Valdes, Ana M., Doherty, Sally A., Muir, Kenneth (Kenneth R.), Zhang, Weiya, Maciewicz, Rose A., Wheeler, Margaret, Arden, N. (Nigel), Cooper, Cyrus and Doherty, M., M.D.. (2012) Genetic contribution to radiographic severity in osteoarthritis of the knee. Annals of the Rheumatic Diseases, Vol.71 (No.9). pp. 1537-1540. ISSN 0003-4967

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Abstract

Objective Knee osteoarthritis (OA) has a significant genetic component. The authors have assessed the role of three variants reported to influence risk of knee OA with p<5×10–8 in determining patellofemoral and tibiofemoral Kellgren Lawrence (K/L) grade in knee OA cases. Methods 3474 knee OA cases with sky-line and weight-bearing antero-posterior x-rays of the knee were selected based on the presentation of K/L grade ≥2 at either the tibiofemoral or patellofemoral compartments for one or both knees. Patients belonging to three UK cohorts, were genotyped for rs143383, rs4730250 and rs11842874 mapping to the GDF5, COG5 and MCF2L genes, respectively. The association between tibiofemoral K/L grade and patellofemoral K/L grade was assessed after adjusting for age, gender and body mass index. Results No significant association was found between the rs4730250 and radiographic severity. The rs11842874 mapping to MCF2L was found to be nominally significantly associated with patellofemoral K/L grade as a quantitative trait (p=0.027) but not as a binary trait. The GDF5 single nucleotide polymorphism rs143383 was associated with tibiofemoral K/L grade (β=0.05 (95% CI 0.02 to 0.08) p=0.0011). Conclusions Our data indicate that within individuals affected by radiographic knee OA, OAGDF5 has a modest but significant effect on radiographic severity after adjustment for the major risk factors.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Health Sciences
Library of Congress Subject Headings (LCSH):	Osteoarthritis -- Genetic aspects, Knee -- Diseases -- Genetic aspects
Journal or Publication Title:	Annals of the Rheumatic Diseases
Publisher:	BMJ
ISSN:	0003-4967
Date:	2012
Volume:	Vol.71
Number:	No.9
Page Range:	pp. 1537-1540
Identification Number:	10.1136/annrheumdis-2012-201382
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Seventh Framework Programme (European Commission) (FP7)
References:	1. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367:1747–57. 2. Chapman K, Valdes AM. Genetic factors in OA pathogenesis. Bone 2011 (In press). 3. Panoutsopoulou K, Southam L, Elliott KS, et al. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study. Ann Rheum Dis 2011;70: 864–7. 4. Valdes AM, Evangelou E, Kerkhof HJ, et al. The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical signifi cance. Ann Rheum Dis 2011;70:873–5. 5. Evangelou E, Valdes AM, Kerkhof HJ, et al. Meta-analysis of genome-wide association studies confi rms a susceptibility locus for knee osteoarthritis on chromosome 7q22. Ann Rheum Dis 2011;70:349–55. 6. Day-Williams AG, Southam L, Panoutsopoulou K, et al. A variant in MCF2L is associated with osteoarthritis. Am J Hum Genet 2011;89:446–50. 7. Cornelis FM, Luyten FP, Lories RJ. Functional effects of susceptibility genes in osteoarthritis. Discov Med 2011;12:129–39. 8. Altman RD, Hochberg M, Murphy WA Jr, et al. Atlas of individual radiographic features in osteoarthritis. Osteoarthr Cartil 1995;3 Suppl A:3–70. 9. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26–35. 10. Valdes AM, Doherty SA, Zhang W, et al. Inverse relationship between preoperative radiographic severity and postoperative pain in patients with osteoarthritis who have undergone total joint arthroplasty. Semin Arthritis Rheum 2012;41:568–75. 11. Cushnaghan J, Bennett J, Reading I, et al. Long-term outcome following total knee arthroplasty: a controlled longitudinal study. Ann Rheum Dis 2009;68:642–7. 12. Conaghan PG, D’Agostino MA, Le Bars M, et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study. Ann Rheum Dis 2010;69:644–7. 13. Miyamoto Y, Mabuchi A, Shi D, et al. A functional polymorphism in the 5’ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 2007;39:529–33. 14. Yamauchi J, Chan JR, Miyamoto Y, et al. The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration. Proc Natl Acad Sci USA 2005;102:5198–203.
URI:	http://wrap.warwick.ac.uk/id/eprint/49242

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