Frequency and phenotype consequence of APOC3 rare variants in patients with very low triglyceride levels

Abstract

Background: High levels of triglycerides (TG ≥200 mg/dL) are an emerging risk factor for cardiovascular disease. Conversely, very low levels of TG are associated with decreased risk for cardiovascular disease. Precision medicine aims to capitalize on recent findings that rare variants such as APOC3 R19X (rs76353203) are associated with risk of disease, but it is unclear how population-based associations can be best translated in clinical settings at the individual-patient level.

Methods: To explore the potential usefulness of screening for genetic predictors of cardiovascular disease, we surveyed BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records (EHRs), for APOC3 19X mutations among adult European American patients (> 45 and > 55 years of age for men and women, respectively) with the lowest percentile of TG levels. The initial search identified 262 patients with the lowest TG levels in the biorepository; among these, 184 patients with sufficient DNA and the lowest TG levels were chosen for Illumina ExomeChip genotyping.

Results: A total of two patients were identified as heterozygotes of APOC3 R19X for a minor allele frequency (MAF) of 0.55% in this patient population. Both heterozygous patients had only a single mention of TG in the EHR (31 and 35 mg/dL, respectively), and one patient had evidence of previous cardiovascular disease.

Conclusions: In this patient population, we identified two patients who were carriers of the APOC3 19X null variant, but only one lacked evidence of disease in the EHR highlighting the challenges of inclusion of functional or previously associated genetic variation in clinical risk assessment.

Keywords: APOC3; Biobank; Electronic health records; Precision medicine; Triglycerides.

Fig. 1

Distribution of low triglyceride levels among European American adults in BioVU. A total of 184 European American adults (men > 45 years and women > 55 years) with at least one triglyceride level in the lowest 1% of BioVU were genotyped on the Illumina HumanExome BeadChip for APOC3 R19X. The frequency (expressed as percent in the study population) is given on the y-axis and the median triglyceride levels (in mg/dL) are given on the x-axis

Fig. 2

Mean triglyceride levels by APOC3 R19X genotype. A total of 184 European American adults (men > 45 years and women > 55 years) with at least one triglyceride level in the lowest 1% of BioVU were genotyped on the Illumina HumanExome BeadChip for APOC3 R19X. Two samples failed genotyping. The means for the first mentioned triglyceride level (y-axis) were calculated for the non-carriers (CC genotype) and carriers (CT genotype) at APOC3 R19X (x-axis). Although the mean triglyceride level in carriers (33 mg/dL; 2.83 standard deviation) was lower compared with the non-carriers (39.51 mg/dL; 18.52 standard deviation), the difference between the two is not statistically significant (two-sided t-test assuming unequal variances; p = 0.11)