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Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand

Lookup NU author(s): Dr Kaye Chapman, Professor John LoughlinORCiD

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Abstract

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 onpolymorphisms 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 x 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.


Publication metadata

Author(s): Evangelou E, Chapman K, Meulenbelt I, Karassa FB, Loughlin J, Carr A, Doherty M, Doherty S, Gomez-Reino JJ, Gonzalez A, Halldorsson BV, Hauksson VB, Hofman A, Hart DJ, Ikegawa S, Ingvarsson T, Jiang Q, Jonsdottir I, Jonsson H, Kerkhof HJM, Kloppenburg M, Lane NE, Li J, Lories RJ, van Meurs JBJ, Nakki A, Nevitt MC, Rodriguez-Lopez J, Shi DQ, Slagboom E, Stefansson K, Tsezou A, Wallis GA, Watson CM, Spector TD, Uitterlinden AG, Valdes AM, Ioannidis JPA

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatism

Year: 2009

Volume: 60

Issue: 6

Pages: 1710-1721

ISSN (print): 0004-3591

ISSN (electronic): 1529-0131

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/art.24524

DOI: 10.1002/art.24524


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Funding

Funder referenceFunder name
Dutch Arthritis Association
Leiden University Medical Center
Center of Medical System Biology, Leiden, The Netherlands
Connecticut
Groton
Pfizer
2 R01-AG-005394-22A1NIH
2 R01-AG-027574-22A1NIH
911-03-012Netherlands Organization of Scientific Research
AR-35584NIH
911-03-01.6Netherlands Organization of Scientific Research
917 66344Netherlands Organization of Scientific Research
AG-05394NIH
AG-05407NIH
AR-35582NIH
AR-35583NIH
HEALTH-F2-2008-00Coordination Theme 1 (Health) of the European Union
K24-AR-04884NIH
MW 904-61-095Netherlands Organization of Scientific Research
R01-AG-027576-22NIH
R01-AG-005407NIH

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