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

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The importance of genetic factors for the development of arthropathy : A longitudinal study of children and adolescents with haemophilia A. / Gomperts, Edward D; Schwarz, John; Donfield, Sharyne M.; Lail, Alice E.; Astermark, Jan; Keith Hoots, W.; Winkler, Cheryl A.; Berntorp, Erik.

I: Thrombosis and Haemostasis, Vol. 117, Nr. 2, 2017, s. 277-285.

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Gomperts, Edward D ; Schwarz, John ; Donfield, Sharyne M. ; Lail, Alice E. ; Astermark, Jan ; Keith Hoots, W. ; Winkler, Cheryl A. ; Berntorp, Erik. / The importance of genetic factors for the development of arthropathy : A longitudinal study of children and adolescents with haemophilia A. I: Thrombosis and Haemostasis. 2017 ; Vol. 117, Nr. 2. s. 277-285.

RIS

TY - JOUR

T1 - The importance of genetic factors for the development of arthropathy

T2 - Thrombosis et diathesis haemorrhagica

AU - Gomperts, Edward D

AU - Schwarz, John

AU - Donfield, Sharyne M.

AU - Lail, Alice E.

AU - Astermark, Jan

AU - Keith Hoots, W.

AU - Winkler, Cheryl A.

AU - Berntorp, Erik

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Arthritis

KW - Genetics

KW - Haemarthrosis

KW - Haemophilia

KW - Joint range of motion

UR - http://www.scopus.com/inward/record.url?scp=85011092548&partnerID=8YFLogxK

U2 - 10.1160/TH16-06-0440

DO - 10.1160/TH16-06-0440

M3 - Article

VL - 117

SP - 277

EP - 285

JO - Thrombosis et diathesis haemorrhagica

JF - Thrombosis et diathesis haemorrhagica

SN - 0340-6245

IS - 2

ER -