Familial combined hyperlipidemia is a polygenic trait

Abstract

Purpose of review: Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified.Recent findings: Recent studies using next-generation genetic analytic methods confirm that FCH has a polygenic basis, with a clear large contribution from the accumulation of small-to-moderate effect common single nucleotide polymorphisms (SNPs) throughout the genome that is associated with raising TG, and probably also those raising LDL cholesterol. On the other hand, rare monogenic variants, such as those causing familial hypercholesterolemia, play a negligible role, if any. Genetic profiling suggests that patients with FCH and hypertriglyceridemia share a strong polygenic basis and show a similar profile of multiple TG-raising common SNPs.Summary: Recent progress in genomics has shown that most if not all of the genetic susceptibility to FCH is polygenic in nature. Future research should include larger cohort studies, with wider ancestral diversity, ancestry-specific polygenic scores, and investigation of epigenetic and lifestyle factors to help further elucidate the causative agents at play in cases where the genetic etiology remains to be defined.

Physiological Bases for the Superiority of Apolipoprotein B Over Low‐Density Lipoprotein Cholesterol and Non–High‐Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk

“…HyperTG normoapoB is the characteristic phenotype seen in mild‐to‐moderate hypertriglyceridemia, which is primarily a non‐Mendelian polygenic phenotype that corresponds to former type IV hyperlipoproteinemia. 88 This contrasts with hyperTG hyperapoB, which is the phenotype of familial combined hyperlipidemia, also primarily a non‐Mendelian polygenic phenotype that corresponds to the former type IIB hyperlipoproteinemia, 89 in which plasma triglycerides and apoB are both increased. 90 In combined hyperlipidemia, hypertriglyceridemia is attributable increased secretion of VLDL particles, whereas, in mild‐to‐moderate hypertriglyceridemia, hypertriglyceridemia is attributable to secretion of triglyceride‐enriched VLDL particles at a normal rate.…”

The clinical utility of polygenic risk scores for combined hyperlipidemia

“…Because levels of apo B, triglyceride, and total cholesterol, and risk for coronary artery disease are closely tied to hepatically derived lipoproteins, individuals who meet diagnostic criteria for combined hyperlipidemia likely have disruptions in the metabolism of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL particles [12,13]. Given these lipoprotein disturbances, combined hyperlipidemia could also be defined as type IIB hyperlipoproteinemia due to increased VLDL and LDL levels [4 ▪▪ ,22 ▪▪ ].…”

“…The use of PRSs to identify individuals with inherited risk for disease provides an opportunity for early adoption of healthy lifestyle behaviors – e.g., smoking cessation, reduction in alcohol intake, increased exercise – to minimize circulating levels of atherogenic biomarkers prior to clinical manifestations of disease and may encourage more frequent clinical monitoring of lipid levels and related biomarkers, all in an effort to reduce ASCVD risk (Fig. 1a)[4 ▪▪ ,5 ▪▪ ,23 ▪ ].…”

“…Almost 50 years ago, combined hyperlipidemia was described as an autosomal dominant disorder based on the inheritance pattern of mixed hyperlipidemia and coronary artery disease [1]; however, after decades of trying to locate a single causative locus, no monogenic factor was identified. Recent research efforts focusing on clinical patient cohorts and large population cohorts have instead demonstrated the complex genetic architecture of combined hyperlipidemia [2 ▪▪ ,3 ▪▪ ,4 ▪▪ ].…”

“…Rare variants disrupting genes involved in low-density lipoprotein (LDL) metabolism ( LDLR , APOB and PCSK9 ) and triglyceride-rich lipoprotein metabolism ( LPL , APOA5 , APOC2 , LMF1 , and GPIHBP1 ) are significantly enriched in individuals with combined hyperlipidemia compared to controls, and are likely contributing towards disease presentation [2 ▪▪ ,4 ▪▪ ]. Dozens of additional genes related to other lipids, lipoproteins, and relevant tissues (i.e., adipocytes) have also been associated with susceptibility to combined hyperlipidemia [4 ▪▪ ,5 ▪▪ ,6 ▪▪ ]. Even more abundant than rare variant carriers are individuals with an enrichment of common variants (i.e., single-nucleotide polymorphisms [SNPs]) that have nonzero effects on lipid levels, particularly LDL cholesterol and triglyceride, compared to controls [2 ▪▪ ].…”