Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand

Evangelos Evangelou, Kay Chapman, Ingrid Meulenbelt, Fotini B. Karassa, John Loughlin, Andrew Carr, Michael Doherty, Sally Doherty, Juan J. Gómez-Reino, Antonio Gonzalez, Bjarni V. Halldorsson, Valdimar B. Hauksson, Albert Hofman, Deborah J. Hart, Shiro Ikegawa, Thorvaldur Ingvarsson, Qing Jiang, Ingileif Jonsdottir, Helgi Jonsson, Hanneke J M KerkhofMargreet Kloppenburg, Nancy E Lane, Jia Li, Rik J. Lories, Joyce B J Van Meurs, Annu Näkki, Michael C. Nevitt, Julio Rodriguez-Lopez, Dongquan Shi, P. Eline Slagboom, Kari Stefansson, Aspasia Tsezou, Gillian A. Wallis, Christopher M. Watson, Tim D. Spector, Andre G. Uitterlinden, Ana M. Valdes, John P A Ioannidis

Research output: Contribution to journalArticle

137 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1710-1721
Number of pages12
JournalArthritis and Rheumatism
Volume60
Issue number6
DOIs
StatePublished - Jun 2009

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Hip Osteoarthritis
Knee Osteoarthritis
Osteoarthritis
Hand
Odds Ratio
Phenotype
Haplotypes
Genetic Loci
Sample Size
Genes
Meta-Analysis
Knee
Alleles
Confidence Intervals

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Evangelou, E., Chapman, K., Meulenbelt, I., Karassa, F. B., Loughlin, J., Carr, A., ... Ioannidis, J. P. A. (2009). Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. Arthritis and Rheumatism, 60(6), 1710-1721. https://doi.org/10.1002/art.24524

Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. / Evangelou, Evangelos; Chapman, Kay; Meulenbelt, Ingrid; Karassa, Fotini B.; Loughlin, John; Carr, Andrew; Doherty, Michael; Doherty, Sally; Gómez-Reino, Juan J.; Gonzalez, Antonio; Halldorsson, Bjarni V.; Hauksson, Valdimar B.; Hofman, Albert; Hart, Deborah J.; Ikegawa, Shiro; Ingvarsson, Thorvaldur; Jiang, Qing; Jonsdottir, Ingileif; Jonsson, Helgi; Kerkhof, Hanneke J M; Kloppenburg, Margreet; Lane, Nancy E; Li, Jia; Lories, Rik J.; Van Meurs, Joyce B J; Näkki, Annu; Nevitt, Michael C.; Rodriguez-Lopez, Julio; Shi, Dongquan; Slagboom, P. Eline; Stefansson, Kari; Tsezou, Aspasia; Wallis, Gillian A.; Watson, Christopher M.; Spector, Tim D.; Uitterlinden, Andre G.; Valdes, Ana M.; Ioannidis, John P A.

In: Arthritis and Rheumatism, Vol. 60, No. 6, 06.2009, p. 1710-1721.

