Large‐scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand
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...
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| Published in | Arthritis and rheumatism Vol. 60; no. 6; pp. 1710 - 1721 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.06.2009
Wiley |
| Subjects | |
| Online Access | Get full text |
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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 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. |
|---|---|
| AbstractList | 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. OBJECTIVEGDF5 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. METHODSFourteen 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. RESULTSA significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09-1.22]) (P=9.4x10(-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). CONCLUSIONEvidence 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. 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. 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. A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09-1.22]) (P=9.4x10(-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). 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. 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 | Ingvarsson, Thorvaldur Hofman, Albert Gómez‐Reino, Juan J. Carr, Andrew Halldorsson, Bjarni V. Jonsson, Helgi Rodriguez‐Lopez, Julio Ioannidis, John P. A. Jiang, Qing Hart, Deborah J. Evangelou, Evangelos Näkki, Annu Chapman, Kay Slagboom, P. Eline Tsezou, Aspasia Valdes, Ana M. Doherty, Sally Kloppenburg, Margreet van Meurs, Joyce B. J. Wallis, Gillian A. Lories, Rik J. Shi, Dongquan Stefansson, Kari Loughlin, John Lane, Nancy E. Jonsdottir, Ingileif Spector, Tim D. Watson, Christopher M. Karassa, Fotini B. Meulenbelt, Ingrid Uitterlinden, Andre G. Li, Jia Gonzalez, Antonio Hauksson, Valdimar B. Ikegawa, Shiro Kerkhof, Hanneke J. M. Nevitt, Michael C. Doherty, Michael |
| AuthorAffiliation | 13 Drum Tower Hospital and Medical School of Nanjing University, Nanjing, Jiangsu, China 19 National Public Health Institute, ORTON Orthopedic Hospital, and ORTON Invalid Foundation, Helsinki, Finland 17 Roche Molecular Systems, Pleasanton, California 14 University of Iceland, Reykjavik, and deCODE Genetics, Reykjavik, Iceland 20 University of California, San Francisco 22 University of Manchester, Manchester, UK 7 Reykjavik University and deCODE Genetics, Reykjavik, Iceland 12 University of Akureyri, Akureyri, and University of Iceland, Reykjavik, Iceland 4 Newcastle University, Newcastle upon Tyne, UK 5 University of Nottingham and City Hospital Nottingham, Nottingham, UK 6 Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain 3 Leiden University Medical Center, Leiden, The Netherlands 21 University of Thessaly Medical School, Larissa, Greece 11 Center for Genomic Medicine, RIKEN, Tokyo, Japan 15 University of Iceland, Reykjavik, and Landspitali University Hospital, Reykjavik, I |
| AuthorAffiliation_xml | – name: 22 University of Manchester, Manchester, UK – name: 17 Roche Molecular Systems, Pleasanton, California – name: 20 University of California, San Francisco – name: 13 Drum Tower Hospital and Medical School of Nanjing University, Nanjing, Jiangsu, China – name: 21 University of Thessaly Medical School, Larissa, Greece – name: 1 University of Ioannina School of Medicine, Ioannina, Greece – name: 10 St. Thomas’ Hospital and Kings College London, London, UK – name: 11 Center for Genomic Medicine, RIKEN, Tokyo, Japan – name: 3 Leiden University Medical Center, Leiden, The Netherlands – name: 2 University of Oxford, Oxford, UK – name: 8 deCODE Genetics, Reykjavik, Iceland – name: 19 National Public Health Institute, ORTON Orthopedic Hospital, and ORTON Invalid Foundation, Helsinki, Finland – name: 4 Newcastle University, Newcastle upon Tyne, UK – name: 14 University of Iceland, Reykjavik, and deCODE Genetics, Reykjavik, Iceland – name: 18 Katholieke Universiteit Leuven, Leuven, Belgium – name: 6 Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain – name: 12 University of Akureyri, Akureyri, and University of Iceland, Reykjavik, Iceland – name: 5 University of Nottingham and City Hospital Nottingham, Nottingham, UK – name: 15 University of Iceland, Reykjavik, and Landspitali University Hospital, Reykjavik, Iceland – name: 23 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 – name: 7 Reykjavik University and deCODE Genetics, Reykjavik, Iceland – name: 9 Erasmus Medical Center, Rotterdam, The Netherlands – name: 16 University of California at Davis Medical Center, Sacramento, California |
