Public Health Genomics in Action: Reducing Morbidity and Mortality from Familial Hypercholesterolemia

In September, 2013, I participated in the International Familial Hypercholesterolemia (FH) Summit  in Annapolis, Maryland. The event was sponsored by the FH Foundation, a patient-centered organization formed in 2011 to raise awareness about the condition and to develop actions for saving lives of patients and families with FH.  The meeting brought together, from the US and around the world, a mix of researchers, patients, industry representatives, state public health programs, and clinical practitioners–including primary care providers and specialists in genetics, cardiology, and lipidology–to develop a public health approach to reduce the burden of FH.

What is FH? It is one of the most common genetic conditions, estimated to affect 1 in 500 people worldwide, including more than 600,000 people in the US.  FH is a disorder of cholesterol metabolism associated with mutations in the low-density lipoprotein (LDL) receptor and a few other genes. FH is inherited in an autosomal dominant fashion. People who have one mutation (heterozygotes) are at high risk of premature heart disease as early as their 30’s and 40s.  People who carry two mutations (homozygotes) are extremely rare in the population but develop heart disease as early as the first decade of life. Stories about FH patients and their families can be found on the FH Foundation website.

Why is FH a priority for public health genomics in the United States? CDC’s Office of Public Health Genomics has defined Tier 1 genomic applications as those for which evidence-based interventions are recommended. Tier 1 applications include cascade screening for FH, as well as for Lynch syndrome and hereditary breast/ovarian cancer (HBOC).  In the US, it is estimated that close to 2 million people are affected with one of these three conditions but most have not been diagnosed. Since all three conditions are inherited in an autosomal dominant fashion, first degree relatives have a 50% chance of being affected. If diagnosed early, they can benefit from available interventions that save lives. Cascade screening is a systematic approach to testing family members of affected persons with the goal of early diagnosis and intervention to reduce risk of disease and death. In 2012, the CDC held a multidisciplinary meeting that resulted in the development of a public health genomics implementation plan. A state-by-state clickable map indicates Tier 1 activities in each state. An implementation toolkit is planned for release by the end of the calendar year.

International estimates suggest that in most countries, the vast majority (>90%) of persons with FH are not diagnosed.  Although FH accounts for less than 1 percent of all coronary heart disease cases, it accounts for a larger proportion of early onset heart disease. Persons with FH have very high levels of LDL cholesterol starting in childhood. The discovery of the LDL receptor mutation in FH patients–for which Goldstein and Brown won the Nobel prize in 1985–led to the development of statins as a new class of drugs to combat high cholesterol, a major cause of heart disease in populations. Millions of people with high holesterol level currently benefit from the use of statins, although most of them do not have FH.

In 2008, the National Institute for Clinical Excellence in the UK recommended that relatives of FH be ascertained by cascade screening because early detection and treatment can reduce morbidity and mortality and can be cost-effective. In 2008, the United States Preventive Services Task Force recommended cholesterol screening starting at age 20 years for people with increased risk of heart disease, including those with a family history of early heart disease.  In 2011, the American Academy of Pediatrics recommended cholesterol screening for all children 9-11 years old and even earlier for children at higher risk.

Participants at the FH summit reviewed results of cascade screening in several countries including the UK, the Netherlands, South Africa and Spain. In the Netherlands, nationwide cascade screening efforts conducted over the past two decades ascertained more than three quarters of all cases, reduced FH morbidity and mortality, and was shown to be cost- effective. The group also discussed possible FH screening approaches in the U.S., including at birth, during childhood, and later on in life. Cholesterol screening around age 10 years may provide better discriminatory power in finding FH patients as compared to later in life. The group also reviewed the potential but currently unclear role of DNA testing in population screening for FH. The group focused on three existing sets of FH diagnostic criteria and noted that data are sparse and inconsistent on the comparative performance of these criteria in US population settings.  Such data are crucial for developing and implementing successful cascade screening recommendations.

A major theme that emerged from the meeting was the need for US population-based data on FH, including data on prevalence and natural history of the condition, the best approaches for case finding, and assessing impact of interventions. Such data are also essential before  developing national long term goals, such as Healthy People 2020 objectives. Such objectives currently exist for HBOC and Lynch syndrome but not for FH.

Several proposed actions from the meeting could facilitate collection of population-based data. These include: 1) developing a consensus case definition for FH screening in the population that is driven by actual data; 2) developing specific ICD codes based on case definition for FH to track the condition in death certificates, hospital discharge diagnoses, and electronic health records; 3) and the launch by the FH foundation of new national CASCADE FH registry. The registry is modeled after existing national registries for other genetic diseases such as the Cystic Fibrosis Foundation registry. The FH registry aims to enroll a substantial fraction of patients with FH and their families in the US in the next few years. Once established, it could help in identifying knowledge gaps, facilitating research and tracking progress over time. In order for such a registry to be informative and representative, public health collaboration with the healthcare system will be needed to raise awareness and involve underserved patients and communities.

The meeting report and recommendations will be published in the next few months. The meeting provides an example of public health genomics in action. It illustrates the convergence of many stakeholders to plan the implementation of evidence-based genomics. With the recent celebration of the 10-year anniversary of the completion of the Human Genome Project, the future prospects of genomic medicine seem very promising. But most such applications are still not ready for clinical practice. Perhaps, by paying close attention to the implementation of the growing list of Tier 1 genomic applications, including FH, we will be able to use genetic information to save lives now, and thereby show early success in the use of  genomics to improve 21^st century medicine and public health.