New Genes Discovered Responsible for High Cholesterol and Heart Disease article and image
Familial Hypercholesterolemia (FH) is one of the most common genetic disorders. It is estimated that one in 300 individuals has FH and that of patients with premature coronary disease, one in 20 is affected by the disease. This disorder is inherited in an autosomal dominant fashion, which means that one defective gene, inherited from either parent, is enough to lead to symptoms.
Familial Hypercholesterolaemia is characterized by the defective clearance of low-density lipoprotein cholesterol (LDL-C), from the blood. This results in extremely elevated levels of LDL – C (the “bad“ cholesterol). Carriers of this gene have a six times higher risk than the general public of developing early onset of coronary artery disease and sudden death.
The most common cause of FH is a genetic defect in the LDL-C receptor in liver cells. Normally, this receptor attaches to the LDL- C particles in the blood which enables the body to excrete them through the liver into the bile. In cells with defective LDL receptors, this normal process is inefficient resulting in high plasma levels of LDL-C. The LDL then accumulates in blood vessels and causes atherosclerotic disease.
Because FH is associated with significant risk, it is important to make the diagnosis in a timely fashion so as to initiate treatment and prevent early death. The Hadassah Center for the Treatment and Prevention of Atherosclerosis leads the Israeli effort to identify families with FH and to offer preventive treatment.
A “Founder Effect” occurs when a group becomes separated from the general population, and remains isolated. This can lead to a high incidence of what are normally unusual diseases in that population, as the genetic mutations of the “founders” of the population spread into the next generations. Founder effects have been identified in many populations in Israel; in the Ashkenazi Jewish population, founder effects date back to the 14th century. Two decades ago the Hadassah lipid team reported a series of genes that were responsible for a large percentage of the FH in Israel. They screened 192 families and found 15 different mutations. The FH patients harboring these 15 mutations originated from 10 countries (Hungary, Iraq, Israel, Lebanon, Lithuania, Morocco, Poland, Romania Russia, and Syria).
We recently tested additional families suspected of being FH carriers, using the newest DNA sequencing technologies. We identified four previously unknown mutations; three in the Jewish population and one in a large Druze family. Results of this analysis were recently published in the prestigious "Atherosclerosis" medical journal.
Our understanding of FH mutations has changed considerably over the past 20 years because of immigration patterns and access to newer technologies to identify mutations. The Hadassah laboratories have been and continue to be leaders in this field. We continue to work on new strategies to improve early screening in our population, and we plan to further explore these new mutations to see if any of them provide clues about how to prevent and treat atherosclerotic disease.
Diagrammatic representation of the LDLR annotated with identified sequence changes in the Israeli FH cohort. The stars indicate novel variants seen only in the Israeli population.
