Familial combined hyperlipidaemia (FCH) is the most prevalent form of familial hyperlipidaemia with a multigenic origin and a complex pattern of inheritance. In this respect, FCH is an oligogenic primary lipid disorder due to interaction of genetic variants and mutations with environmental factors. Patients with FCH are at increased risk of cardiovascular disease and often have other associated metabolic conditions. Despite its relevance in cardiovascular prevention, FCH is frequently underdiagnosed and very often undertreated. In this review, emphasis is placed on the most recent advances in FCH, in order to increase its awareness and ultimately contribute to improving its clinical control.
Keywords: Dislipidemia; Dyslipidaemia; Familial combined hyperlipidaemia; Hipercolesterolemia; Hiperlipemia familiar combinada; Hipertrigliceridemia; Hypercholesterolaemia; Hypertriglyceridaemia. *1
Abstract
Familial combined hyperlipidemia (FCH) is the most frequent genetic dyslipidemia (DLP) with high risk of early atherosclerosis manifestation. It is characterized by elevated both triglycerides 1.5 mmol/l and apolipoprotein B 1.2 g/l (hyper-TG/hyper-ApoB fenotype), with at least two affected family members. Despite the fact that plasmatic levels of total cholesterol and LDL-C are usually lower than in familial hypercholesterolemia and full expression of DLP in FCH occurs in adulthood, risk of premature manifestation of atherosclerosis is similar in both these familial DLP. It is probably due to the presence of other atherogenic lipid and non-lipid risk factors, such as increased levels of triglyceride rich lipoprotein remnants, presence of small dense LDL, reduction of HDL-C, presence of insulin resistance with impaired glucose homeostasis, hepatic steatosis, arterial hypertension, hyperuricemia and presence of increased markers of systemic inflammation. The term "familial" usually implicates a monogenic trait. However, FCH is almost always nonmendelian. According to recent knowledge FCH is mostly polygenic with variable presence of large effect mutations, accumulation of several small-effect polymorphisms and some environmental influences. Therefore, FCH is rather a syndrome with common clinical presentation but multigenic causes. The term "familial combined hyperlipidemia" is embedded in clinical practice and so it is not necessary to abandon it, as it nearly urges to examination of first degree relatives. This might help to identify a great number of risk subjects who deserve appropriate management.Key words: apolipoprotein B - familial combined hyperlipidemia - genetics - insulin resistance - premature atherosclerosis - triglycerides.*2
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.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. *3
Abstract
Purpose of review: Combined hyperlipidemia is the most common lipid disorder and is strongly polygenic. Given its prevalence and associated risk for atherosclerotic cardiovascular disease, this review describes the potential for utilizing polygenic risk scores for risk prediction and management of combined hyperlipidemia.
Recent findings: Different diagnostic criteria have led to inconsistent prevalence estimates and missed diagnoses. Given that individuals with combined hyperlipidemia have risk estimates for incident coronary artery disease similar to individuals with familial hypercholesterolemia, early identification and therapeutic management of those affected is crucial. With diagnostic criteria including traits such apolipoprotein B, low-density lipoprotein cholesterol, and triglyceride, polygenic risk scores for these traits strongly associate with combined hyperlipidemia and could be used in combination for clinical risk prediction models and developing specific treatment plans for patients.
Summary: Polygenic risk scores are effective tools in risk prediction of combined hyperlipidemia, can provide insight into disease pathophysiology, and may be useful in managing and guiding treatment plans for patients. However, efforts to ensure equitable polygenic risk score performance across different genetic ancestry groups is necessary before clinical implementation in order to prevent the exacerbation of racial disparities in the clinic.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
PubMed Disclaimer *4
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.
Keywords: Apolipoprotein B-100; Combined hyperlipidemia; FCHL; Familial hypercholesterolemia; Genome-wide association study; UK Biobank.
Copyright © 2021 Elsevier B.V. All rights reserved.*5
*1Familial combined hyperlipidaemia/polygenic mixed hyperlipidaemia
[Article in English, Spanish]
Juan Pedro-Botet et al. Clin Investig Arterioscler. 2021 May.
*2Familial combined hyperlipidemia - the most common genetic dyslipidemia in population and in patients with premature atherothrombotic cardiovascular disease]
[Article in Czech]
Helena Vaverková et al. Vnitr Lek. 2018 Winter
*3Familial combined hyperlipidemia is a polygenic trait
Praneet K Gill et al. Curr Opin Lipidol. 2022.
*4The clinical utility of polygenic risk scores for combined hyperlipidemia
Jacqueline S Dron. Curr Opin Lipidol. 2023.
*5Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia
Mark Trinder et al. Atherosclerosis. 2022 Jan.
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