Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2013

New genetic architecture of the dyslipidaemias: Frederickson revisited (#205)

Gerald F Watts 1
  1. Metabolic Research Centre and Cardiometabolic Service, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia

Recent advances in gene sequencing and genome-wide association studies, have facilitated a re-evaluation of the bases for the dyslipoproteinaemias beyond the phenotypic definition first described by Frederickson and still employed by the WHO (ICD). This is most relevant to the elucidation of the aetiology of hypertriglyceridaemia (HTG), the genetic bases for autosomal dominant (AD) hypercholesterlaemia now being well attributed to the LDL receptor and apoB, and more recently to PCSK9 and the LDLRAP.

HTG , usually in the range of 2 to 6 mmol/L, is clinical important because it reflects the accumulation in plasma of triglyceride-rich lipoproteins that are causally related to atherosclerotic cardiovascular disease (CVD), as confirmed by recent Mendelian randomization studies. HTG also reflects hepatic steatosis  and above 10 mmol/L increases the risk of acute pancreatitis.

HTG underlies 5 Fredrickson phenotypes. Severe monogenic HTG (Type I) is rare and is transmitted as an AD disorder, being caused by loss-of-function mutations in 6 genes (LPL, APOC2, APOA5, LMF1, GPIHBP1, GPD1). Most clinical presentations of HTG are associated with secondary, non-genetic factors (diet, obesity, diabetes, endocrinopathies, nephropathies, drugs, autoimmune conditions and systemic infections), usually follow no clear Mendelian inheritance pattern, and involve common single nucleotide polymorphisms and rare gene variants. Clustering of HTG in families (Types IIb, III, IV and V) is due to a mosaic of genetic effects, including common gene variants and a burden of heterozygous rare variants. Familial combined hyperlipidaemia has a population prevalence of up to 2% and involves multiple genes that affect the metabolism of adipose tissue ( USF1, PNPLA2), TRLs ( APO A1/C3/A4/A5/USF1) and LDL ( LDLR, PCSK9). E2E2 homozygosity, with a prevalence of 1 %, is a necessary but not sufficient cause of type III dysbetalipoproteinaemia, which is rare (1 in 10,000) and increasingly precipitated by obesity and insulin resistance. Types IV and V HTG also have high HTG risk alleles and gene scores. While the different biochemical phenotypes appear to be polygenic, they share one of two gene variants in apoA5.

These advances in genetic findings allow a new nosological definition of the dyslipidaemias that may facilitate diagnosis and management. The discovery of new genes is also important because these become targets for discovery medicine and novel therapies ( eg apoC-III antisense, LPL gene replacement ). At a practical level, by contrast to AD hypercholesterolaemia, genetic cascade testing is not at present recommended in screening for HTG within families. The decision to screen for and treat HTG should also be based phenotypically on global CVD risk and the risk of acute pancreatitis and steatohepatitis.