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Study Explores Familial Hypercholesterolemia Genetic Risk, Targeted Screening Possibilities

NEW YORK – New research suggests that targeted genetic testing for heterozygous familial hypercholesterolemia (FH) can pick up individuals at risk of premature heart disease who would be missed by screening for clinical features alone.

"Screening for familial hypercholesterolemia should include clinical factors and genetic testing," first and co-corresponding author Brandon Bellows, a doctor of pharmacy affiliated with Columbia University's Division of General Medicine, said in a statement.

As they reported in the Journal of the American Heart Association, the researchers began by bringing together data for nearly 50,000 individuals from the UK Biobank project, using FH variant profiles and clinical clues to come up with a model for predicting FH risk variant status from related clinical data.

From there, the team used those genetic and clinical ties to predict FH-related genetic risk in nearly 40,000 more individuals enrolled in the US National Health and Nutrition Examination Survey (NHANES) effort, based on clinical features documented in NHANES participants and their family members.

The authors explained that they set out to estimate the probability of having any FH variants based on clinical characteristics and genotype data from participants in the UK Biobank. Then, they applied the UK Biobank-developed predictive model to NHANES adult participants to estimate FH screening yields based on the modified Dutch Lipid Clinic Network (DLCN) clinical criteria alone, genetic testing alone, and by combining clinical criteria with genetic testing.

Using clinical features such as blood cholesterol levels or a close family history of premature heart disease, for example, the team flagged some 3.7 FH cases for every 1,000 adult participants screened, on average, in the NHANES cohort. The estimates suggested that genetic testing for FH-related risk variants would unearth a similar proportion of FH cases, at roughly 3.8 cases per 1,000 screened individuals.

In contrast, the researchers found that a combined clinical and genetic test-based screening strategy would detect roughly 6.6 cases of FH in 1,000 adults who were screened. Within a subset of young adult NHANES participants in the 20- to 39-year-old group, the clinical and genetic screening strategy is expected to find 4.2 FH cases in each 1,000 individuals screened — up from 1.3 FH cases they would expect to detect in a group that size with clinical criteria alone.

While low-density lipoprotein cholesterol testing and heart risk factor assessments are relatively widespread in the clinic for adults in the US, the authors explained, genetic testing for FH is far less common, despite the potential benefits of detecting such variants in high-risk individuals at risk of early heart disease.

"If a young adult is identified to have familial hypercholesterolemia, they would likely benefit from earlier and more aggressive treatment to prevent heart attack and stroke," Bellows said in a statement, adding that FH screening "should include clinical factors and genetic testing."

Based on their findings, Bellows suggested that FH genetic testing should be offered to individuals known to have high blood cholesterol levels as well as those who have a family history of premature heart disease, particularly heart attacks in relatively young individuals.

"Early diagnosis and treatment of familial hypercholesterolemia are the best ways to reduce the risk of early heart attack or stroke," he explained, noting that targeted screening with FH testing may overcome the hurdles associated with trying to implement broader universal screening programs.