Differences in the genetic coding for HFE, HMOX1 and haptoglobin, important in handling of iron and haem, in relation to the severity of haemophilic arthropathy

In the genetic bleeding disorder haemophilia, recurrent joint bleeds lead to
specific changes in synovium and cartilage called haemophilic arthropathy.
There is an unexplained variation in the susceptibility to joint damage. Even
with a similar bleeding pattern, the amount of radiological joint damage
differs between patients.
It is shown that haemoglobin and its degradation products haem and iron are
important factors contributing to this joint damage. Impaired clearance of iron
from the joint might play a role in developing more severe joint damage.
Several mechanisms might be involved. In this study we focus on three
genetically determined mechanisms (polymorphisms). 1) A pilot study in
haemophiliacs suggested the association between carriership of a
haemochromatosis gene (HFE) mutation and the severity of haemophilic
arthropathy. 2) A possible mechanism of protection against haem-induced damage
is haem-oxygenase (HO)-1 that breaks down haem. The length of a
guanine-thymidine (GT)n-repeat in the promoter region of the gene encoding HO-1
(HMOX1) determines the level of HO-1 induction. A long (GT)n-repeat (n-repeat *
25) resulting in less HO-1 expression, is in rheumatoid arthritis associated
with more severe joint damage. 3) There may be protection of joint damage by
the haemoglobin-scavenging molecule haptoglobin (Hp). There are two alleles of
the Hp gene coding for three different phenotypes; Hp2-2 has a lower
haemoglobin binding ability compared to the other two phenotypes, suggesting
more susceptibility to blood-induced joint damage.

The aim of the study is to evaluate whether these three genetic characteristics
are able to predict the susceptibility to joint damage in haemophilia patients.
Therefore we want to determine the association between the progression of
radiographic joint damage and these three genetic characteristics: carriership
of an HFE mutation, the (GT)n-repeat length within the HMOX1 promoter region,
and the Hp genotype.

The study is designed as a cross-sectional study to collect biomaterials, using
retrospectively collected longitudinal clinical data, and without an
intervention performed. Severe haemophilia patients visit the Van
Creveldkliniek on a regular base, two to three times a year, and moderate
haemophilia patients at least once a year. During these visits blood is taken
for regular care activities to perform routine tests, e.g. to determine the
development of inhibitors against factor VIII/IX. When blood is drawn for these
routine tests, patients are asked to give an additional 3x10ml blood for the
proposed study.

There are no considerable risks or direct benefits for the patients. In general
care X-rays to determine radiological damage are made routinely at least every
5 years by the Van Creveldkliniek and registration of joint bleeds in a diary
is standard. An additional 3x10ml blood is taken for research purposes of the
present study during a visit at the Van Creveldkliniek at the time of regular
blood sampling for patient care, routinely by a nurse dedicated to venipuncture
by these patients.
The final outcome of the study may lead to a change in prophylactic treatment
of patients to prevent bleedings even better in those with the highest risk of
damage.