Is there a relation between the P blood group status and Fabry disease severity?

Fabry disease (OMIM 301500) is an X-linked lysosomal storage disease caused by
a deficiency of the lysosomal enzyme alpha-galactosidase A1. This enzyme is
essential in the degradation of certain glycosphingolipids (predominantly GB3,
also known as blood group antigen Pk) and as a consequence Fabry patients
accumulate these glycosphingolipids. Lipid accumulation occurs in many
cell-types, including the vascular endothelium which in turn is thought to
cause progressive renal insufficiency, cardiac hypertrophy and cerebral
infarctions, which are often seen in this disorder2. The Fabry phenotype is
very heterogeneous, and the contributing factors to this broad expression are
poorly understood. The lack of a reliable predictor for disease severity
troubles predicting individual prognosis, and hampers decisions about treatment
indication.
One hypothesis to explain the phenotypic variability is that the
synthesis and presence of GB3 in cells might differ between Fabry patients
(e.g. the more GB3 a Fabry patient synthesizes, the more they may suffer from
Fabry disease). Recently a single nucleotide polymorphism ( SNP 42C>T) in the
GB3 synthase (*-1,4-galactosyltransferase, A4GALT) gene was discovered which
influences the correct splicing of the GB3 synthase mRNA leading to lower
levels of the enzyme and consequently to decreased levels of GB3 and other
glycosphingolipids on erythrocytes 3. Presence or absence of the 42C>T-SNP
determines an individual's blood group P status (e.g. erythrocyte GB3
expression). The P status can now be defined as P1P1, P1P2 or P2P2, where P2P2
has less GB3 erythrocyte surface expression than P1P1 and P1P2 intermediate GB3
surface expression.
Though blood group P status correlates with GB3 content on erythrocytes
it is unknown how it influences GB3 status on other cell types. We hypothesized
that, if blood group P correlates with GB3 content on all cells, blood group P
status could be a predictor of GB3 burden and predict phenotype heterogeneity
in Fabry disease. To test our hypothesis we chose to examine this in
fibroblasts for practical reasons: they were yet available in a biobank of the
lab Genetisch Metabole Ziekten (with informed consent). White blood cells of
healthy controls are necessary to see whether data of Thuresson et al. 3 are
reproducible.
An earlier study in Fabry patients could not find a correlation between
blood group P status and Fabry disease severity 4. However, this study
determined blood group P serologically, which is less precise than the genetic
determination. Further restrictions of this study were a small Fabry cohort and
the lack of a disease severity classification. Also the relation of blood group
P to different cell types was not investigated.

The following research questions were formulated:
• Does blood group P status (presence or absence of the 42C>T-SNP) correlate to
GB3 content on fibroblasts and white blood cells of healthy controls?
• Does blood group P status correlate to (lyso) GB3 in plasma or urine of Fabry
patients?
• Does blood group P status correlate to Fabry disease severity?

This study consists of two parts. Part one is an observational laboratory study
on white blood cells and fibroblasts of healthy subjects. Part two is an
observational retrospective cohort analysis on (existing) clinical and
biochemical data (DNA, Fabry biomarkers) of Fabry patients. The data of Fabry
patients was earlier collected for routine health care.

Participation in this study has no direct advantage for the participants.
However, the risks associated with venapunctions are negligible and little
physical or psychological discomfort associated with participation is expected.