Thromb Haemost 2017; 117(02): 277-285
DOI: 10.1160/TH16-06-0440
Coagulation and Fibrinolysis
Schattauer GmbH

The importance of genetic factors for the development of arthropathy: a longitudinal study of children and adolescents with haemophilia A

Edward D. Gomperts
1  Keck School of Medicine, University of Southern California and Children’s Hospital Los Angeles, Los Angeles, California, USA
,
John Schwarz
2  Department of Biostatistics, Rho, Inc., Chapel Hill, North Carolina, USA
,
Sharyne M. Donfield
2  Department of Biostatistics, Rho, Inc., Chapel Hill, North Carolina, USA
,
Alice E. Lail
2  Department of Biostatistics, Rho, Inc., Chapel Hill, North Carolina, USA
,
Jan Astermark
3  Lund University, Centre for Thrombosis and Haemostasis, Malmö, Sweden
,
W. Keith Hoots
4  Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
,
Cheryl A. Winkler
5  Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
,
Erik Berntorp
3  Lund University, Centre for Thrombosis and Haemostasis, Malmö, Sweden
› Institutsangaben
Financial 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.
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Publikationsverlauf

Received:09. Juni 2016

Accepted after major revision:10. November 2016

Publikationsdatum:
01. Dezember 2017 (online)

Summary

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.