Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study

Abstract

Objective: Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection.

Methods: We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded.

Results: A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald.

Conclusion: Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Keywords: APOB protein, human; Besseling; Dutch Lipid Clinic Network Score; Hyperlipoproteinemia type II; LDLR protein, human; PCSK9 protein, human.

Fig. 1. Proportions of patients with no identified FH variant/benign, VUS, and likely pathogenic or pathogenic FH variant given selected characteristics (mg/dL units).

VUS, variants of uncertain significance; FH, familial hypercholesterolaemia; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; DLCNS, Dutch Lipid Clinic Network Score.

Fig. 2. ROC curves for LDL-C (Friedewald), LDL-C (Sampson), total cholesterol, non-HDL-C, DLCNS (pre-mutation) and Besseling et al.

ROC, receiver operating characteristic; FH, familial hypercholesterolaemia; LDL-C, low density lipoprotein cholesterol; AUC, area under the curve; HDL-C, high density lipoprotein cholesterol; DLCNS, Dutch Lipid Clinic Network Score.