The importance of genetic factors for the development of arthropathy: a longitudinal study of children and adolescents with haemophilia AFinancial support: This work is supported by the National Institutes of Health, National Institute of Child Health and Human Development, R01-HD-41224; by the Lund University, Centre for Thrombosis and Haemostasis, Skåne University Hospital Malmö/Lund, Malmö, Sweden; by an investigator-initiated grant from Baxter BioScience; and in part with federal funds from the NIH National Cancer Institute (NCI) under Contract No. HHSN261200800001E, and the Intramural Research Program of the NIH-NCI Center for Cancer Research.
Received:09. Juni 2016
Accepted after major revision:10. November 2016
01. Dezember 2017 (online)
Haemophilia A is a congenital bleeding disorder characterised by recurrent haemorrhages into the major joints. Haemophilic arthropathy is a well-established outcome of recurrent joint bleeding; however, it is clear that multiple factors determine the extent and severity of its occurrence. We sought to identify genetic factors related to abnormalities in range of motion (ROM) in the knees, ankles and elbows in a cohort of children and adolescents with haemophilia A not treated primarily with regular prophylaxis. Using data from the Haemophilia Growth and Development Study, we examined associations between 13,342 genetic markers and ROM scores measured at six-month intervals for up to seven years. As a first step, ordered logistic regression models were fit for each joint separately. A subset of SNP markers showing significant effects (p<0.01) on the right and left sides for at least two joints were included in a full model fit using a multivariate generalised linear mixed model assuming an ordinal response. The models contained all ROM scores obtained at all visits. Twenty-five markers analysed in the full model showed either increased or decreased risk of ROM abnormalities at the p<0.001 level. Several genes identified at either the first or second stage of the analysis have been associated with arthritis in a variety of large studies. Our results support the likelihood that risk for haemophilic arthropathy is associated with genetic factors, the identification of which holds promise for further advancing the individualisation of treatment.
- 1 Arnold WD, Hilgartner M. Hemophilic arthropathy. Current concepts of pathogenesis and management. J Bone Joint Surg Am 1977; 59: 287-305.
- 2 Madhok R, York J, Sturrock RD. Haemophilic arthritis. Ann Rheum Dis 1991; 50: 588-591.
- 3 Aledort L, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994; 236: 391-399.
- 4 Pollmann H, Richter H, Ringkamp H. et al. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr 1999; 158: S166-S170.
- 5 Soucie JM, Cianfrini C, Janco RL. et al. Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors. Blood 2004; 103: 2467-2473.
- 6 Nijdam A, Altisent C, Carcao MD. et al. Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades. Haematologica 2015; 100: e84.
- 7 Miners A, Sabin C, Tolley K. et al. Assessing health-related quality-of-life in individuals with haemophilia. Haemophilia 1999; 05: 378-385.
- 8 Mainardi CL, Levine PH, Werb Z. et al. Proliferative synovitis in hemophilia. Biochemical and morphologic observations. Arthritis Rheum 1978; 21: 137-144.
- 9 Valentino L. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Heamost 2010; 08: 1895-1902.
- 10 Hakobyan N, Enockson C, Cole A. et al. Experimental haemophilic arthropathy in a mouse model of a massive haemarthrosis: gross, radiological and histological changes. Haemophilia 2008; 14: 804-809.
- 11 Forsyth A, Rivard GÉ, Valentino L. et al. Consequences of intra-articular bleeding in haemophilia: science to clinical practice and beyond. Haemophilia 2012; 18 (Suppl. 04) 112-119.
- 12 Roosendaal G, Vianen ME, Wenting MJ. et al. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia. J Bone Joint Surg Br 1998; 80: 540-545.
- 13 Roosendaal G, Van Rinsum A, Vianen M. et al. Haemophilic arthropathy resembles degenerative rather than inflammatory joint disease. Histopathology 1999; 34: 144-153.
- 14 Decker J, Malone D, Haraoui B. et al. Rheumatoid arthritis: evolving concepts of pathogenesis and treatment. Ann Intern Med 1984; 101: 810-824.
