Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand
Evangelos Evangelou
University of Ioannina School of Medicine, Ioannina, Greece
Search for more papers by this authorIngrid Meulenbelt
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorFotini B. Karassa
University of Ioannina School of Medicine, Ioannina, Greece
Search for more papers by this authorMichael Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorSally Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorJuan J. Gómez-Reino
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Search for more papers by this authorAntonio Gonzalez
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Search for more papers by this authorBjarni V. Halldorsson
Reykjavik University and deCODE Genetics, Reykjavik, Iceland
Drs. Halldorsson, Jonsdottir, and Stefansson own stock and/or stock options in deCODE Genetics.
Search for more papers by this authorAlbert Hofman
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorDeborah J. Hart
St. Thomas' Hospital and Kings College London, London, UK
Search for more papers by this authorThorvaldur Ingvarsson
University of Akureyri, Akureyri, and University of Iceland, Reykjavik, Iceland
Search for more papers by this authorQing Jiang
Drum Tower Hospital and Medical School of Nanjing University, Nanjing, Jiangsu, China
Search for more papers by this authorIngileif Jonsdottir
University of Iceland, Reykjavik, and deCODE Genetics, Reykjavik, Iceland
Drs. Halldorsson, Jonsdottir, and Stefansson own stock and/or stock options in deCODE Genetics.
Search for more papers by this authorHelgi Jonsson
University of Iceland, Reykjavik, and Landspitali University Hospital, Reykjavik, Iceland
Search for more papers by this authorHanneke J. M. Kerkhof
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorMargreet Kloppenburg
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorNancy E. Lane
University of California at Davis Medical Center, Sacramento, California
Search for more papers by this authorJoyce B. J. van Meurs
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorAnnu Näkki
National Public Health Institute, ORTON Orthopedic Hospital, and ORTON Invalid Foundation, Helsinki, Finland
Search for more papers by this authorJulio Rodriguez-Lopez
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Search for more papers by this authorDongquan Shi
Drum Tower Hospital and Medical School of Nanjing University, Nanjing, Jiangsu, China
Search for more papers by this authorP. Eline Slagboom
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorKari Stefansson
University of Iceland, Reykjavik, and deCODE Genetics, Reykjavik, Iceland
Drs. Halldorsson, Jonsdottir, and Stefansson own stock and/or stock options in deCODE Genetics.
Search for more papers by this authorAspasia Tsezou
University of Thessaly Medical School, Larissa, Greece
Search for more papers by this authorChristopher M. Watson
University of Ioannina School of Medicine, Ioannina, Greece
Search for more papers by this authorTim D. Spector
St. Thomas' Hospital and Kings College London, London, UK
Search for more papers by this authorAndre G. Uitterlinden
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorAna M. Valdes
St. Thomas' Hospital and Kings College London, London, UK
Search for more papers by this authorCorresponding Author
John P. A. Ioannidis
University of Ioannina Medical School of Medicine and Foundation for Research and Development–Hellas, Ioannina, Greece, and Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, GreeceSearch for more papers by this authorEvangelos Evangelou
University of Ioannina School of Medicine, Ioannina, Greece
Search for more papers by this authorIngrid Meulenbelt
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorFotini B. Karassa
University of Ioannina School of Medicine, Ioannina, Greece
Search for more papers by this authorMichael Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorSally Doherty
University of Nottingham and City Hospital Nottingham, Nottingham, UK
Search for more papers by this authorJuan J. Gómez-Reino
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Search for more papers by this authorAntonio Gonzalez
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Search for more papers by this authorBjarni V. Halldorsson
Reykjavik University and deCODE Genetics, Reykjavik, Iceland
Drs. Halldorsson, Jonsdottir, and Stefansson own stock and/or stock options in deCODE Genetics.
Search for more papers by this authorAlbert Hofman
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorDeborah J. Hart
St. Thomas' Hospital and Kings College London, London, UK
Search for more papers by this authorThorvaldur Ingvarsson
University of Akureyri, Akureyri, and University of Iceland, Reykjavik, Iceland
Search for more papers by this authorQing Jiang
Drum Tower Hospital and Medical School of Nanjing University, Nanjing, Jiangsu, China
Search for more papers by this authorIngileif Jonsdottir
University of Iceland, Reykjavik, and deCODE Genetics, Reykjavik, Iceland
Drs. Halldorsson, Jonsdottir, and Stefansson own stock and/or stock options in deCODE Genetics.
