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Genetic testing may offer diagnostic advantage at lipid clinics
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MIAMI — Genetic testing can be used by clinicians who treat patients at lipid clinics, especially for the diagnosis of conditions such as familial hypercholesterolemia, according to a presentation at the National Lipid Association Scientific Sessions.
History of genetic testing
“Genetic testing has a role in clinical lipidology and cardiovascular prevention today,” Cardiology Today Editorial Board Member Seth S. Martin, MD, MHS, FACC, FAHA, FASPC, associate professor of medicine and cardiologist at the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, said during the presentation. “We’ve really come a long way in 50 years.”
Martin previously collaborated with Emily Brown, MGC, CGC, genetic counselor at Johns Hopkins, to introduce genetic testing to their lipid clinic. She also presented results on genetic testing for familial hypercholesterolemia at another session and won the Hunninghake award at the meeting.
There was an article published in The New England Journal of Medicine in 1967 by Donald S. Fredrickson, MD and colleagues on assessing fat transport in lipoproteins. It included a table that listed the types of hyperlipoproteinemia such as familial chylomicronemia by indices to plasma lipoprotein concentrations including paper electrophoretic bands, analytical ultracentrifuge, preparative ultracentrifuge, particles separated by starch electrophoresis, precipitation with high-molecular-weight polymers and immunoprecipitation.
“We do a standard lipid profile in clinical practice and maybe some others,” Martin said during the presentation. “We’re not doing all these things. We’re not able to phenotype patients the way it was being done here, but it’s interesting and something that’s adopted by WHO. It’s something that’s taught in medical schools. It’s something that we’re thinking about in our lipid clinic. I’m sure you’re thinking about what type patients are in your lipid clinics, but you’re not doing it by all these different methods.”
The conclusion of the paper stated, “The plasma is often the only window from which one can see the state of intracellular metabolism. The view is limited, and all ingenuity is demanded to gain the sharpest perspective.” That statement and the conclusion as a whole from the 1967 paper still stands today, Martin added.
In a paper published in Pathology in 2019, other authors detailed the potential benefits of genetic testing, which included the opportunity to improvement management and disease prevention, increased likelihood for a definitive diagnosis and a way to advance overall understanding and knowledge of complex metabolic processes and pathways.
This paper also listed possible indications for the genetic testing of dyslipidemias such as strong clinical suspicion, maybe changing management, family planning, patient preference, eligibility for new drugs, early interventions, other syndromic features and strong family history.
Familial hypercholesterolemia, which is the bulk of genetic testing at Martin’s lipid clinic, was discussed in a scientific expert panel published in the Journal of the American College of Cardiology in 2018. The paper included a figure on the phenotypic spectrum of familial hypercholesterolemia. Factors such as the clinical phenotypes, molecular etiology and genetic background overlap each other.
“All of this impacts the ultimate exposure to LDL and alter coronary risk,” Martin said during the presentation.
Negative tests
The paper also includes a figure on different categories of patients who may undergo genetic testing for familial hypercholesterolemia, and those with the familial hypercholesterolemia phenotype may undergo genetic testing for LDLR, APOB and PCSK9. Alternative molecular etiologies may be considered if the patient tests negative.
“If they test negative, it does not mean that they do not have [familial hypercholesterolemia], but depending on the pretest probability of having [familial hypercholesterolemia], it might be that 40% will test negative or even more than that.”
In a table within the Journal of the American College of Cardiology paper, when researchers compared patients who tested negative for familial hypercholesterolemia with an LDL less than 130 mg/dL with those who tested negative with an LDL greater than 220 mg/dL had 7.7-fold risk for CAD, whereas those with LDL levels greater than 220 mg/dL and a positive genetic test had 25.8-fold risk. Patients in the 190 mg/dL to 220 mg/dL group who tested positive had a 17-fold risk vs. 5.2-fold risk for those who tested negative.
The LDL threshold at which genetic testing is considered is 160 mg/dL, according to the paper.
“Genetic results must be placed in clinical context and are best used by clinicians with experience interpreting results and collaborating with a genetic counselor,” Martin said during the presentation. “We do need strong guidance from the NLA and I believe that’s forthcoming in the working group to give expert guidance on the use of genetic testing in clinical practice.” – by Darlene Dobkowski
Reference:
Martin SS. Session III: 2019 Manuscripts for the Clinical Setting. Presented at: National Lipid Association Scientific Sessions; May 16-19, 2019; Miami.
Disclosure: Martin reports he serves on scientific advisory boards for Akcea, Amgen, Esperion, Novo Nordisk and Sanofi/Regeneron.