Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis

A.M. Valdes, J. Loughlin, K.M. Timms, J.J.B. Van Meurs, L. Southam, Scott Wilson, S. Doherty, R.J. Lories, F.P. Luyten, A. Gutin, V. Abkevich, D. Ge, A. Hofman, A.G. Uitterlinden, D.J. Hart, F. Zhang, G. Zhai, R.J. Egli, M. Doherty, J. Lanchbury & 1 others T.D. Spector

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Abstract

Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p <1 × 10−5 were estimated to have probabilities of being false positives ≤0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5′ to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio ORmh = 1.55 95% C.I. 1.30–1.85, p <6.9 × 10−7). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p <1.0 × 10−6). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA.
Original languageEnglish
Pages (from-to)1231-1240
JournalThe American Journal of Human Genetics
Volume82
Issue number6
DOIs
Publication statusPublished - 2008

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Knee Osteoarthritis
Genome-Wide Association Study
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Osteoarthritis
Replacement Arthroplasties
Chromosome Mapping
Chromosomes, Human, Pair 1
Linkage Disequilibrium
Articular Cartilage
Netherlands
Arthritis
Cartilage
Odds Ratio
Messenger RNA
Enzymes
Genes

Cite this

Valdes, A.M. ; Loughlin, J. ; Timms, K.M. ; Van Meurs, J.J.B. ; Southam, L. ; Wilson, Scott ; Doherty, S. ; Lories, R.J. ; Luyten, F.P. ; Gutin, A. ; Abkevich, V. ; Ge, D. ; Hofman, A. ; Uitterlinden, A.G. ; Hart, D.J. ; Zhang, F. ; Zhai, G. ; Egli, R.J. ; Doherty, M. ; Lanchbury, J. ; Spector, T.D. / Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis. In: The American Journal of Human Genetics. 2008 ; Vol. 82, No. 6. pp. 1231-1240.
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abstract = "Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p <1 × 10−5 were estimated to have probabilities of being false positives ≤0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5′ to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio ORmh = 1.55 95{\%} C.I. 1.30–1.85, p <6.9 × 10−7). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p <1.0 × 10−6). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA.",
author = "A.M. Valdes and J. Loughlin and K.M. Timms and {Van Meurs}, J.J.B. and L. Southam and Scott Wilson and S. Doherty and R.J. Lories and F.P. Luyten and A. Gutin and V. Abkevich and D. Ge and A. Hofman and A.G. Uitterlinden and D.J. Hart and F. Zhang and G. Zhai and R.J. Egli and M. Doherty and J. Lanchbury and T.D. Spector",
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Valdes, AM, Loughlin, J, Timms, KM, Van Meurs, JJB, Southam, L, Wilson, S, Doherty, S, Lories, RJ, Luyten, FP, Gutin, A, Abkevich, V, Ge, D, Hofman, A, Uitterlinden, AG, Hart, DJ, Zhang, F, Zhai, G, Egli, RJ, Doherty, M, Lanchbury, J & Spector, TD 2008, 'Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis' The American Journal of Human Genetics, vol. 82, no. 6, pp. 1231-1240. https://doi.org/10.1016/j.ajhg.2008.04.006

Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis. / Valdes, A.M.; Loughlin, J.; Timms, K.M.; Van Meurs, J.J.B.; Southam, L.; Wilson, Scott; Doherty, S.; Lories, R.J.; Luyten, F.P.; Gutin, A.; Abkevich, V.; Ge, D.; Hofman, A.; Uitterlinden, A.G.; Hart, D.J.; Zhang, F.; Zhai, G.; Egli, R.J.; Doherty, M.; Lanchbury, J.; Spector, T.D.

In: The American Journal of Human Genetics, Vol. 82, No. 6, 2008, p. 1231-1240.

Research output: Contribution to journalArticle

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T1 - Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis

AU - Valdes, A.M.

AU - Loughlin, J.

AU - Timms, K.M.

AU - Van Meurs, J.J.B.

AU - Southam, L.

AU - Wilson, Scott

AU - Doherty, S.

AU - Lories, R.J.

AU - Luyten, F.P.

AU - Gutin, A.

AU - Abkevich, V.

AU - Ge, D.

AU - Hofman, A.

AU - Uitterlinden, A.G.

AU - Hart, D.J.

AU - Zhang, F.

AU - Zhai, G.

AU - Egli, R.J.

AU - Doherty, M.

AU - Lanchbury, J.

AU - Spector, T.D.

PY - 2008

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N2 - Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p <1 × 10−5 were estimated to have probabilities of being false positives ≤0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5′ to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio ORmh = 1.55 95% C.I. 1.30–1.85, p <6.9 × 10−7). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p <1.0 × 10−6). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA.

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JF - The American Journal of Human Genetics

SN - 0002-9297

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