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Estrogen receptor-alpha gene haplotype is associated with primary knee osteoarthritis in Korean population.

ABSTRACT: Estrogen and estrogen receptors (ERs) are known to play important roles in the pathophysiology of osteoarthritis (OA). To investigate ER-alpha gene polymorphisms for its associations with primary knee OA, we conducted a case-control association study in patients with primary knee OA (n = 151) and healthy individuals (n = 397) in the Korean population. Haplotyping analysis was used to determine the relationship between three polymorphisms in the ER-alpha gene (intron 1 T/C, intron 1 A/G and exon 8 G/A) and primary knee OA. Genotypes of the ER-alpha gene polymorphism were determined by PCR followed by restriction enzyme digestion (PvuII for intron 1 T/C, XbaI for intron 1 A/G, and BtgI for exon 8 G/A polymorphism). There was no significant difference between primary knee OA patients and healthy control individuals in the distribution of any of the genotypes evaluated. However, we found that the allele frequency for the exon 8 G/A BtgI polymorphism (codon 594) was significantly different between primary knee OA patients and control individuals (odds ratio = 1.38, 95% confidence interval = 1.01-1.88; P = 0.044). In haplotype frequency estimation analysis, there was a significant difference between primary knee OA patients and control individuals (degrees of freedom = 7, chi2 = 21.48; P = 0.003). Although the number OA patients studied is small, the present study shows that ER-alpha gene haplotype may be associated with primary knee OA, and genetic variations in the ER-alpha gene may be involved in OA.

SUBMITTER: Jin SY

PROVIDER: S-EPMC546279 | biostudies-literature | 2004

REPOSITORIES: biostudies-literature

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Estrogen receptor-alpha gene haplotype is associated with primary knee osteoarthritis in Korean population.

Jin Sheng-Yu SY Hong Seung-Jae SJ Yang Hyung In HI Park Sang-do SD Yoo Myung-Chul MC Lee Hee Jae HJ Hong Mee-Suk MS Park Hae-Jeong HJ Yoon Seo Hyun SH Kim Bum-Shik BS Yim Sung-Vin SV Park Hun-Kuk HK Chung Joo-Ho JH

Arthritis research & therapy 20040719 5

Estrogen and estrogen receptors (ERs) are known to play important roles in the pathophysiology of osteoarthritis (OA). To investigate ER-alpha gene polymorphisms for its associations with primary knee OA, we conducted a case-control association study in patients with primary knee OA (n = 151) and healthy individuals (n = 397) in the Korean population. Haplotyping analysis was used to determine the relationship between three polymorphisms in the ER-alpha gene (intron 1 T/C, intron 1 A/G and exon ...[more]

PMID: 15380041

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Project description:IntroductionMillions of patients are currently suffering from pain and dysfunction caused by osteoarthritis (OA), and billions of dollars have been invested into treatment. Because there is no effective treatment that can reverse the progression of knee OA, it is important to determine the risk factors that may influence the progression. However, although there are many studies that examine risk factors for progression, there are only a few that specifically focus on the impact of each risk factor for predicting progression of knee OA. This study aimed to develop a cohort of patients with primary knee OA in the Beijing area to establish models that identify the influence of each risk factor on the prediction of knee OA progression.Methods and analysisThis is a prospective, multicentre, hospital-based cohort study. The study population comprises 2000 patients with primary knee OA from the Beijing area. The recruitment and baseline visits started in December 2017 and will finish in November 2018. After baseline visits, the patients will be followed for 3 years or until the occurrence of primary outcomes. Demographic variables will be collected during the baseline visit. Influencing factors including occupational exposures, family history and treatment will be collected at baseline and each follow-up visit. The primary outcome measure is a comprehensive index which will be combined with clinical WOMAC score, imaging K-L grade and clinical outcomes. These data will also be collected at baseline and each follow-up visit.Ethics and disseminationThis study protocol has been approved by Peking University Third Hospital Medical Science Research Ethics Committee. All the eligible participants will give written informed consent. The findings will be published in peer-reviewed journals and presented at national or international conferences. Besides, the results will be disseminated to all participants via the social software 'WeChat'.Trial registration numberChiCTR-ROC-17013790; preresults.

Project description:ObjectiveWithin the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time.Design1153 Caucasian adults (age range: 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective.ResultsOf 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression [odds ratio (OR) 1.91 (95%CI 1.16-3.15); P = 0.012]. Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype.ConclusionA significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.

Project description:Arthrofibrosis is characterized by excessive extracellular matrix (ECM) deposition that results in restricted joint motion after total knee arthroplasty (TKA). Current surgical and pharmacologic treatment options are limited. Therefore, an in vitro model for joint myofibroblastogenesis is valuable to investigate the arthrofibrotic process and identify diagnostic biomarkers and treatment options. In this study, we obtained intraoperative posterior capsule (PC), quadriceps tendon (QT), and suprapatellar pouch (SP) tissue from knees of four patients undergoing primary TKA for osteoarthritis and characterized primary outgrowth cells from these tissues in the absence and presence of transforming growth factor beta 1 (TGFβ1), a pro-myofibroblastic cytokine. Light microscopy of knee outgrowth cells revealed spindle-shaped cells while immunofluorescence (IF) established staining for the fibroblast-specific antigen TE-7 and Vimentin, which are characteristics of fibroblasts. These fibroblasts differentiate readily into myofibroblasts as highlighted by enhanced alpha smooth muscle actin (ACTA2) mRNA and protein expression and increased collagen mRNA (i.e., collagen type 1 (COL1A1) and collagen type 3 (COL3A1)) expression and collagenous matrix deposition in the presence of TGFβ1. Of note, these studies also revealed that knee-derived fibroblasts are more sensitive to TGFβ1-mediated myofibroblastogenesis than adipose-derived mesenchymal stem cells. Importantly, while outgrowth fibroblasts isolated from four patients and three anatomical regions exhibit similar gene expression profiles, these knee fibroblasts form a unique gene expression cluster within the fibroblast niche as revealed by RNA-sequencing analysis. In conclusion, our study provides a fibroblast/myofibroblast model of outgrowth knee cells derived from patients undergoing primary TKA that can be employed to assess myofibroblast-related processes and test novel pharmacological strategies in vitro for arthrofibrosis.

Dataset Information

Estrogen receptor-alpha gene haplotype is associated with primary knee osteoarthritis in Korean population.

Publications

Estrogen receptor-alpha gene haplotype is associated with primary knee osteoarthritis in Korean population.

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