A systematic review of LDLR, PCSK9, and APOB variants in Asia
Graphical abstract
Introduction
Pathogenic variants of the LDLR gene, as the main cause of familial hypercholesterolemia (FH, OMIM: #143890), lead to about two percent of early myocardial infarction (MI) [1]. FH is one of the common lipid disorders with an approximate prevalence of 1:250 [2]. It has autosomal dominant inheritance [3] although there is a low frequency of autosomal recessive pattern with an estimated prevalence of 1 in 200,000 to 300,000 [4,5]. The frequency of FH varies among different populations and a proportion of affected individuals remain undiagnosed [6]. There is no study about the prevalence of FH in Asia. It seems that the prevalence may differ because of sociodemographic characteristics.
FH has a wide spectrum of clinical symptoms, due to defects in proteins involved in LDL uptake and catabolism [7], including the proteins encoded by LDL-receptor (LDLR), apolipoprotein-B (APOB), LDL receptor adaptor protein (LDLRAP1) and PCSK9 (PCSK9) [4]. More than 90% of FH cases are due to pathogenic variants in the LDLR gene [8]. Pathogenic variants in LDLR lead to an abnormal increase in low-density lipoprotein cholesterol (LDL-C) resulting in 5–8 times higher risk of premature coronary artery disease (CAD) [9]. Xanthomas, premature and progressive atherosclerotic cardiovascular disease (ACVD) are seen in the patients [8].
To date, approximately more than two thousands pathogenic variants have been reported in LDLR in HGMD professional 2019 (http://www.hgmd.cf.ac.uk), including different types of variants i.e. missense, nonsense, large deletion, duplication, indel, regulatory and splicing mutations. The type of variant could affect the degree of increased LDL and cholesterol, severity of the disease and risk of CAD development [10]. Different types of variants have been reported among various Asian countries and we aim to investigate the distribution, frequency, functional variants, zygosity, and clinical phenotype in Asia. Only the developed Asian countries have a systematic review of the variants in their population. The aim of this systematic review is to explore all records of FH LDLR, APOB and PCSK9 mutations reported in databases for Asia as the major genetic causes of monogenic FH. In patients with no causative mutation, the polygenic cause is suggested, which is out of the scope of this manuscript. In addition, the genotypic spectrum of the Iranian population is studied and reported in this survey to add new data on LDLR mutations to Asia.
Section snippets
Search strategy
A systematic search was conducted on the Asian published articles about familial hypercholesterolemia patients with LDLR, APOB and PCSK9 pathogenic variants. All the English published articles in databases (PubMed, Science Direct, John Wiley, Google Scholar) were searched from 1950 to 2019 using the following keywords: LDLR [title] gene mutations OR LDLR, AND familial hypercholesterolemia. LDLR and name of each Asian country were specifically used to find all the relevant articles, for example
Search analysis
The search strategy yielded 14,003 articles since 1970. Duplicates were removed and 1925 articles remained. These articles were reviewed according to inclusion and exclusion criteria. 1458 articles remained only based on title and abstract; 1000 articles were excluded after review of published literature considering the criteria. After data extraction, 160 eligible articles were included in our systematic analysis (Fig. 1). Any entry that could not be verified was deleted from this study.
Among
Discussion
To the best of our knowledge, this is the first systematic review of LDLR, APOB, PCSK9-related FH patients within Asian countries. To date, only few systematic reviews were conducted on the LDLR gene mutations in China, Arabic and Latin American countries [[28], [29], [30]]. We gathered and analyzed a comprehensive panel and geographical distribution of mutations in monogenic FH patients reported in Asian countries. The polygenic influence of the mutations in HeHF was not studied in this
CRediT authorship contribution statement
Nejat Mahdieh: Validation, Project administration, Writing - review & editing. Katayoun Heshmatzad: Validation, Writing - original draft, Writing - review & editing. Bahareh Rabbani: Writing - review & editing.
Declaration of competing interest
The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
Acknowledgements
The study was approved by the Iran University of Medical Sciences, Tehran, Iran (IR.IUMS.REC.1398.1111).
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