Longitudinal LDL-C and risk associated with a genetic variant of familial hypercholesterolemia

Longitudinal low-density lipoprotein cholesterol (LDL-C) data available in electronic health records that are 10 years or older do not fully summarize the risk of coronary heart disease (CAD) associated with carrying a genetic variant of familial hypercholesterolemia (HF). These findings were published in Circulation: genomics and precision medicine.

Compared to a single LDL-C measurement, CAD risk is presented independently by FH genetic variants. Given the availability of LDL-C data over time through electronic health records, genetic testing for FH variants may or may not further delineate risk information.

The researchers sought to examine the hypothesis that multiple LDL-C measurements over time may explain the risk of coronary artery disease associated with carrying an FH variant. To do this, the researchers conducted a prospective, nested case-control study using electronic health record data from the Million Veteran Program. This program included 23,091 CAD cases (97.4% male; mean age 66.3 ± 9.1 years at enrollment; 76% European, 15.7% African, 6.2% Hispanic , 0.6% Asian, 1.5% unclassified) and 230,910 matched control patients with virtually identical statistics. for sex, age and ancestry group.

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The primary outcome, determined from electronic health record codes for acute myocardial infarction and coronary revascularization, was coronary artery disease. Case and control exposure windows were matched using incidence density sampling. LDL-C adjustments were analyzed. A custom genotype table was used to assess FH variants in LDL receptors (LDLR), the major protein present in LDL (APOB), and the protein that controls LDLR number (PCSK9).

Carriers of the FH variant had an increased risk of coronary artery disease (odds ratio [OR]1.53 [95% CI, 1.24-1.89]). The risk estimate was moderated by adjusting for mean LDL-C, but still recorded a significant risk (odds ratio, 1.33 [95% CI, 1.08-1.64]). The number and spread of available LDL-C measurements did not affect the amount of attenuation.

Study limitations include the majority of CAD cases occurring up to 20 years prior to enrollment and Million Veteran program participants tend to be older at enrollment and have more risk factors for coronary artery disease compared to other biobanks, which creates a bias for survivors. Other limitations included the use of a genotyping array rather than gene sequencing, care outside of VA was not captured, researchers did not consider anti-LDL drugs other than statins and there were an overwhelming number of men in the study.

“We believe that the residual risk associated with FH variants reflects the limitations of clinical phenotyping to capture genetic risk,” the researchers wrote. “While FH variants have a continuous impact on LDL-C exposure across the lifespan, clinical LDL-C measurements can only sample a fraction of this exposure.”


Clarke SL, Tcheandjieu C, Hilliard AT, et al. Risk of coronary heart disease from genetic variants of familial hypercholesterolemia independent of clinically observed longitudinal cholesterol exposure. Circ Genom Precis Med. Published online February 10, 2022. doi:10.1161/CIRCGEN.121.003501

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