A search for novel genes causing familial hypercholesterolemia on the former island of Urk

(medical)genetics familial hypercholesterolemia

Prof. dr. T.P.W. Kamphuisen
dr. J.A. Kuivenhoven
J. Balder

Nature of the research:
Patient-related and fundamental research

Fields of study:
genetics vascular medicine cardiology

Background / introduction
Familial hypercholesterolemia (FH) is a common monogenic disease which presents with increased levels of cholesterol1,2. Increased levels of cholesterol lead to accelerated development of atherosclerosis. In 60% of the individuals with FH, mutations are present in known genes. In the remaining cases, no mutation in candidate genes can be found. Unravelling of the exact molecular mechanisms that causes FH in these individuals can provide knowledge to develop pharmaceutical strategies to decrease LDLc in those at high risk of atherosclerosis.
To this extent, the identification of families with unexplained FH constitutes is a first step. Because Urk has been an isolated island for centuries, chances of finding genetic disorders is increased. At this moment we are collaborating with several general practitioners from Urk. They provided us with a database of all the lipid measurements conducted since 2011. With this database we will select the most interesting index patients and start the identification of the most interesting families with increased levels of cholesterol. For further selection, we will look at family history of CVD, clinical history, physical examination (using the Dutch Lipid Clinic Netwerk criteria).
The student can help us in selecting the most interesting families and actively recruit these families for scientific research.
Research question / problem definition
1. How many interesting families with FH are present in the population of Urk?
2. Initiate the collection of patient-derived materials to help the search for the molecular origin of hypercholesterolemia
The student will participate in the identification and recruitment of the families. In a next step, he/she will help with the harvesting of materials from these individuals. DNA/RNA analyses will be performed under direct guidance of Dr. Antoine Rimbert (postdoc) and Dr. Jan Albert Kuivenhoven. The work will be performed in collaboration with the Department of Genetics (Prof R.J. Sinke).

Parameters to select index cases:
- Presence of increased levels of cholesterol
- Presence of family members with increased levels of cholesterol
- Presence of clinical symptoms of FH
- Manifestations of cardiovascular disease
After selection of the most interesting cases, the families of these patients will be recruited to obtain blood to:
- Measure the lipid levels
- Isolate DNA for sequencing genes that are known to cause FH
- Isolate mRNA from peripheral blood mononuclear cells for RNA sequencing
- Urine for metabolomics and lipidomic analyses.
1. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: Prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97(11):3956-3964.
2. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the european atherosclerosis society. Eur Heart J. 2013;34(45):3478-90a.
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