APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

Abstract

Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.

Additive Effect of APOE Rare Variants on the Phenotype of Familial Hypercholesterolemia

“…In addition, strict pairwise comparison could not be achieved, however, all except one LDLR variants led to drastic reduction of LDLR activity, and MoM expression was used for age and sex adjustment. Finally, whereas an improved response to statins was reported in 2 different ADH or familial combined hyperlipidemia cohorts of APOE carriers alone, 4,62 it could not be studied here.…”

“…In addition, rare APOE variants may be in linkage disequilibrium with common APOE variants as seen in our patients and as reported in the literature between the p.(Leu46Pro) and the ε4 allele and between the (p.Gly145Asp) and the ε2 allele. 4,29,31 Consequently, this linkage disequilibrium may hamper the interpretation of the specific effect of the rare variant. 43 Lehrman et al 45 1…”

“…2,3 Recent cohort studies suggest that APOE variants may explain 1-2% of ADH cases in some countries. 3,4 The variability of phenotypic expression in ADH may be influenced by (1) variant type and gene involved 5 ; (2) polygenic effect evaluated by weighted polygenic risk score 6 ; (3) gene-environment interactions (including the effect of diet and lifestyle) 7 ; (4) background epigenetic mechanisms. 8 In addition, some studies described patients with double heterozygotes familial hypercholesterolemia with both LDLR/APOB, [9][10][11][12][13][14] LDLR/PCSK9, 15,16 or APOB/PCSK9 17 variants leading to severe phenotypes.…”

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

“…The involvement of the APOE gene in several dyslipidemias is emblematic of the interrelation between the metabolisms of different lipid classes. A recent screening showed the involvement of several rare variants in the APOE gene in both autosomal dominant hypercholesterolemia and FCH [ 52 ]. Sometimes, the partial overlapping phenotype and familiarity makes it hard to distinguish FH from FCH.…”

Análise dos genes STAP1, APOE, ABCG5 e ABCG8 em pacientes hipercolesterolêmicos com diagnóstico molecular negativo para os genes LDLR, APOB e PCSK9

“…Um estudo realizado por Khalil et al 38 Dentre as variantes encontradas, duas já foram reportadas na literatura médica, porém nenhuma delas foi relacionada à hipercolesterolemia ou à HF, mas sim para a doença de Alzheimer ou Hipertrigliceridemia. Já a variante p.(Leu167del), primeira variante associada à HF no gene APOE, não foi identificada em nossa coorte.…”