Abstract
The objective of this review is to unify the various genetic defects along with elaborating metabolic pathways in Familial Combined Hyperlipidemia(FCHL) and also to differentiate the phenotype of FCHL from metabolic syndrome.
PubMed and Cochrane s library was searched for keyword Familial combined hyperlipidemia and latter with Familial combined hyperlipidemia genes to finally shortlist 23 articles. Further search with key words molecular pathogenesis of familial combined hyperlipidemia and metabolic syndrome and familial combined hyperlipidemia was carried out for finding molecular defects in FCHL, non-molecular findings distinguishing FCHL from metabolic syndrome and overlapping features between FCHL and metabolic syndrome.
Major culprit regions identified included Chromosome-1q21-q24(USF1 and FOXA2) , Ch-11q (APOA5), Ch-16q24, Ch-20q12-q13.1, Ch.4q32.3 (rs6829588), and Ch-19q13.32 containing PVRL-2 gene (Also known as Nectin-2). The genetic and metabolic pathways linked to FCHL may involve: 1-Defective clearance of Apo-B containing lipoproteins, 2-Overproduction of Apo-B containing lipoprotein i.e., VLDL and 3-Adipose tissue dysfunction. FCHL phenotype showed close resemblance with metabolic syndrome clinical and biochemical features with slight differences.
The reviewed data suggested that FCHL phenotype is the resultant end outcome from multiple molecular defects and thus underlying genetic defect identification in the index case is important for personalized medicine and incoming gene therapy. Further research is warranted to explore specific genetic defects.
Author Contributions
Copyright© 2019
Hayat Khan Sikandar.
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Competing interests The authors have declared that no competing interests exist.
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Introduction
Familial Combined Hyperlipidemia (FCHL) supersedes most other genetic lipid and non-lipid disorders in most of the shared scientific evidence with disease prevalence ranging from 1% to 2.5% in different parts of the globe. FCHL is not a singular entity in pathology or a monogenic genetic disorder. Molecular and genetic studies and phenotypic disease presentations have identified it as heterogeneous disease which not only vary in terms of temporo-spatial presentation clinical traits, being very pleiotropic due to probable multiple molecular triggers and the clinical appreciation variability resulting from the subtype of cholesterol surge or decline and very high prevalence in myocardial survivors. Most primary physicians lack the knowledge and details about the gravity underlying the interpretation of a lipid profile along with being oblivious of underlying lipid pathology, so patients are dealt as per conventional wisdom with disregard to any attempt to provide the patient with complete diagnosis along with advice on family screening. Furthermore, the disease is in definitive demand of a biochemical or molecular biomarker to allow predictive screening, identifying the specific genetic defect in lipid physiology, genetic risk scoring, cascade screening of family members, preventive guidance to carriers and patients and most importantly to provide a way forward to curative medicine by gene therapy like CRISPR-Cas9 techniques. This mini review attempts to segregate the molecular subtypes of FCHL, brief details of molecular pathogenesis, overlapping and contrasting evidence linking FCHL and metabolic syndrome in order to bridge the gap with some recent data and not so recent concepts about FCHL.