Research output: Contribution to journalArticle

Evangelou, E, Chapman, K, Meulenbelt, I, Karassa, FB, Loughlin, J, Carr, A, Doherty, M, Doherty, S, Gómez-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, Näkki, A, Nevitt, MC, Rodriguez-Lopez, J, Shi, D, Slagboom, PE, Stefansson, K, Tsezou, A, Wallis, GA, Watson, CM, Spector, TD, Uitterlinden, AG, Valdes, AM & Ioannidis, JPA 2009, 'Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand', Arthritis and Rheumatism, vol. 60, no. 6, pp. 1710-1721. https://doi.org/10.1002/art.24524
Evangelou, Evangelos ; Chapman, Kay ; Meulenbelt, Ingrid ; Karassa, Fotini B. ; Loughlin, John ; Carr, Andrew ; Doherty, Michael ; Doherty, Sally ; Gómez-Reino, Juan J. ; Gonzalez, Antonio ; Halldorsson, Bjarni V. ; Hauksson, Valdimar B. ; Hofman, Albert ; Hart, Deborah J. ; Ikegawa, Shiro ; Ingvarsson, Thorvaldur ; Jiang, Qing ; Jonsdottir, Ingileif ; Jonsson, Helgi ; Kerkhof, Hanneke J M ; Kloppenburg, Margreet ; Lane, Nancy E ; Li, Jia ; Lories, Rik J. ; Van Meurs, Joyce B J ; Näkki, Annu ; Nevitt, Michael C. ; Rodriguez-Lopez, Julio ; Shi, Dongquan ; Slagboom, P. Eline ; Stefansson, Kari ; Tsezou, Aspasia ; Wallis, Gillian A. ; Watson, Christopher M. ; Spector, Tim D. ; Uitterlinden, Andre G. ; Valdes, Ana M. ; Ioannidis, John P A. / Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. In: Arthritis and Rheumatism. 2009 ; Vol. 60, No. 6. pp. 1710-1721.
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title = "Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand",
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 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.",
author = "Evangelos Evangelou and Kay Chapman and Ingrid Meulenbelt and Karassa, {Fotini B.} and John Loughlin and Andrew Carr and Michael Doherty and Sally Doherty and G{\'o}mez-Reino, {Juan J.} and Antonio Gonzalez and Halldorsson, {Bjarni V.} and Hauksson, {Valdimar B.} and Albert Hofman and Hart, {Deborah J.} and Shiro Ikegawa and Thorvaldur Ingvarsson and Qing Jiang and Ingileif Jonsdottir and Helgi Jonsson and Kerkhof, {Hanneke J M} and Margreet Kloppenburg and Lane, {Nancy E} and Jia Li and Lories, {Rik J.} and {Van Meurs}, {Joyce B J} and Annu N{\"a}kki and Nevitt, {Michael C.} and Julio Rodriguez-Lopez and Dongquan Shi and Slagboom, {P. Eline} and Kari Stefansson and Aspasia Tsezou and Wallis, {Gillian A.} and Watson, {Christopher M.} and Spector, {Tim D.} and Uitterlinden, {Andre G.} and Valdes, {Ana M.} and Ioannidis, {John P A}",
year = "2009",
month = "6",
doi = "10.1002/art.24524",
language = "English (US)",
volume = "60",
pages = "1710--1721",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
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TY - JOUR

T1 - Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand

AU - Evangelou, Evangelos

AU - Chapman, Kay

AU - Meulenbelt, Ingrid

AU - Karassa, Fotini B.

AU - Loughlin, John

AU - Carr, Andrew

AU - Doherty, Michael

AU - Doherty, Sally

AU - Gómez-Reino, Juan J.

AU - Gonzalez, Antonio

AU - Halldorsson, Bjarni V.

AU - Hauksson, Valdimar B.

AU - Hofman, Albert

AU - Hart, Deborah J.

AU - Ikegawa, Shiro

AU - Ingvarsson, Thorvaldur

AU - Jiang, Qing

AU - Jonsdottir, Ingileif

AU - Jonsson, Helgi

AU - Kerkhof, Hanneke J M

AU - Kloppenburg, Margreet

AU - Lane, Nancy E

AU - Li, Jia

AU - Lories, Rik J.

AU - Van Meurs, Joyce B J

AU - Näkki, Annu

AU - Nevitt, Michael C.

AU - Rodriguez-Lopez, Julio

AU - Shi, Dongquan

AU - Slagboom, P. Eline

AU - Stefansson, Kari

AU - Tsezou, Aspasia

AU - Wallis, Gillian A.

AU - Watson, Christopher M.

AU - Spector, Tim D.

AU - Uitterlinden, Andre G.

AU - Valdes, Ana M.

AU - Ioannidis, John P A

PY - 2009/6

Y1 - 2009/6

N2 - 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.

AB - 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.

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