Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in theAPOEgene

Abstract

Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterolenriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling.

Contribution of APOE Genetic Variants to Dyslipidemia

“…The assignment of pathogenicity of rare gene variants is an important medical problem nowadays. 33 LDLR gene-specific software improves predicting capacity for assessing the pathogenicity of LDLR variants in FH. 34 Given the large number of APOE genetic variants described so far, 11 and probably more in the next future, the implementation of such a tool would constitute a valuable approach to help to solve the problem.…”

Low-carbohydrate diets in type 1 diabetes: balancing benefits and risks

“…A case series of five hyper responders with T2D or prediabetes on VLCKD noted one patient with a APOE E2/E2 genotype, and three with a high burden of genetic polymorphisms [26 ▪ ]. Monogenetic causes include familial hypercholesterolaemia, elevated lipoprotein (a) (Lp(a)), and familial dysbetalipoproteinaemia with variations in ApoE, particularly E2/E2 [32 ▪ ,33 ▪ ]. Heterozygous familial hypercholesterolaemia affects 1 in 250 people, and homozygous familial hypercholesterolaemia occurs in 1 in 300 000 people; however, despite being easily diagnosed and treated, only 10% of patients are thought to be diagnosed, with many unidentified and at risk [32 ▪ ].…”

Applicability of Diagnostic Criteria and High Prevalence of Familial Dysbetalipoproteinemia in Russia: A Pilot Study

“…FD has not only an autosomal recessive but also an autosomal dominant form. Approximately 30 APOE variants associated with the autosomal dominant FD have been previously reported [13][14][15]. However, the assessment of the pathogenicity of these variants has either not been previously carried out or has not been presented in full.…”

“…It was also shown that around 10% of patients could have the autosomal dominant FD associated with a single copy of the defective APOE allele. Approximately 30 APOE variants associated with the autosomal dominant FD have been reported [13][14][15]. However, there are insufficient data regarding the relationship between the described APOE variants and FD [15].…”

“…Approximately 30 APOE variants associated with the autosomal dominant FD have been reported [13][14][15]. However, there are insufficient data regarding the relationship between the described APOE variants and FD [15].…”