Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Castaño-Betancourt, Martha C.; Evans, D.; Ramos, Yolande F M; Boer, Cindy G.; Metrustry, Sarah; Liu, Youfang; Hollander, Wouter den; Rooij, Jeroen van; Kraus, Virginia B.; Yau, Michelle S.; Mitchell, Braxton D.; Muir, Kenneth; Hofman, Albert; Doherty, Michael; Doherty, Sally; Zhang, Weiya; Kraaij, Robert; Rivadeneira, Fernando; Barrett‐Connor, Elizabeth; Maciewicz, Rose A.; Arden, N K; Nelissen, Rob G H H; Kloppenburg, Margreet; Jordan, Joanne M.; Nevitt, Michael C.; Slagboom, P. Eline; Hart, Deborah; Lafeber, Floris P. J. G.; Styrkársdóttir, Unnur; Zeggini, Eleftheria; Εvangelou, Εvangelos; Spector, Tim D.; Uitterlinden, André G.; Lane, Nancy E.; Meulenbelt, Ingrid; Valdes, Ana M.; Meurs, Joyce B. J. van

doi:10.1371/journal.pgen.1006260

Cited by 84 publications

(83 citation statements)

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“…We found a strong association with finger OA (p value=3.09*10 –08 , OR=1.25) and nominal significant association with severe hand OA (p value=2.80*10 –2 , OR=1.36), which has a low frequency in the population (online supplementary table S4). To see if rs4764133 also confers risk for other forms of OA, that is, OA of the hip and knee, we used the GWAS summary data of the treat OA consortium27 and the recently published minimal joint space width of the hip (mJSW) meta-analysis 18. No association was found between rs4764133 and hip or knee OA (online supplementary table S4).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

et al. 2017

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Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10−10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10−9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10−15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10−16). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.

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Section: Resultsmentioning

confidence: 99%

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

et al. 2017

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“…We investigated 18 novel OA risk loci that had been reported as being associated with the disease at a significance level close to or surpassing the genome‐wide threshold of P < 5 × 10 −8 (Table ). If the OA‐associated SNP was directly genotyped on an Illumina HumanOmniExpress array, we utilized those SNP data.…”

Section: Methodsmentioning

confidence: 99%

“…We had both methylation and genotype data available for a total of 87 patients who had undergone knee or hip joint arthroplasty (57 knee OA patients, 14 hip OA patients, and 16 patients who had undergone hip replacement due to a femoral neck fracture (Supplementary Table 1 OA loci investigation and mQTL analysis. We investigated 18 novel OA risk loci that had been reported as being associated with the disease at a significance level close to or surpassing the genome-wide threshold of P < 5 × 10 −8 (13)(14)(15)(16)(17)(18)(19)(20) ( Table 1). If the OA-associated SNP was directly genotyped on an Illumina HumanOmniExpress array, we utilized those SNP data.…”

Section: Methodsmentioning

confidence: 99%

Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci

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Sorial

et al. 2019

Arthritis & Rheumatology

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Objective To identify methylation quantitative trait loci (mQTLs) correlating with osteoarthritis (OA) risk alleles and to undertake mechanistic characterization as a means of target gene prioritization. Methods We used genome‐wide genotyping and cartilage DNA methylation array data in a discovery screen of novel OA risk loci. This was followed by methylation, gene expression analysis, and genotyping studies in additional cartilage samples, accompanied by in silico analyses. Results We identified 4 novel OA mQTLs. The most significant mQTL contained 9 CpG sites where methylation correlated with OA risk genotype, with 5 of the CpG sites having P values <1 × 10−10. The 9 CpG sites reside in an interval of only 7.7 kb within the PLEC gene and form 2 distinct clusters. We were able to prioritize PLEC and the adjacent gene GRINA as independent targets of the OA risk. We identified PLEC and GRINA expression QTLs operating in cartilage, as well as methylation‐expression QTLs operating on the 2 genes. GRINA and PLEC also demonstrated differential expression between OA hip and non‐OA hip cartilage. Conclusion PLEC encodes plectin, a cytoskeletal protein that maintains tissue integrity by regulating intracellular signaling in response to mechanical stimuli. GRINA encodes the ionotropic glutamate receptor TMBIM3 (transmembrane BAX inhibitor 1 motif–containing protein family member 3), which regulates cell survival. Based on our results, we hypothesize that in a joint predisposed to OA, expression of these genes alters in order to combat aberrant biomechanics, and that this is epigenetically regulated. However, carriage of the OA risk–conferring allele at this locus hinders this response and contributes to disease development.

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“…Genome-wide association studies showed that common single variants in the DOT1L gene, with minor allele frequencies of 0.20–0.40, protect against osteoarthritis67. However, it is unknown how DOT1L affects this devastating disease.…”

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confidence: 99%

DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

et al. 2017

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Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis.

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Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Cited by 84 publications

References 49 publications

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci

DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

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