- 15 Hooiveld MJ, Roosendaal G, Van Den Berg H. et al. Haemoglobin-derived iron-dependent hydroxyl radical formation in blood-induced joint damage: an in vitro study. Rheumatology 2003; 42: 784-790.
- 16 Wen F-Q, Jabbar AA, Chen Y-X. et al. C-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide. Blood 2002; 100: 912-916.
- 17 Hooiveld M, Roosendaal G, Wenting M. et al. Short-term exposure of cartilage to blood results in chondrocyte apoptosis. Am J Pathol 2003; 162: 943-951.
- 18 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-544.
- 19 Ragni M, Fogarty P, Josephson N. et al. Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres. Haemophilia 2012; 18: 63-68.
- 20 Nilsson I, Berntorp E, Löfqvist T. et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32.
- 21 Carcao MD, van den Berg HM, Ljung R. et al. Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A. Blood 2013; 121: 3946-3952.
- 22 Ahlberg A. Indicence, treatment and prophylaxis of arthropathy and other musculoskeletal manifestations of haemophilia A and B. Acta Orthop Scand 1965; 05: 20-39.
- 23 Astermark J, Donfield S, Gomperts E. et al. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood 2013; 121: 1446-1454.
- 24 Hilgartner MW, Donfield SM, Willoughby A. et al. Hemophilia Growth and Development Study: Design, Methods Entry Data. J Pediatr Hematol Oncol 1993; 15: 208-218.
- 25 Lakich D, Kazazian H, Antonarakis S. et al. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993; 05: 236-241.
- 26 Oldenburg J. Mutation profiling in haemophilia A. Thromb Haemost 2001; 85: 577-579.
- 27 Price AL, Patterson NJ, Plenge RM. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904-909.
- 28 Eleftherohorinou H, Hoggart CJ, Wright VJ. et al. Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways. Hum Mol Gen 2011; 20: 3494-3506.
- 29 Hüffmeier U, Uebe S, Ekici AB. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nature Genet 2010; 42: 996-999.
- 30 Feng B, Sun L, Soltani-Arabshahi R. et al. Multiple loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet 2009; 05: 0e1000606.
- 31 Liu Y, Helms C, Liao W. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 2008; 04: e1000041.
- 32 Gregersen P, Amos C, Lee A. et al. REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat Genet 2009; 41: 820-823.
- 33 Ellinghaus E, Stuart PE, Ellinghaus D. et al. Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL. J Invest Dermatol 2012; 132: 1133-1140.
- 34 Wang J, Bansal A, Martin M. et al. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics 2013; 13: 235-241.
- 35 Stahl E, Raychaudhuri S, Remmers E. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature Genet 2010; 42: 508-514.
- 36 Sheth T, Pitchumoni C, Das K. Musculoskeletal Manifestations in Inflammatory Bowel Disease: A Revisit in Search of Immunopathophysiological Mechanisms. J Clin Gastroenterol 2014; 48: 308-317.
- 37 Zhang M, Wang J. Epigenetics and Osteoarthritis. Genes Dis 2015;. Epub ahead of print.
- 38 Fransen M, Simic M, Harmer A. Determinants of MSK health and disability: Lifestyle determinants of symptomatic osteoarthritis. Best Pract Res Clin Rheumatol 2014; 28: 435-460.
- 39 Roosendaal G, Jansen NW, Schutgens R. et al. Haemophilic arthropathy: the importance of the earliest haemarthroses and consequences for treatment. Haemophilia 2008; 14 (Suppl. 06) 4-10.
- 40 Roosendaal G, Lafeber FP. Pathogenesis of haemophilic arthropathy. Haemophilia 2006; 12 (Suppl. 03) 117-121.
- 41 Astermark J, Petrini P, Tengborn L. et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Brit J Haematol 1999; 105: 1109-1113.
- 42 Fischer K, Carlsson K, Petrini P. et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013; 122: 1129-1136.