Elsevier

Atherosclerosis

Volume 305, July 2020, Pages 50-57
Atherosclerosis

A systematic review of LDLR, PCSK9, and APOB variants in Asia

https://doi.org/10.1016/j.atherosclerosis.2020.05.004Get rights and content

Highlights

  • This systematic review provides information on LDLR, APOB, PCSK9 variants in Asia.

  • Among 8994 FH families in 48 Asian countries, 629 LDLR variants were reported.

  • Twenty variants were reported as the common variants in Asia.

  • The frequency and distribution of the variants were high in East Asia.

Abstract

Background and aims

Genetic identification is a public health care concern for management of familial hypercholesterolemia (FH) associated cardiovascular morbidity and mortality. This study presents the spectrum and distribution of LDLR, APOB, PCSK9 gene mutations in Asia.

Methods

Databases were searched for English papers from 1950 to 2019. The spectrum of the variants was investigated in 8994 FH families in 48 Asian countries. We determined the frequency of variants, zygosity, and clinical features.

Results

Twenty countries have studied LDLR variants. A total of 629 mutations were reported and twenty variants were accounted as common variants in different populations. China, Japan, India and Taiwan constituted 68% of published articles. The most frequent mutation was reported in Japan but was not common in other countries. Other missense variants accounted for 50% of the mutations, frameshifts 19%, and nonsense 11%. The pooled frequency of variation was estimated in 1867 individuals. Approximately 67% of Iranian families were homozygous.,The common variant was p.Ser130Ter. p.Arg3527Trp in APOB was common among 184 heterozygous patients; the common variant of PCSK9 was p.Glu32Lys.

Conclusions

This is the first systematic review of LDLR, APOB, PCSK9 mutations in FH patients in Asia. These findings underscore the need to fill in the gap of studies on different populations in Asia. It also underlies the importance of early detection and management to decrease atherosclerosis and cardiovascular risk in different ethnicities.

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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