Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis

Martha C. Castano Betancourt; Frederic Cailotto; Hanneke J. Kerkhof; Frederique M. F. Cornelis; Sally A. Doherty; Deborah J. Hart; Albert Hofman; Frank P. Luyten; Rose A. Maciewicz; Massimo Mangino; Sarah Metrustry; Kenneth Muir; Marjolein J. Peters; Fernando Rivadeneira; Maggie Wheeler; Weiya Zhang; Nigel Arden; Tim D. Spector; Andre G. Uitterlinden; Michael Doherty; Rik J. U. Lories; Ana M. Valdes; Joyce B. J. van Meurs

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Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis

机译：全基因组关联和功能研究确定DOT1L基因与软骨厚度和髋骨关节炎有关

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Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8× KT~(-10)). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysisP value of 1.1 × 10~(-11). The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10~(-4)). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondro-genesis in vitro. Dotil knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage ho-meostasis. DOT1L may represent a therapeutic target for OA.

机译：髋骨关节炎（HOA）是最致残和最常见的关节疾病之一，但是遗传成分尚不明确。迄今为止，骨关节炎（OA），特别是HOA中的全基因组关联研究（GWAS）仅产生了很少的基因座，这在OA定义中部分解释了异质性。因此，我们在这里集中于射线照相测量的关节间隙宽度（JSW），软骨厚度的替代物和HOA的重要基础中间性状。在髋关节JSW上的6,523个个体的GWAS中，我们确定了染色体19p13.3上rs12982744的G等位基因与5％更大的JSW相关（P = 4.8×KT〜（-10））。该关联在来自三个英国队列的4,442个人中复制，总体荟萃分析P值为1.1×10〜（-11）。 SNP也与降低HOA风险12％密切相关（P = 1×10〜（-4））。 SNP位于DOT1L基因中，该基因是进化上保守的组蛋白甲基转移酶，最近被鉴定为白血病中Wnt靶基因激活的潜在专用酶。小鼠肢体中DOT1L蛋白的免疫组织化学染色支持DOT1L在软骨分化和成人关节软骨中的作用。 DOT1L也在OA关节软骨细胞中表达。沉默Dot11抑制体外软骨发生。 Dotil组合物可降低蛋白聚糖和胶原蛋白含量，并减少软骨形成过程中的矿化作用。在ATDC5软骨形成模型系统中，DOT1L与TCF和Wnt信号相互作用。这些数据是进一步了解Wnt信号在软骨形成和软骨全稳态过程中的作用的又一步。 DOT1L可能代表OA的治疗目标。

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《Proceedings of the National Academy of Sciences of the United States of America》 |2012年第21期|p.8218-8223|共6页
作者
Martha C. Castano Betancourt; Frederic Cailotto; Hanneke J. Kerkhof; Frederique M. F. Cornelis; Sally A. Doherty; Deborah J. Hart; Albert Hofman; Frank P. Luyten; Rose A. Maciewicz; Massimo Mangino; Sarah Metrustry; Kenneth Muir; Marjolein J. Peters; Fernando Rivadeneira; Maggie Wheeler; Weiya Zhang; Nigel Arden; Tim D. Spector; Andre G. Uitterlinden; Michael Doherty; Rik J. U. Lories; Ana M. Valdes; Joyce B. J. van Meurs;
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作者单位

Department of Internal Medicine and Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands,Netherlands GenomicsInitiative, Netherlands Consortium for Healthy Aging, 2300 RC Leiden, The Netherlands;

Laboratory for Skeletal Development and Joint Disorders,Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Belgium;

Department of Internal Medicine and Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands,Netherlands GenomicsInitiative, Netherlands Consortium for Healthy Aging, 2300 RC Leiden, The Netherlands;

Laboratory for Skeletal Development and Joint Disorders,Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Belgium;

Academic Rheumatology, University of Nottingham, City HospitalNottingham, NG5 1PB Nottingham, United Kingdom;

Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College, WC2R2LS London, United Kingdom;

Department of Epidemiology, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands;

Laboratory for Skeletal Development and Joint Disorders,Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Belgium,Division of Rheumatology, University Hospitals Leuven, B-3000 Leuven, Belgium;

Respiratory and Inflammation ResearchArea, AstraZeneca, LE11 5RH Loughborough, United Kingdom;

Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College, WC2R2LS London, United Kingdom;

Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College, WC2R2LS London, United Kingdom;

Health Sciences Research Institute, Warwick Medical School, University of Warwick, CV4 7ALCoventry, United Kingdom;

Department of Internal Medicine and Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands,Netherlands GenomicsInitiative, Netherlands Consortium for Healthy Aging, 2300 RC Leiden, The Netherlands;

Department of Internal Medicine and Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands,Netherlands GenomicsInitiative, Netherlands Consortium for Healthy Aging, 2300 RC Leiden, The Netherlands;

Academic Rheumatology, University of Nottingham, City HospitalNottingham, NG5 1PB Nottingham, United Kingdom;

Academic Rheumatology, University of Nottingham, City HospitalNottingham, NG5 1PB Nottingham, United Kingdom;

Musculoskeletal Biomedical Research Unit, University of Oxford, OX3 7LD Oxford, United Kingdom;

Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College, WC2R2LS London, United Kingdom;

Department of Internal Medicine and Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands,Netherlands GenomicsInitiative, Netherlands Consortium for Healthy Aging, 2300 RC Leiden, The Netherlands;

Academic Rheumatology, University of Nottingham, City HospitalNottingham, NG5 1PB Nottingham, United Kingdom;

Laboratory for Skeletal Development and Joint Disorders,Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Belgium,Division of Rheumatology, University Hospitals Leuven, B-3000 Leuven, Belgium;

Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College, WC2R2LS London, United Kingdom;

Department of Internal Medicine and Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands,Netherlands GenomicsInitiative, Netherlands Consortium for Healthy Aging, 2300 RC Leiden, The Netherlands;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
complex diseasem; joint development; synovial joint; common variant; pleiotropism;

机译：复杂疾病共同发展;滑膜关节常见变体多效性;

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6. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis [O] . Martha C. Castaño Betancourt, Frederic Cailotto, Hanneke J. Kerkhof, 2012

机译：全基因组关联和功能研究确定DOT1L基因与软骨厚度和髋骨关节炎有关
7. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. [O] . Castaño Betancourt, MC, Cailotto, F, Kerkhof, HJ, 2012

机译：全基因组关联和功能研究确定DOT1L基因与软骨厚度和髋骨关节炎有关。

Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis

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