Clinical and biochemical features of atherogenic hyperlipidemias with different genetic basis: A comprehensive comparative study

Abstract

Patients with genetically-based hyperlipidemias exhibit a wide phenotypic variability. Investigation of clinical and biochemical features is important for identifying genetically-based hyperlipidemias, determining disease prognosis, and initiating timely treatment. We analyzed genetic data from 3374 samples and compared clinical data, lipid levels (low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a)), frequency, age at onset of coronary heart disease (CHD), and the severity of carotid and femoral atherosclerosis (plaque number, maximum stenosis, total stenosis, maximum plaque height, and plaque score) among patients with familial hypercholesterolemia (FH), familial dysbetalipoproteinemia (FD), polygenic hypercholesterolemia (HCL), severe HCL, and those without lipid disorders (n = 324). FH patients exhibited the highest LDL-C (median 8.03 mmol/L, p < 0.001). FD patients had elevated triglyceride levels (median 4.10 mmol/L), lower LDL-C (median 3.57 mmol/L), and high-density lipoprotein cholesterol (median 1.03 mmol/L) compared to FH, polygenic HCL, and severe HCL, p < 0.05. FH and FD patients had similar early onset of CHD, with a median age of 44 and 40 years and comparable frequencies of 29.5% and 31.0%, respectively. They were more likely to develop CHD than subjects without lipid disorders (p = 0.042 and p < 0.001, respectively). Additionally, FH patients had higher a carotid plaque number, total carotid stenosis, and carotid plaque score. This study presents the first simultaneous comparison of clinical and biochemical features among FD, FH, polygenic, and severe HCL, along with the first comprehensive evaluation of carotid and femoral atherosclerosis ultrasound parameters in FD patients. The results highlight distinct phenotypic features unique to each hyperlipidemia analyzed and underscore FH and FD as the most atherogenic hyperlipidemias.

Fig 1. Study design.

DLCN, Dutch Lipid Clinic Network criteria; FD, familial dysbetalipoproteinemia; FH, familial hypercholesterolemia; HCL, hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.

Fig 2. Distribution of analyzed patients by NGS data.

The orange color indicates a 24-gene custom panel, while the purple color indicates a 6-gene custom panel. FD, familial dysbetalipoproteinemia; FH, familial hypercholesterolemia; HCL, hypercholesterolemia; NGS, next-generation sequencing.

Fig 3. Overview of study findings.

The summary results table uses color coding to indicate the severity of parameter values: green represents the significantly lower severity. Red represents the significantly higher severity. When differences were found between several groups, we used orange to indicate intermediate severity between green and red. Only the most significant ultrasound parameters of carotid and femoral atherosclerosis (plaque number and maximum stenosis) are presented. *Median values are shown in all cells. IDL-C, intermediate-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol.

Fig 4. Lipid levels among hyperlipidemia groups and compared with the control group.

A: LDL-C; B: HDL-C; C: TG; D: Lp(a) levels. Сentral lines represent the median, box limits represent upper and lower quartiles, vertical lines represent 1.5 times the quartile range, and points represent outliers. Horizontal square brackets with p-values above indicate significantly different groups. Only significant differences are indicated among groups. P-values were adjusted by the Holm-Bonferroni method. FD, familial dysbetalipoproteinemia; FH, familial hypercholesterolemia; HCL, hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); TG, triglycerides.

Fig 5. Distribution of Lp(a) by group.

Ranges: minimum-Q1 highlighted in green, Q1-Q2 in yellow, Q2-Q3 in blue, and Q3-maximum in purple. The red background indicates an elevated Lp(a) level (≥ 50.0 mg/dL). Threshold >180 mg/dL indicates very high Lp(a) level. Only significant differences are indicated. FD, familial dysbetalipoproteinemia; FH, familial hypercholesterolemia; HCL, hypercholesterolemia; Lp(a), lipoprotein(a).

Fig 6. Frequency and age at onset of CHD among hyperlipidemia groups compared with the control group.

A: age at onset. Central lines represent the median, box limits represent upper and lower quartiles, vertical lines represent 1.5 times the quartile range, and points represent outliers. Only significant differences are indicated among groups. P-values were adjusted by the Holm-Bonferroni method; B: frequency. Horizontal square brackets with p-values above indicate significantly different groups. Only significant differences are indicated among groups. P-values were adjusted by the Holm-Bonferroni method. FD, familial dysbetalipoproteinemia; FH, familial hypercholesterolemia; HCL, hypercholesterolemia; Me, median.

Fig 7. Severity of carotid and femoral atherosclerosis.

A: number of carotid plaques; B: total carotid stenosis; С: carotid plaque score; D: number of femoral plaques; E: total femoral stenosis; F: femoral plaque score. Central lines represent the median, box limits represent upper and lower quartiles, vertical lines represent 1.5 times the quartile range, and points represent outliers. Horizontal square brackets with p-values above indicate significantly different groups. Only significant differences are indicated among groups. For study groups, p-values were obtained from linear regression with adjustments, and from the Mann-Whitney test for control vs. study groups. P-values were adjusted by the Holm-Bonferroni method. FD, familial dysbetalipoproteinemia; FH, familial hypercholesterolemia; HCL, hypercholesterolemia; Me, median.