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J Med Genet. 2014 Sep;51(9):596-604. doi: 10.1136/jmedgenet-2014-102478. Epub 2014 Jul 23.

Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.

Author information

1
Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
2
Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
3
NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK Arthritis Research UK, Sport, Exercise and Osteoarthritis Centre of Excellence, London, UK.
4
Department of Rheumatology, Nordic Bioscience, Herlev, Denmark.
5
Department of Gerontology and Geriatrics, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands.
6
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA The Framingham Heart Study, Framingham, Massachusetts, USA.
7
Institute of Molecular and Cell Biology and Estonian Genome Center, University of Tartu, Tartu, Estonia Department of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA Broad Institute, Cambridge, Massachusetts, USA.
8
Department of Hygiene & Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
9
Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA.
10
Department of Hygiene & Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece Department of Medicine, Stanford Prevention Research Center, Stanford, USA Department of Health Research and Policy, Stanford University School of Medicine, Stanford, USA Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, USA.
11
Department of Rheumatology & Clinical Epidemiology, LUMC, Leiden, The Netherlands.
12
Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.
13
Institute of Molecular and Cell Biology and Estonian Genome Center, University of Tartu, Tartu, Estonia.
14
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
15
The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
16
Global Analytical Science, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, USA.
17
Academic Rheumatology, University of Nottingham, Nottingham, UK.

Abstract

BACKGROUND:

Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II).

METHODS:

Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage.

RESULTS:

Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage.

CONCLUSIONS:

We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.

KEYWORDS:

Genetic epidemiology; Genome-wide; Osteoarthritis

PMID:
25057126
DOI:
10.1136/jmedgenet-2014-102478
[Indexed for MEDLINE]

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