Transcriptional Associations of Osteoarthritis-Mediated Loss of Epigenetic Control in Articular Cartilage

被引：55

作者：

den Hollander, Wouter ^{[1
]}

Ramos, Yolande F. M. ^{[1
]}

Bomer, Nils ^{[1
]}

Elzinga, Stefan ^{[1
]}

van der Breggen, Ruud ^{[1
]}

Lakenberg, Nico ^{[1
]}

de Dijcker, Wesley J. ^{[1
]}

Suchiman, H. Eka D. ^{[1
]}

Duijnisveld, Bouke J. ^{[1
]}

Houwing-Duistermaat, Jeanine J. ^{[1
]}

Slagboom, P. Eline ^{[1
,2
]}

Bos, Steffan D. ^{[1
,2
]}

Nelissen, Rob G. H. H. ^{[1
]}

Meulenbelt, Ingrid ^{[1
,2
]}

机构：

[1] Leiden Univ, Med Ctr, NL-2300 RC Leiden, Netherlands

[2] Netherlands Genom Initiat Sponsored Netherland Co, Rotterdam, Netherlands

来源：

ARTHRITIS & RHEUMATOLOGY | 2015年 / 67卷 / 08期

关键词：

WIDE DNA METHYLATION; TYROSINE KINASE; VI COLLAGEN; EXPRESSION; BONE; ROR2; HIP; IDENTIFICATION; VARIANTS; PROMOTER;

D O I：

10.1002/art.39162

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Objective. To identify osteoarthritis (OA) progression-modulating pathways in articular cartilage and their respective regulatory epigenetic and genetic determinants in end-stage disease. Methods. Transcriptional activity of CpG was assessed using gene expression data and DNA methylation data for preserved and lesional articular cartilage samples. Disease-responsive transcriptionally active CpG were identified by means of differential methylation between preserved and lesional cartilage. Transcriptionally relevant genetic determinants were addressed by means of single-nucleotide polymorphisms (SNPs) proximal to the OA-responsive transcriptionally active CpG. Statistical analyses were corrected for age, sex, joint, and technical covariates. A random effect was included to correct for possible correlations between paired samples. Results. Of 9,838 transcribed genes in articular cartilage, 2,324 correlated with the methylation status of 3,748 transcriptionally active CpG; both negative (n=1,741) and positive (n=2,007) correlations were observed. Hypomethylation and hypermethylation (false discovery rate of <0.05, vertical bar Delta beta vertical bar > 0.05) were observed for 62 and 25 transcriptionally active CpG, respectively, covering 70 unique genes. Enrichment for developmental and extracellular matrix maintenance pathways indicated possible reactivation of endochondral ossification. Finally, we observed 31 and 26 genes for which methylation and expression, respectively, were additionally affected by genetic variation. Conclusion. We identified tissue-specific genes involved in OA disease progression, reflected by genetic and pathologic epigenetic regulation of transcription, primarily at genes involved in development. Therefore, transcriptionally active SNPs near these genes may serve as putative susceptibility alleles. Our results constitute an important step toward understanding the reported widespread epigenetic changes occurring in OA articular cartilage and toward subsequent development of treatments targeting disease-driving pathways.

引用

页码：2108 / 2116

页数：9

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