Ósseas/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Regulação da Expressão Gênica , Frequência do Gene , Fator 5 de Diferenciação de Crescimento , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único/fisiologia , TransfecçãoRESUMO
Genetic factors have been implicated in osteoarthritis (OA), particularly in OA of the hip joint (hip OA). Several instances of familial hip OA that show distinctive modes of inheritance but that differ from chondrodysplasia have been reported. Here, we report the characterization of a large Japanese family with an inherited disease of the hip that is indistinguishable from common hip OA, as evidenced by clinical symptoms and radiographs of the joint. This family contained eight patients in 4 generations. Affected individuals develop pain in the hip joint during adolescence, and the disease progresses to severe crippling before age 60 years. Patients generally are in good health, height is not reduced, and there is no extraskeletal involvement suggestive of chondrodysplasia. The skeletal change is bilateral acetabular dysplasia followed by OA, which occurs after age approximately 40 years and is indistinguishable from idiopathic nonfamilial dysplastic hip OA. This trait shows autosomal dominant inheritance, with a considerably consistent phenotype. Genomewide screening revealed linkage at chromosome 13q22, and haplotype analysis narrowed the locus to a 6.0-cM interval between markers D13S1296 and D13S162, with a maximal multipoint LOD score of 3.57. The family described here represents a novel genetic entity as a monogenic form of hip OA. Its further characterization can aid in elucidating the etiology and pathogenesis of a common idiopathic form of OA.