Single Nucleotide Polymorphisms within LIPA (Lysosomal Acid Lipase A) Gene Are Associated with Susceptibility to Premature Coronary Artery Disease. A Replication in the Genetic of Atherosclerotic Disease (GEA) Mexican Study

Gilberto Vargas-Alarcón,Carlos Posadas-Romero,Rosalinda Posadas-Sánchez,Guillermo Cardoso,Aida Medina-Urrutia,Edith Alvarez-León,Teresa Villarreal-Molina,Eric Kimura-Hayama,Javier Angeles,Maite Vallejo,Tanja Zeller

doi:10.1371/journal.pone.0074703

Abstract

AimThe rs1412444 and rs2246833 polymorphisms within the LIPA gene were recently found to be significantly associated with coronary artery disease (CAD) in genome-wide association studies in Caucasian and Asian populations. The aim of the present study was to replicate this association in an independent population with a different genetic background.MethodsThe rs1412444 and rs2246833 polymorphisms of the LIPA gene were genotyped by 5′ exonuclease TaqMan genotyping assays in a sample of 899 Mexican patients with premature CAD, 270 individuals with subclinical atherosclerosis, and 677 healthy unrelated controls. Haplotypes were constructed after linkage disequilibrium analysis.ResultsUnder recessive and additive models, the rs1412444 T and rs2246833 T alleles were associated with an increased risk of premature CAD when compared to controls adjusting for age, gender, BMI, and total cholesterol (OR = 1.53, PRec = 0.0013 and OR = 1.34, PAdd = 5 × 10-4 for rs1412444 and OR = 1.45, PRec = 0.0039 and OR = 1.28, PAdd = 0.0023 for rs2246833). The effect of the two polymorphisms on various metabolic cardiovascular risk factors was analyzed in premature CAD and controls (CAC score = 0). The T alleles in both polymorphisms after adjusting for age, gender, BMI, and medication were associated with hypo-α-lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus using recessive and additive models. The polymorphisms were in strong linkage disequilibrium and, based on SNP functional prediction software, only the rs1412444 polymorphism seemed to be functional.ConclusionsThese results indicate that the rs1412444 and rs2246833 of the LIPA gene are shared susceptibility polymorphisms for CAD among different ethnicities.

Highlights

Coronary artery disease (CAD) is a complex multifactorial and polygenic disorder resulting from an excessive inflammatory response to various forms of injurious stimuli to the arterial wall [1,2,3]
Recent Genome wide association (GWA) studies followed by two states of replication and a final meta-analysis in Caucasian individuals led to the identification of a novel CAD susceptibility locus on chromosome 10q23, 31, the LIPA gene [11]
Considering these studies, the aim of a present work was to determine whether the association of two single nucleotide polymorphisms (SNPs) with CAD, reported in Caucasian and Asian populations, is replicated in Mexican patients with premature CAD

Summary

Introduction

Coronary artery disease (CAD) is a complex multifactorial and polygenic disorder resulting from an excessive inflammatory response to various forms of injurious stimuli to the arterial wall [1,2,3]. Recent GWA studies followed by two states of replication and a final meta-analysis in Caucasian individuals led to the identification of a novel CAD susceptibility locus on chromosome 10q23, 31, the LIPA (lysosomal acid lipase A) gene [11]. The role of the LIPA locus in CAD was corroborated in another GWA study in Caucasian and Asian populations [9]. Considering these studies, the aim of a present work was to determine whether the association of two SNPs with CAD, reported in Caucasian and Asian populations, is replicated in Mexican patients with premature CAD. The analysis of independent populations with different ethnic background often helps to unravel the genetic implications in associated regions by narrowing down the linkage structure

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