Search for more papers by this authorHelgi Jonsson
University of Iceland, Reykjavik, and Landspitali University Hospital, Reykjavik, Iceland
Search for more papers by this authorHanneke J. M. Kerkhof
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorMargreet Kloppenburg
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorNancy E. Lane
University of California at Davis Medical Center, Sacramento, California
Search for more papers by this authorJoyce B. J. van Meurs
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorAnnu Näkki
National Public Health Institute, ORTON Orthopedic Hospital, and ORTON Invalid Foundation, Helsinki, Finland
Search for more papers by this authorJulio Rodriguez-Lopez
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Search for more papers by this authorDongquan Shi
Drum Tower Hospital and Medical School of Nanjing University, Nanjing, Jiangsu, China
Search for more papers by this authorP. Eline Slagboom
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorKari Stefansson
University of Iceland, Reykjavik, and deCODE Genetics, Reykjavik, Iceland
Drs. Halldorsson, Jonsdottir, and Stefansson own stock and/or stock options in deCODE Genetics.
Search for more papers by this authorAspasia Tsezou
University of Thessaly Medical School, Larissa, Greece
Search for more papers by this authorChristopher M. Watson
University of Ioannina School of Medicine, Ioannina, Greece
Search for more papers by this authorTim D. Spector
St. Thomas' Hospital and Kings College London, London, UK
Search for more papers by this authorAndre G. Uitterlinden
Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorAna M. Valdes
St. Thomas' Hospital and Kings College London, London, UK
Search for more papers by this authorCorresponding Author
John P. A. Ioannidis
University of Ioannina Medical School of Medicine and Foundation for Research and Development–Hellas, Ioannina, Greece, and Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, GreeceSearch for more papers by this authorAbstract
Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
Results
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| ART_24524_sm_SupplTab1.doc84 KB | Supplemental Table 1 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Luyten FP. Cartilage-derived morphogenetic protein-1. Int J Biochem Cell Biol 1997; 29: 1241–4.
- 2 Francis-West PH, Abdelfattah A, Chen P, Allen C, Parish J, Ladher R, et al. Mechanisms of GDF-5 action during skeletal development. Development 1999; 126: 1305–15.
- 3 Edwards CJ, Francis-West PH. Bone morphogenetic proteins in the development and healing of synovial joints. Semin Arthritis Rheum 2001; 31: 33–42.
- 4 Mikic B. Multiple effects of GDF-5 deficiency on skeletal tissues: implications for therapeutic bioengineering. Ann Biomed Eng 2004; 32: 466–76.
- 5 Nickel J, Kotzsch A, Sebald W, Mueller TD. A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol 2005; 349: 933–47.
- 6 Enomoto-Iwamoto M, Kitagaki J, Koyama E, Tamamura Y, Wu C, Kanatani N, et al. The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev Biol 2002; 251: 142–56.
- 7 Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, et al. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A 2004; 101: 9757–62.
- 8 Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 2007; 56: 4095–103.
- 9 Miyamoto Y, Mabuchi A, Shi D, Kubo T, Takatori Y, Saito S, et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 2007; 39: 529–33.
- 10 Southam L, Rodriguez-Lopez J, Wilkins JM, Pombo-Suarez M, Snelling S, Gomez-Reino JJ, et al. An SNP in the 5′-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage. Hum Mol Genet 2007; 16: 2226–32.
- 11 Tsezou A, Satra M, Oikonomou P, Bargiotas K, Malizos KN. The growth differentiation factor 5 (GDF5) core promoter polymorphism is not associated with knee osteoarthritis in the Greek population. J Orthop Res 2008; 26: 136–40.
- 12 Chapman K, Takahashi A, Meulenbelt I, Watson C, Rodriguez-Lopez J, Egli R, et al. A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5′ UTR of GDF5 with osteoarthritis susceptibility. Hum Mol Genet 2008; 17: 1497–504.
- 13 Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, Houwing-Duistermaat JJ, Seymour AB, et al. Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum 2005; 52: 1077–80.
- 14 Lane NE, Lian K, Nevitt MC, Zmuda JM, Lui L, Li J, et al. Frizzled-related protein variants are risk factors for hip osteoarthritis. Arthritis Rheum 2006; 54: 1246–54.
