Association between HMOX1 and HP polymorphisms and joint damage in haemophiliacs

Haemophilia is an X-chromosome linked, recessive bleeding disorder due to a
deficiency or functional defect of coagulation factor VIII or IX. Due to
recurrent joint bleeds (haemarthroses) specific changes occur in synovium and
cartilage in the joint.
Our group showed that haemoglobin-derived iron is one of the major contributors
of blood-induced cartilage damage. Possible mechanisms of protection against
haem-induced oxidative and inflammatory stress are haem-oxygenase (HO-1) that
breaks down haem, and the haemoglobin-scavenging molecule haptoglobin (Hp).
The length of a guanine-thymidine (GT)n-repeat polymorphism in the promoter
region of the HMOX1 gene determines the level of HO-1 induction. In RA patients
a long (GT)n-repeat (n >= 25; less HO-1 expression) is associated with joint
damage, but not with disease activity. The Hp gene codes for three phenotypes,
Hp 1-1, Hp 1-2, and Hp 2-2. Hp 1-1 is characterized by a higher haemoglobin
binding ability, suggesting that haemophilia patients with this phenotype will
be better protected against blood-induced joint damage.
Unless prophylactic treatment of haemophiliacs with clotting factors, patients
still have the tendency to bleed and to develop joint damage. Until now, there
are no indications which patients will develop more severe joint damage after
bleedings. Even with a similar bleeding pattern, the amount of radiological
joint damage differs between patients.

With this study we want to get more insight in genetic characteristics that are
able to predict the susceptibility to joint damage in haemophilia patients.
Therefore we want to determine the association between the (GT)n-repeat length
within the HMOX1 promoter region and radiographic joint damage in haemophilia
patients, and the association between the HP phenotype and radiographic joint
damage.

This study is designed as a cross-sectional study: at one time point in the
disease process, biomaterials will be collected and evaluated. No intervention
is performed. Severe haemophilia patients visit the Van Creveld Clinic on a
regular base, two or three times a year, and a moderate patient once a year.
During these visits blood will be taken to perform routine tests, like
determination of antibodies against factor VIII or IX. When blood is drawn for
routine tests, we will ask the patient to give an additional 2x10 ml blood for
our study once.

There are no considerable risks or benefits for the patients. X-rays to
determine radiological damage are made every 5 years by the Van Creveld Clinic
and the number of bleedings is kept in daily practice by the patients. During a
visit at the Van Creveld Clinic we will draw an additional 2x10 ml while blood
is taken routinely by a nurse.