Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction

Chongyou Lee,Dan Hu,Sufang Li,Feng Zhang,Manyan Wu,Long Li,Yuxia Cui,Junxian Song,Hong Chen

doi:10.1186/s12944-019-1042-3

Abstract

BackgroundThe incidence of premature myocardial infarction (PMI) has gradually increased in recent years. Genetics plays a central role in the development of PMI. Familial hypercholesterolemia (FH) is one of the most common genetic disorders of cholesterol metabolism leading to PMI.ObjectiveThis study investigated the relationship between FH-associated genes and the phenotype of PMI to clarify the genetic spectrum of PMI diseases.MethodThis study enrolled PMI patients (n = 225) and detected the mutations in their FH-associated genes (LDLR, APOB, PCSK9, LDLRAP1) by Sanger sequencing. At the same time, patients free of PMI (non-FH patients, n = 56) were enrolled as control, and a logistic regression analysis was used to identify risk factors associated with PMI. The diagnosis of FH was confirmed using “2018 Chinese expert consensus of FH screening and diagnosis” before the prevalence and clinical features of FH were analyzed.ResultsPathogenic mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes were found in 17 of 225 subjects (7.6%), and all mutations were loss of function (LOF) and heterozygous. The genotype-phenotype relationship of patients carrying FH-associated mutations showed high heterogeneity. The logistic regression analysis showed that the smoking history, obesity and the family history of premature CHD were independent risk factors of PMI. In this study, a total of 19 patients (8.4%) were diagnosed as FH, and the proportion of smoking subjects in FH patients was higher than that in non-FH patients.ConclusionsFH-associated gene mutations were present in about 7.6% of Chinese patients with PMI. In addition to genetic factors, smoking history, lifestyle and other environmental factors may play a synergistic role in determining the phenotype of PMI.Trial registrationEssential gene mutation of cholesterol metabolism in patients with premature myocardial infarction. ChiCTR-OCH-12002349.Registered 26 December 2014, http://www.chictr.org.cn/showproj.aspx?proj=7201.

Highlights

As the most severe type of coronary artery diseases, myocardial infarction (MI) has posed a threat to public health because of its high morbidity and mortality
Familial hypercholesterolemia (FH)-associated gene mutations were present in about 7.6% of Chinese patients with premature myocardial infarction (PMI)
In addition to genetic factors, smoking history, lifestyle and other environmental factors may play a synergistic role in determining the phenotype of PMI

Summary

Introduction

As the most severe type of coronary artery diseases, myocardial infarction (MI) has posed a threat to public health because of its high morbidity and mortality. It has been shown that genetics plays a central role in the development of PMI, with its heritability estimated at approximately 63% [4]. It was reported that about 10–15% of PMI cases were caused by essential mutations in genes related to cholesterol metabolism [5]. Familial hypercholesterolemia (FH) is one of the most common genetic disorders of cholesterol metabolism [6], and the mutations in FH-associated genes, such as low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and lowdensity lipoprotein receptor adaptor protein 1 (LDLRAP1), can increase the plasma levels of low-density lipoprotein cholesterol (LDL-C) and lead to PMI. Familial hypercholesterolemia (FH) is one of the most common genetic disorders of cholesterol metabolism leading to PMI

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