Incidence of type 2 diabetes mellitus and cardiovascular disease in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is a highly prevalent genetic
dyslipidemia in Western society. It is characterized by elevated plasma
cholesterol and triglycerides levels in families with a premature myocardial
infarction (i.e. before the age of 60).
After four decades of intensive research, we have learned that FCHL is a
complex genetic disease, i.e. multiple susceptibility genes (currently up to 35
genes have been described) interact with environmental factors, i.e. unhealthy
life style habits, to finally result in the combined hyperlipidemic phenotype.
FCHL is associated with the metabolic syndrome: many FCHL patients are
charcterized by metabolic syndrome associated factors: insulin resistance,
abdominal obesity, hypertension and nonalcoholic fatty liver disease. FCHL is
also a heterogeneous disease: some genetic abnormalities are frequent among
FCHL pedigrees with usually a modest effect on plasma cholesterol and
triglycerides, whereas other genetic defects are rare with a substantial effect
on clinical phenotype. In context of the latter, cholesteryl ester storage
disease (CESD) is of interest. This is a rare inborn error of metabolism,
characterized by combined hyperlipidemia, fatty liver and premature
atherosclerosis, which is exactly the phenotype that characterizes FCHL.
Therefore, in theory, some FCHL pedigrees could be affected by CESD.

Despite advanced knowlegde, little is known with regard to the natural history
of FCHL. Two complications are of particular clinical interest:
1) Type 2 diabetes mellitus (T2DM); it is known that the metabolic syndrome is
associated with an increased risk to develop T2DM. A five-year follow-up study
in FCHL patients indeed suggested an increased risk to develop T2DM. This study
was, however, was conducted in a small group of patients and was of a
relatively short duration to come to a reliable estimate of the incidence of
T2DM in FCHL families. Not only FCHL patients are of interest, but also their
normolipidemic relatives as they exhibit features of the metabolic syndrome as
well.
2) Cardiovascular disease (CVD); to date, only 1 longitudinal study has
examined the incidence of CVD in FCHL. This study reported only mortality (and
not non-fatal cases). Moreover, it was conducted in an era in which
cardiovascular prevention was only starting. It is anticipated that CVD risk
has improved, but this has not been investigated yet.

To determine:
1) the incidence of type 2 diabetes mellitus in FCHL patients,
normolipidemic relatives and their spouses
2) the incidence of cardiovascular disease in FCHL patients,
normolipidemic relatives and their spouses
3) the prevalence of CESD in FCHL pedigrees

This is a longitudinal, comparitve study

Subjects will be asked to visit the research unit after an overnight fast and
to refrain from smoking on the day of their visit. In addition, they will be
asked not to consume any alcohol 3 days prior to the measurements. Measurements
will take approximately 1-1.5 hours in total and include: questionnaires,
anthropometrics (weight, height, waist/hip circumference and skinfold
measurements), blood pressure determination and blood withdrawal (6 tubes will
be drawn, 32 ml in total). The health risks associated with this procedure is
low: some will develop haematomas, which normally resolve spontaneously.

Potential benefits: subjects will undergo a cardiovascular risk assessment,
including blood pressure, plasma glucose and plasma lipids, which may be
beneficial to prevent future cardiovascular events. In addition, dyslipidemic
subjects will also be tested for the presence of CESD, for which currently
clinical intervention trials are undertaken.