Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia

Abstract

Background and aims: Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid phenotypes, characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. The genetic inheritance of FCHL remains poorly understood. The goals of this study were to investigate the polygenetic architecture and cardiovascular risk associated with FCHL. Methods and results: We identified individuals with an FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n = 39,961), 5.01% (n = 17,485), 1.48% (n = 5,153), 1.10% (n = 3,838), and 0.48% (n = 1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria and identified 175 independent loci associated with FCHL at genome-wide significance. We investigated the association of genetic and clinical risk with FCHL and found that polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome were associated with greater prevalence of FCHL. Participants with an FCHL phenotype had a similar risk of incident coronary artery disease compared to participants with monogenic familial hypercholesterolemia (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31-3.21] and 1 .90 [1.30-2.78]). Conclusions: These results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. The cardiovascular risk associated with an FCHL phenotype is similar to that of monogenic familial hypercholesterolemia, despite being ~5x more common.

Cascade testing for elevated lipoprotein(a) in relatives of probands with high lipoprotein(a)

“…A similar discordance between FH and elevated Lp(a) was previously reported [ 12 , 13 ]. These data accord with the notion that the heritability of Lp(a) is distinct and independent of other dyslipidemias, including FH, FCHL and CH [ 12 , 13 , [15] , [16] , [17] ].…”

“…Probands with high Lp(a) were identified from patients with common dyslipidemias, typically FCHL and CH. We found comparable detection rates of elevated Lp(a) among relatives of probands with FCHL or CH, both being polygenic disorders [15] , [16] , [17] . Accordingly, there was a poor agreement between the detection of FCHL (or CH) and elevated Lp(a) among the relatives.…”

“…While ASCVD risk may begin at a threshold >30 mg/dL [2] , our definition of elevated Lp(a) (i.e., ≥50 mg/dL) in relatives was based on current guidelines [ 6 , 8 ], corresponding to the 80th centile for Caucasian populations [6] . We carefully and phenotypically defined the dyslipidemias in our probands after excluding those with FH, noting FCHL and CH might have been more accurately defined using polygenic lipid scores [ 16 , 17 ]. The lack of a non-dyslipidemic control group is a potential limitation.…”

A Tale of Two New Targets for Hypertriglyceridaemia: Which Choice of Therapy?

“…Mild-to-moderate HTG is usually a result of multiple common allelic gene variants interacting with an unhealthy diet and lifestyle that impair TRL metabolism [12]. The most common forms of genetic HTG are familial combined hyperlipidaemia (FCHL) and familial hypertriglyceridaemia [14,15]. FCHL can present as elevated total and LDL cholesterol levels with mild triglycerides, elevated triglycerides alone, or predominately elevated triglycerides and slightly elevated LD.…”

Fatty Liver as Potential Biomarker of Atherosclerotic Damage in Familial Combined Hyperlipidemia

“…Familial combined hyperlipidemia (FCH) is likely the most common inherited lipid disorder, since its estimated prevalence is 0.5–4% [ 1 ]. Although FCH was described already in 1973 [ 2 ], half century of progress has not led to a consensus on a simple and definitive set of diagnostic criteria [ 3 , 4 ].…”