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Geisinger Researchers Win $7M for Familial Hypercholesterolemia Studies With Genetic Testing


NEW YORK – Researchers at Geisinger Health System hope new funding will advance genetic testing and improve outcomes for patients with familial hypercholesterolemia. Two teams at the health system were recently awarded a total of $7 million for studies incorporating genetic testing for FH from the National Institutes of Health's National Heart, Lung, and Blood Institute. 

Familial hypercholesterolemia is one of the most common genetic disorders, impacting roughly one in every 250 people in the US. It can lead to high cholesterol, premature coronary artery disease, strokes, and early death. FH is also considered underdiagnosed and undertreated, as a patient's risk is often not discovered until after a major health event, like a heart attack. 

Race and place impact FH, too, with Black and Hispanic people as well as individuals in rural areas less likely to be diagnosed and receive early interventions like lipid-lowering medications. 

According to Laney Jones, the principal investigator on one of the NHLBI-funded studies, an early FH diagnosis can be lifesaving if patients are given medication and counseling. It can also help a patient's family members who might be tested in turn and treated early through cascade screening. 

Jones' study, called the Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia, or CARE-FH, will be funded by $3.3 million over five years. 

As described earlier this year in the Journal of Personalized Medicine, the trial will roll out different strategies to engage primary care clinicians in FH screening. It will include educational interventions about FH, as well as instruction in how to perform a screening and diagnostic evaluation. 

As part of the diagnostic evaluation, if a patient has high levels of low-density lipoprotein and a family history indicative of FH, clinicians will be encouraged to perform genetic screening. Patients can decide whether they want the genetic testing, Jones said, and sequencing will be performed by send-out labs. The study will be rolled out in five phases over two-and-a-half years, with results from each iteration informing the next. 

The primary outcome will be clinician adoption of the FH diagnostic evaluation in primary care, with secondary outcome measures pertaining to the acceptability and feasibility for patients and providers as well as measures of the expenditure required of the health system to implement the screening program. And, importantly, the team plans to measure whether the screening impacts patient health outcomes, such as whether or not they received genetic testing, saw a reduction in LDL levels, or had their diagnosis lead to increased cascade screening for their families. 

Overall, "we're trying to bring FH care and diagnosis earlier into the mainstream clinical process at Geisinger," Jones said. As such, the project targets community medicine, internal medicine, and pediatric clinics, to ultimately prevent future cardiovascular events. 

"We are really hoping to increase the number of individuals that we suspect have FH in our system who undergo clinical genetic testing," she said. "We are going to educate our primary care clinicians on how to order the [genetic] test," she added, and the team will also help with counseling and resources to help patients decide whether they want genetic testing. 

Jones is also collaborating with PI Matthew Oetjens on Geisinger's second recently announced NHLBI-funded project, dubbed RISK-FH. That study was provided $3.7 million in funding for a project scheduled to last five years. 

In an interview, Oetjens said that some cases of FH are monogenic, and three genes in particular — APOB, LDLR, and PCSK9 — can signal risk of disease. 

But polygenic causes of the hypercholesterolemia phenotype have also come to light in the past two decades, as have patients with the phenotype that isn't clearly linked to gene changes. 

To understand how different genes may impact disease and outcomes, RISK-FH will screen samples from three biobanks, incorporating additional causes of the FH phenotype and comparing them to understand risks, Oetjens said. 

"We can identify people who have the FH phenotype, but what we really want to know is whether the cause of the phenotype is informative for risk stratification," he said. 

The team will use samples from 800,000 people in the UK Biobank, Mount Sinai BioMe biobank, and Geisinger's own MyCode Community Health Initiative

MyCode has been returning genetic testing results to patients since it was established in 2007. In April, the health system announced that MyCode reached a milestone of enrolling 300,000 patients and returning clinically actionable results to 3,100. 

Another aim of RISK-FH was to have a cohort representing diverse populations, Oetjens said. Geisinger's MyCode will be able to inform on rural populations, while the Mount Sinai BioMe biobank has a diversity of race and ethnicity that can capture additional health disparities. 

"Health disparities are important for health, but they might be even more so in the presence of a genetic disorder like FH, where the risk is greater for not receiving treatment," Jones said. 

The RISK-FH study will also incorporate Jones' expertise to evaluate the best way to communicate risk to clinicians and patients. 

The team recently presented preliminary results of its UK Biobank screen at an American Heart Association meeting, showing a difference in atherosclerotic cardiovascular disease risk based on whether the patient had monogenic or polygenic signals, or had no discernable genetic cause of their high LDL. The team found that monogenic FH led to a 2.7-fold increased risk of cardiovascular disease among patients treated with lipid-lowering medication compared to controls, while patients classified as having polygenic hypercholesterolemia have no increased risk. 

Last year, Geisinger researchers were also awarded a five-year, $2.8 million grant for a project called IMPACT-FH that used ChatBot to communicate with patients' relatives, and Jones is currently the primary investigator on that study as well. 

Due to IMPACT-FH's initial focus on optimized methods to improve identification and cascade screening of FH, the RISK-FH and CARE-FH projects can now incorporate the automated approaches to improve detection of FH, Jones said. 

And although Geisinger does not currently have an FH institute per se, the teams from the three grants have been meeting together and collaborating for the past several years. 

"We have really started to create a strategic plan around FH care at Geisinger because of its underdiagnosis and undertreatment," Jones said. 

Now, the team is "really trying to fit all the pieces together," she said, and create a robust program to decrease barriers to implementing FH care, with the CARE-FH implementation piece potentially enabling rapid utilization of any discoveries from RISK-FH. 

"We want to prevent preventable diseases," Jones said.