- 15 Valdes AM, Loughlin J, van Oene M, Chapman K, Surdulescu GL, Doherty M, et al. Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee [published erratum appears in Arthritis Rheum 2009;60:178]. Arthritis Rheum 2007; 56: 137–46.
- 16 Lories RJ, Boonen S, Peeters J, de Vlam K, Luyten FP. Evidence for a differential association of the Arg200Trp single-nucleotide polymorphism in FRZB with hip osteoarthritis and osteoporosis [letter]. Rheumatology (Oxford) 2006; 45: 113–4.
- 17 Rodriguez-Lopez J, Pombo-Suarez M, Liz M, Gomez-Reino JJ, Gonzalez A. Further evidence of the role of frizzled-related protein gene polymorphisms in osteoarthritis. Ann Rheum Dis 2007; 66: 1052–5.
- 18 Kerkhof JM, Uitterlinden AG, Valdes AM, Hart DJ, Rivadeneira F, Jhamai M, et al. Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts. Osteoarthritis Cartilage 2008; 16: 1141–9.
- 19 Ioannidis JP, Trikalinos TA, Khoury MJ. Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases. Am J Epidemiol 2006; 164: 609–14.
- 20 Kavvoura FK, Liberopoulos G, Ioannidis JP. Selection in reported epidemiological risks: an empirical assessment. PLoS Med 2007; 4: e79.
- 21 Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957; 16: 494–502.
- 22 Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum 1990; 33: 1601–10.
- 23 Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum 1991; 34: 505–14.
- 24 Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum 1986; 29: 1039–49.
- 25 Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003; 35: 131–8.
- 26 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–58.
- 27 Ioannidis JP, Patsopoulos NA, Evangelou E. Uncertainty in heterogeneity estimates in meta-analyses. BMJ 2007; 335: 914–6.
- 28 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60.
- 29 Patsopoulos NA, Evangelou E, Ioannidis JP. Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol 2008; 37: 1148–57.
- 30 Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127: 820–6.
- 31 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–88.
- 32 Kavvoura FK, Ioannidis JP. Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls. Hum Genet 2008; 123: 1–14.
- 33 Ioannidis JP. Calibration of credibility of agnostic genome-wide associations. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 964–72.
- 34 Ioannidis JP. Effect of formal statistical significance on the credibility of observational associations. Am J Epidemiol 2008; 168: 374–83.
- 35 Ioannidis JP, Boffetta P, Little J, O'Brien TR, Uitterlinden AG, Vineis P, et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 2008; 37: 120–32.
- 36 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–89.
- 37 Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 2005; 76: 449–62.
- 38 Erlacher L, McCartney J, Piek E, ten Dijke P, Yanagishita M, Oppermann H, et al. Cartilage-derived morphogenetic proteins and osteogenic protein-1 differentially regulate osteogenesis. J Bone Miner Res 1998; 13: 383–92.
- 39 Savarirayan R, White SM, Goodman FR, Graham JM Jr, Delatycki MB, Lachman RS, et al. Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. Am J Med Genet A 2003; 117A: 136–42.
- 40 Masuya H, Nishida K, Furuichi T, Toki H, Nishimura G, Kawabata H, et al. A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. Hum Mol Genet 2007; 16: 2366–75.
- 41 Ioannidis JP. Why most discovered true associations are inflated. Epidemiology 2008; 19: 640–8.
- 42 Burton PR, Hansell AL, Fortier I, Manolio TA, Khoury MJ, Little J, et al. Size matters: just how big is BIG? Quantifying realistic sample size requirements for human genome epidemiology. Int J Epidemiol 2009; 38: 263–73.
- 43 Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118: 1590–605.
- 44 Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ. A navigator for human genome epidemiology. Nat Genet 2008; 40: 124–5.
- 45 Patsopoulos NA, Tatsioni A, Ioannidis JP. Claims of sex differences: an empirical assessment in genetic associations. JAMA 2007; 298: 880–93.
- 46 Hart DJ, Spector TD. The classification and assessment of osteoarthritis. Baillieres Clin Rheumatol 1995; 9: 407–32.
- 47 Schiphof D, Boers M, Bierma-Zeinstra SM. Differences in descriptions of Kellgren and Lawrence grades of knee osteoarthritis. Ann Rheum Dis 2008; 67: 1034–6.
