Dataset Information

Putative functional variants of lncRNA identified by RegulomeDB were associated with knee osteoarthritis susceptibility.

ABSTRACT: BACKGROUND:Knee osteoarthritis (KOA) is the most common form of chronic degenerative joint disease worldwide. Its incidence has increased in recent years. Aberrant expression profile of lncRNAs in damaged bone and cartilage of KOA patients has been reported recently, indicating its potential contributions in KOA development and a promising target for disease diagnosis and treatment. The aim of this study was to identify the association between genetic variation in lncRNA and KOA. METHODS:We retrieved relevant articles from the PubMed, Medline and Embase databases up to Jul 2017 investigating the association between lncRNA and the risk of osteoarthritis. There are 15 lncRNAs which show connection with osteoarthritis. We selected potential functional polymorphisms identified by RegulomeDB database in these lncRNAs. A case-control study was conducted which contained 278 KOA patients and 289 OA-free controls. RESULTS:Logistic regression analyses revealed that H19 rs2067051 T allele was significantly associated with decreased risk of KOA after adjusted for age, gender and BMI in recessive genetic model (OR?=?0.63, P?=?0.03) and additive genetic model (OR?=?0.79, P?=?0.03). MEG3 rs4378559 T allele was significantly associated with increased risk of KOA in additive genetic model (OR?=?1.32, P?=?0.04). Heterogeneity tests proved that H19 rs2067051, MEG3 rs4378559 and HOTTIP rs202384's risk effects on KOA were more remarkable for female, BMI???25 and younger age (age?

SUBMITTER: Wang K

PROVIDER: S-EPMC6081910 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Putative functional variants of lncRNA identified by RegulomeDB were associated with knee osteoarthritis susceptibility.

Wang Kejie K Chu Minjie M Ding Wenge W Jiang Qing Q

BMC musculoskeletal disorders 20180807 1

<h4>Background</h4>Knee osteoarthritis (KOA) is the most common form of chronic degenerative joint disease worldwide. Its incidence has increased in recent years. Aberrant expression profile of lncRNAs in damaged bone and cartilage of KOA patients has been reported recently, indicating its potential contributions in KOA development and a promising target for disease diagnosis and treatment. The aim of this study was to identify the association between genetic variation in lncRNA and KOA.<h4>Meth ...[more]

PMID: 30086750

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Project description:ObjectiveSingle-nucleotide polymorphism (SNP) rs143383 (T to C) in the 5'-untranslated region (5'-UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk-associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis-acting GDF5 regulatory polymorphisms.MethodsTissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383.ResultsWe observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint-wide. We identified a second polymorphism, located in the 3'-UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) to the 2 alleles of rs143383.ConclusionThese findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis-acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF-1 is a trans-acting factor that merits further investigation as a potential tool for modulating GDF5 expression.

Project description:INTRODUCTION: Osteoarthritis (OA) is considered to be a multifactorial and polygenic disease and diagnosis is mainly clinical and radiological. Correlation between radiographic data and clinical status has been reported. However, very few studies, especially in Caucasian people, describe the association between the Kellgren and Lawrence OA grading scale (KL) and genetic alterations to better understand OA etiopathogenesis and susceptibility. In order to update the knee OA grading, in this study we assessed the associations between KL grade, clinical features such as American Knee Society Score (AKSS), age, and polymorphisms in the principal osteoarthritis susceptibility (OS) genes in Sicilian individuals. METHODS: In 66 Sicilian individuals affected by primary knee OA, the clinical and radiographic evaluation was performed using 2 sub-scores of AKSS (knee score (KS) and function score (FS)) and KL. The patients were also classified according to age. Online Mendelian Inheritance in Man (OMIM) and Database of Single Nucleotide Polymorphisms (dbSNP) Short Genetic Variations databases were used to select gene regions containing the following polymorphisms to analyze: FRZB rs288326 and rs7775, MATN3 rs77245812, ASPN D14 repeats, PTHR2 rs76758470, GDF5 rs143383 and DVWA rs11718863. Patient genotypes were obtained using Sanger DNA sequencing analysis. RESULTS: In our cohort of patients a statistical association between the variables analyzed was reported in all associations tested (KL versus KS, FS and age). We observed that a mild to severe OA radiographic grade is related to severe clinical conditions and loss of articular function and that the severity of symptoms increases with age. Concerning the genotyping analysis, our results revealed a significant statistical association between KL grading and GDF5 rs143383 and DVWA rs11718863 genetic alterations. The latter was also associated with a more severe radiographic grade, displaying its predictive role as OA marker progression. Statistically significant association between clinical, radiographic and genetic signs observed, suggests extending the actual grading of knee OA based mainly on X-ray features. CONCLUSIONS: This work represents a multidisciplinary and translational medicine approach to study OA where clinical, radiological, and OS5 and OS6 SNPs evaluation could contribute to better define grading and progression of OA and to the development of new therapies.

Dataset Information

Putative functional variants of lncRNA identified by RegulomeDB were associated with knee osteoarthritis susceptibility.

Publications

Putative functional variants of lncRNA identified by RegulomeDB were associated with knee osteoarthritis susceptibility.

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