By Eran Leiterdorg
Familial hypercholesterolemia is a common genetic condition that can cause dangerously high levels of cholesterol to accumulate in the blood, increasing the risk of heart disease, stroke and heart attack at an early age. Among Ashkenazi Jews around the world, the incidence of FH is 2-5 times higher than in the general population. But despite this finding, FH remains widely unknown and is often undiagnosed among Ashkenazi Jews until a serious event such as a heart attack or stroke occurs.
The community of Ashkenazi Jews was founded when a group of settlers in 14thCentury Europe moved east to escape challenges ranging from the Crusades to the bubonic plague. To survive, Ashkenazi Jews in areas of Poland and Lithuania created tight-knit communities of mutual support and cooperation.
When a new community is established by a small group of families who live in close proximity for several generations, there is the chance that certain genetic traits can remain prevalent as they pass from one generation to the next. Known as the “Founder Effect,” this occurrence can increase the likelihood that members of a community will share certain physical characteristics or a risk of developing certain diseases. For Ashkenazi Jews, the Founder Effect was responsible for the increased incidence of Tay-Sachs and Gaucher disease, both of which are fairly well known. It was also responsible for the increased risk of FH among Ashkenazi Jews, which remains widely undiagnosed and relatively unknown.
FH is agenetic disorder that can be passed on to children by either one or both parents. Itis one of the most common inherited metabolic diseases in the world, found in about 1 in every 500 people. FH is caused by genetic mutations that lead to abnormalities on the surface of liver cells responsible for clearing LDL(bad cholesterol) particles from the blood. As a result, cholesterol accumulates in the bloodstream beginning at an early age. All first-degree relatives of someone with FH have a 50 percent chance of inheriting the disorder. As a result, FH families can have striking patterns of very high cholesterol levels and heart disease, heart attack or stroke early in adulthood. Early heart disease is defined as heart disease that occurs before age 65 in women and age 55 in men. In many cases, untreated people with FH who are in their 40s have arteries that are more like someone in their 80s. In addition to Ashkenazi Jews, FH is more prevalent among certain populations of people of French Canadian, Christian Lebanese andSouth African Afrikaner descent.
Only about 20 percent of people with FH have had a proper genetic diagnosis. One challenge in identifying FH is the fact that people can appear healthy and show no symptoms until they develop vascular disease that leads to a heart attack or stroke. In addition, high cholesterol is often considered to be a problem that affects people who are older or who have risk factors such as high blood pressure, diabetes or obesity. Children and young adults are rarely screened for high cholesterol.
If FH is diagnosed early, the associated vascular problems can often be properly treated and monitored, helping to delay or prevent serious events including heart attack and stroke. Many FH patients can manage their condition with cardiac medications and changes in diet and exercise. However, children who inherit the trait from both parents, and even some who inherit it from only one parent, can develop a severe form of FH that leads to cholesterol levels 2-4 times above the target level even with lifestyle changes and treatment with the maximum doses of cholesterol lowering medicines.
All families, and especially those at high risk of carrying the trait for FH, should develop a family tree to identify family members who had high cholesterol, heart attack or stroke at an early age. When one person in a family is diagnosed with FH, doctors will often suggest that parents, siblings, and children also be screened. The latest guidelines from the National Heart, Lung, and Blood Institute (NHLBI) and The American Academy of Pediatrics (AAP) recommend that children in families with a pattern of early heart attacks or heart disease have their cholesterol screened between the ages of 2 and 8.
FH in Ashkenazi Jews
In the late 1980s researchers at Hadassah University Hospital in Jerusalem led an effort to identify the trait that is associated with FH in Ashkenazi Jews, and found a genetic mutation called G197del LDLR that may have been prevalent in the Jewish settler communities of the 14th Century.
The research showed that G197del LDLR is now prevalent among populations of Ashkenazi Jews in many locations around the world, including families in the United States, South Africa, the United Kingdom, Germany and Russia. A decade of exhaustive historical and medical research unveiled a prevalence of G197del LDLR well-beyond the initial discovery, showing that it was particularly common in South Africa and Israel. Researchers were able to piece together clues through a process called linkage disequilibrium analysis, and worked backwards to develop a timeline mapping the migration of the gene mutation.
Results suggest G197del LDLR originated in the late Middle Ages when new opportunities for a Founder Effect were offered by a small group of European Jewish settlers moving eastward. The settlers eventually established a community in Lithuania around 1338. Favorable conditions led the community to grow to a population of 10-12 thousand Ashkenazi Jews living in Lithuania and Poland by 1500.
Russia conquered Lithuania in the 17th century, and Ashkenazi Jews continued their migration east, settling in St. Petersburg. There they remained in relative isolation until the turn of the 19th Century, when significant pogroms sparked a massive emigration by Jewish families. Many traveled to Great Britain, South Africa, Australia, Palestine, and America, carrying with them the G197del LDLR mutation.
There are now many online and other resources available to help people learn about FH and how to protect themselves and their families, including www.FHJourneys.comand www.learnyourlipids.com. For most patients, the tools to identify and manage high cholesterol associated with FH are available. Among Ashkenazi Jews, we must continually reinforce the risk of FH and the need to research family history, get tested, and talk to a doctor early, before problems become severe and life threatening.