Geisinger and Regeneron study finds life-threatening genetic disorder is substantially underdiagnosed
FOR IMMEDIATE RELEASE:
DANVILLE, PA -- A study conducted by Geisinger Health System in collaboration with the Regeneron Genetics Center (RGC) has found that a life-threatening genetic disorder known as Familial Hypercholesterolemia (FH) is both underdiagnosed and undertreated. It was published in the peer-reviewed journal Science on Dec. 23 alongside another significant study from the same Geisinger-RGC collaboration known as DiscovEHR. That foundational paper describes the exome sequencing and analyses of the first 50,726 adult participants in the DiscovEHR cohort – all members of the Geisinger MyCode Community Health Initiative.
In the FH study, the collaborators examined genetic variants causing FH in the DiscovEHR cohort and then compared the findings against the de-identified medical histories of these patients as contained in Geisinger electronic health records.
Traditionally, in the United States, FH is diagnosed in patients with high cholesterol who also have a family history of early heart attacks and strokes. Genetic testing for FH is currently uncommon in clinical practice.
FH is caused by a defect that makes the body unable to remove “bad” cholesterol from the blood. This cholesterol (low density lipoprotein cholesterol or LDL-C) then accumulates, often undetected, and can lead to early death from heart attacks or stroke – even in very young people.
Results of the new study found many undiagnosed cases of FH and helped to define the extent of FH in the general population and the extent to which it is systematically undertreated.
“The study shows us that FH is about twice as common as it was once thought to be, and that large-scale genetic testing for FH helps identify cases that would otherwise be missed,” said Michael F. Murray, M.D., Geisinger director of clinical genomics. “We now hope to use DNA sequencing to guide better management for patients.”
“FH is a serious disease that can have severe consequences for some people, but also has available treatment options,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer, Regeneron. “We hope that this study will drive higher awareness of the prevalence of FH, since with greater vigilance more patients could be accurately diagnosed and treated with effective therapies.”
Among the many findings of the study were that 1 in every 256 people has a disease-causing mutation, or variant, in one of the three FH genes. It showed that participants with a deleterious FH gene variant had significantly higher “bad” cholesterol than those without an FH gene variant. They also had significantly increased odds of both general and premature coronary artery disease.
The study identified 35 mutations, or variants, in the genes that have been determined to cause FH: LDLR, APOB, and PCSK9. Only 24 percent of people who carry FH-causing variants had sufficient criteria within their electronic health records to support a probable or definite FH diagnosis, meaning that without genetic confirmation, many of these patients would go undiagnosed. Additionally, 42 percent of people with these FH-causing variants did not have a recent active prescription for statins, the first line therapy for cholesterol lowering. Among statin-treated people with FH-causing variants, less than half met goals for cholesterol lowering, suggesting the need for more intensive cholesterol-lowering therapy.
“We’ve focused on this condition for research at this time because of the Centers for Disease Control and Prevention’s (CDC) interest in this condition as a public health genomics priority, and the long-standing understanding that this condition goes undiagnosed in the vast majority of cases,” Geisinger’s Murray said.
“Being able to connect patient’s de-identified medical records with their DNA data is an advantage that few others in this field have, particularly with this large number of patients. Paired with the RGC’s unique technological and analytical resources, we are able to make meaningful discoveries that may advance the implementation of precision medicine today and the development of new or improved medicines tomorrow,” said Noura Abul-Husn, M.D., Ph.D., associate director of translational genetics at the RGC and co-author of the paper.
“Geisinger is committed to translating this important research directly into improved care for our patients,” said Geisinger Executive Vice President and Chief Scientific Officer David H. Ledbetter, Ph.D. “We have begun a major effort to confirm individual patient findings and inform individual participants and their doctors when genetic findings, that are known to cause illness, are discovered in our population,” he said.
FH is one of 27 genetic conditions being targeted at Geisinger. So far, some 200 patients – including 29 FH carriers – have already been informed they carry one or more disease-causing genetic mutations with consequences that can be treated. These conditions are mainly related to risk for cancer or cardiovascular illness. The effort to return individual results will continue as more findings are confirmed. For details see go.geisinger.org/results.
About Geisinger
Geisinger is among the nation’s leading providers of value-based care, serving 1.2 million people in urban and rural communities across Pennsylvania. Founded in 1915 by philanthropist Abigail Geisinger, the non-profit system generates $10 billion in annual revenues across 134 care sites - including 10 hospital campuses, and Geisinger Health Plan, with 600,000 members in commercial and government plans. The Geisinger College of Health Sciences educates more than 5,000 medical professionals annually and conducts more than 1,400 clinical research studies. With 26,000 employees, including 1,600 employed physicians, Geisinger is among Pennsylvania’s largest employers with an estimated economic impact of $14 billion to the state’s economy. On March 31, 2024, Geisinger became the first member of Risant Health, a new nonprofit charitable organization created to expand and accelerate value-based care across the country. Learn more at geisinger.org or connect with us on Facebook, Instagram, LinkedIn and X.
About MyCode
The MyCode Community Health Initiative is a precision medicine project at Geisinger Health System in which Geisinger patient-participants have consented to donate blood and other biological samples to a systemwide biobank designed to store those samples for wide research use and for genomic personalized or precision medicine. Begun in 2007, the MyCode research project was expanded in 2014 by Geisinger in collaboration with Regeneron Pharmaceuticals Inc. MyCode participants have consented to have parts of their genomes read or analyzed – the technical term is “sequenced.” The information gleaned will contribute to a broad range of research aimed at understanding, preventing or improving treatments for disease. The goal is to help improve health care by finding ways to diagnose medical conditions earlier, even before they appear as symptoms, and also to help find new treatments or medications to manage these diseases.
About DiscovEHR
The DiscovEHR human genetics study population for this analysis includes 50,726 adult Geisinger Health System patients who agreed to participate in the MyCode Community Health Initiative. More than 126,000 MyCode participants have consented into the program to date. MyCode volunteers have given informed consent to allow sharing of de-identified electronic health records, provide samples that can be linked to their health records for broad research, and permit re-contact for additional studies. Electronic health records for the group in this DiscovEHR study are available for a median of 14 years of clinical care. For MyCode participants who are suspected to harbor a pathogenic variant in one of the 76 clinically actionable genes, Geisinger will confirm preliminary research findings in a lab facility that is certified to the Clinical Laboratory Improvement Amendments (CLIA) Act, the federal standard for clinical testing. Qualified Geisinger personnel will provide the results of confirmatory CLIA-certified testing to patients and their primary care providers along with genetic counseling and appropriate referrals to other specialists.
About the Regeneron Genetics Center
The RGC is a fully integrated genomics program that spans early gene discovery and functional genomics and facilitates drug development. The primary goal of the RGC is to improve patient outcomes by identifying novel drug targets, clinical indications for development programs, and genomic biomarkers for pharmacogenomic applications. The RGC is tackling various sequencing (exomes, targeted sequencing, etc.) and analytical approaches and has established numerous collaborations with leading human genetics researchers. To enable this large-scale sequencing and analysis program, the RGC utilizes fully-automated sample preparation and data processing, as well as cutting-edge cloud-based informatics. Including efforts with Geisinger, the RGC has sequenced de-identified DNA from more than 130,000 individuals to date and is now sequencing at a rate of 150,000 individuals per year.