Longitudinal LDL-C and Risk Associated With a Familial Hypercholesterolemia Genetic Variant

LDL-C test
LDL-C test
Researchers examined the effect of genetic testing for familial hypercholesterolemia variants with consideration of longitudinal LDL-C on risk stratification for patients.

Longitudinal low-density lipoprotein cholesterol (LDL-C) data available in electronic health records dating back 10 years or more does not totally encapsulate the risk for coronary artery disease (CAD) associated with carrying a familial hypercholesterolemia (FH) genetic variant. These findings were published in Circulation: Genomic and Precision Medicine.

Compared with a single measurement of LDL-C, risk for CAD is presented independently by FH genetic variants. Considering 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.

Researchers sought to examine the hypothesis that multiple LDL-C measurements over time can account for the risk for CAD associated with carrying an FH variant. To accomplish this, researchers conducted a nested case-control prospective study utilizing electronic health record data from the Million Veteran Program. This program included 23,091 CAD cases (97.4% men; mean aged 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.

The primary outcome, determined from electronic health record codes for acute myocardial infarction and coronary revascularization, was CAD. Case and control exposure windows were matched utilizing incidence density sampling. LDL-C adjustments were analyzed. Custom genotype array was used to assess FH variants in LDL receptors (LDLRs), the main protein found in LDLs (APOB), and the protein that controls the number of LDLRs (PCSK9).

FH variant carriers had an increased risk for CAD (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 significant risk (odds ratio, 1.33 [95% CI, 1.08-1.64]). The number and the spread of LDL-C measures available did not affect the amount of weakening.

Study limitations include the majority of CAD cases occurred up to 20 years prior to enrollment and Million Veteran Program participants tend to be older at enrollment and have more CAD risk factors compared with other biobanks, creating to survivor bias. Other limitations included the use of genotyping array rather than gene sequencing, care outside of the VA was not captured, researchers did not account for non-statin LDL-lowering medications 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 for capturing genetic risk,” the researchers wrote. “Whereas FH variants impact LDL-C exposure continuously throughout life, clinical measurements of LDL-C can only sample a fraction of this exposure.”


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