| Author_xml | – sequence: 1 givenname: Evangelos surname: Evangelou fullname: Evangelou, Evangelos – sequence: 2 givenname: Kay surname: Chapman fullname: Chapman, Kay – sequence: 3 givenname: Ingrid surname: Meulenbelt fullname: Meulenbelt, Ingrid – sequence: 4 givenname: Fotini B. surname: Karassa fullname: Karassa, Fotini B. – sequence: 5 givenname: John surname: Loughlin fullname: Loughlin, John – sequence: 6 givenname: Andrew surname: Carr fullname: Carr, Andrew – sequence: 7 givenname: Michael surname: Doherty fullname: Doherty, Michael – sequence: 8 givenname: Sally surname: Doherty fullname: Doherty, Sally – sequence: 9 givenname: Juan J. surname: Gómez‐Reino fullname: Gómez‐Reino, Juan J. – sequence: 10 givenname: Antonio surname: Gonzalez fullname: Gonzalez, Antonio – sequence: 11 givenname: Bjarni V. surname: Halldorsson fullname: Halldorsson, Bjarni V. – sequence: 12 givenname: Valdimar B. surname: Hauksson fullname: Hauksson, Valdimar B. – sequence: 13 givenname: Albert surname: Hofman fullname: Hofman, Albert – sequence: 14 givenname: Deborah J. surname: Hart fullname: Hart, Deborah J. – sequence: 15 givenname: Shiro surname: Ikegawa fullname: Ikegawa, Shiro – sequence: 16 givenname: Thorvaldur surname: Ingvarsson fullname: Ingvarsson, Thorvaldur – sequence: 17 givenname: Qing surname: Jiang fullname: Jiang, Qing – sequence: 18 givenname: Ingileif surname: Jonsdottir fullname: Jonsdottir, Ingileif – sequence: 19 givenname: Helgi surname: Jonsson fullname: Jonsson, Helgi – sequence: 20 givenname: Hanneke J. M. surname: Kerkhof fullname: Kerkhof, Hanneke J. M. – sequence: 21 givenname: Margreet surname: Kloppenburg fullname: Kloppenburg, Margreet – sequence: 22 givenname: Nancy E. surname: Lane fullname: Lane, Nancy E. – sequence: 23 givenname: Jia surname: Li fullname: Li, Jia – sequence: 24 givenname: Rik J. surname: Lories fullname: Lories, Rik J. – sequence: 25 givenname: Joyce B. J. surname: van Meurs fullname: van Meurs, Joyce B. J. – sequence: 26 givenname: Annu surname: Näkki fullname: Näkki, Annu – sequence: 27 givenname: Michael C. surname: Nevitt fullname: Nevitt, Michael C. – sequence: 28 givenname: Julio surname: Rodriguez‐Lopez fullname: Rodriguez‐Lopez, Julio – sequence: 29 givenname: Dongquan surname: Shi fullname: Shi, Dongquan – sequence: 30 givenname: P. Eline surname: Slagboom fullname: Slagboom, P. Eline – sequence: 31 givenname: Kari surname: Stefansson fullname: Stefansson, Kari – sequence: 32 givenname: Aspasia surname: Tsezou fullname: Tsezou, Aspasia – sequence: 33 givenname: Gillian A. surname: Wallis fullname: Wallis, Gillian A. – sequence: 34 givenname: Christopher M. surname: Watson fullname: Watson, Christopher M. – sequence: 35 givenname: Tim D. surname: Spector fullname: Spector, Tim D. – sequence: 36 givenname: Andre G. surname: Uitterlinden fullname: Uitterlinden, Andre G. – sequence: 37 givenname: Ana M. surname: Valdes fullname: Valdes, Ana M. – sequence: 38 givenname: John P. A. surname: Ioannidis fullname: Ioannidis, John P. A. email: jioannid@cc.uoi.gr |
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| Cites_doi | 10.1002/sim.1186 10.1002/ajmg.b.30721 10.1002/art.21673 10.1093/ije/dyn065 10.1136/ard.2007.079020 10.1093/hmg/ddm174 10.1023/B:ABME.0000017549.57126.51 10.1136/ard.2006.065938 10.1093/aje/kwn156 10.1002/art.20993 10.1038/ng1245 10.1359/jbmr.1998.13.3.383 10.1038/2005 10.1002/art.1780331101 10.1038/ng0208-124 10.1097/EDE.0b013e31818131e7 10.1086/319501 10.1002/art.23137 10.1093/rheumatology/kei148 10.1016/0197-2456(86)90046-2 10.1002/jor.20464 10.1093/aje/kwj259 10.1002/art.1780290816 10.1016/j.jmb.2005.04.015 10.1073/pnas.0403456101 10.1093/ije/dym159 10.1086/428594 10.1136/bmj.39343.408449.80 10.1002/art.1780340502 10.1006/dbio.2002.0802 10.1172/JCI34772 10.1371/journal.pmed.0040079 10.1093/ije/dyn147 10.1136/ard.16.4.494 10.1016/S1357-2725(97)00025-3 10.1053/sarh.2001.24875 10.1093/hmg/ddn038 10.1007/s00439-007-0445-9 10.1001/jama.298.8.880 10.7326/0003-4819-127-9-199711010-00008 10.1093/hmg/ddm195 10.1016/S0950-3579(05)80198-0 10.1002/art.22301 10.1002/ajmg.a.10924 10.1242/dev.126.6.1305 10.1016/j.joca.2008.02.007 |
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| Keywords | Knee Knee osteoarthritis Diseases of the osteoarticular system Rheumatology Arthropathy Degenerative disease Osteoarthritis Hand Hip |
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| Snippet | Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies... GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the... Abstract Objective GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies... OBJECTIVEGDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies... |
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| SubjectTerms | Aged Aged, 80 and over Bayes Theorem Biological and medical sciences Case-Control Studies Diseases of the osteoarticular system Female Genetic Predisposition to Disease - genetics Glycoproteins - genetics Growth Differentiation Factor 5 - genetics Hand Joints Haplotypes - genetics Humans Intracellular Signaling Peptides and Proteins Male Medical sciences Middle Aged Miscellaneous. Osteoarticular involvement in other diseases Osteoarthritis Osteoarthritis - genetics Osteoarthritis, Hip - genetics Osteoarthritis, Knee - genetics Phenotype Polymorphism, Genetic - genetics |
| Title | Large‐scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand |
| URI | https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fart.24524 https://www.ncbi.nlm.nih.gov/pubmed/19479880 https://search.proquest.com/docview/67381832 https://pubmed.ncbi.nlm.nih.gov/PMC4412885 |
| Volume | 60 |
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