Genetic variation at the CYP2C19 gene associated with metabolic syndrome susceptibility in a South Portuguese population: results from the pilot study of the European Health Examination Survey in Portugal

Vânia Gaio,Ana Paula Gil,Francisco Mendonça,Mafalda Bourbon,Astrid Vicente,Filomena Horta Correia,Álvaro Beleza,Aida Fernandes,Carlos Matias Dias,Marta Barreto Da Silva,Baltazar Nunes

doi:10.1186/1758-5996-6-23

Abstract

BackgroundMetabolic syndrome (MetS) is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and diabetes. Since pathways implicated in different diseases reveal surprising insights into shared genetic bases underlying apparently unrelated traits, we hypothesize that there are common genetic components involved in the clustering of MetS traits. With the aim of identifying these common genetic components, we have performed a genetic association study by integrating MetS traits in a continuous MetS score.MethodsA cross-sectional study developed in the context of the Portuguese Component of the European Health Examination Survey (EHES) was used. Data was collected through a detailed questionnaire and physical examination. Blood samples were collected and biochemical analyses were performed. Waist circumference, blood pressure, glucose, triglycerides and high density lipoprotein cholesterol (HDL) levels were used to compute a continuous MetS score, obtained by Principal Component Analysis. A total of 37 single nucleotide polymorphisms (SNPs) were genotyped and individually tested for association with the score, adjusting for confounding variables.ResultsA total of 206 individuals were studied. Calculated MetS score increased progressively with increasing number of risk factors (P < 0.001). We found a significant association between CYP2C19 rs4244285 and the MetS score not detected using the MetS dichotomic approach. Individuals with the A allelic variant seem to be protected against MetS, displaying a lower MetS score (Mean difference: 0.847; 95%CI: 0.163-1.531; P = 0.015), after adjustment for age, gender, smoking status, excessive alcohol consumption and physical inactivity. An additive genetic effect of GABRA2 rs279871, NPY rs16147 and TPMT rs1142345 in the MetS score variation was also found.ConclusionsThis is the first report of a genetic association study using a continuous MetS score. The significant association found between the CYP2C19 polymorphism and the MetS score but not with the individual associated traits, emphasizes the importance of lipid metabolism in a MetS common etiological pathway and consequently on the clustering of different cardiovascular risk factors. Despite the sample size limitation of our study, this strategy can be useful to find genetic factors involved in the etiology of other disorders that are defined in a dichotomized way.

Highlights

Metabolic syndrome (MetS) is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and diabetes
There are multiple evidences that a continuous outcome increases the statistical power in genetic association studies instead of a dichotomous phenotype [8], and for genetic epidemiological approaches, a continuous MetS score, obtained by integrating all MetS traits, would be a more appropriate and valid alternative to study the underlying risk factors responsible for that condition [11]. Taking these issues into account, the purpose of this study was to identify genetic factors associated with MetS, using a Principal Component Analysis (PCA) derived continuous MetS score, which has been previously validated [11], to perform a genetic association study using Single nucleotide polymorphism (SNP) in candidate genes related to MetS features, like glucose/insulin homeostasis, cardiovascular regulation, body mass index and lipid/drug metabolism
General linear model analysis Using general linear model analysis, we found that differences on the MetS score between subjects with GG genotype and GA + AA genotype on the CYP2C19 rs4244285 remain significant after adjustment for age, gender, smoking status, excessive alcohol consumption and physical inactivity (Mean difference: 0.847; 95%CI: 0.163-1.531; P = 0.015)

Summary

Introduction

Metabolic syndrome (MetS) is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and diabetes. Metabolic syndrome (MetS) is a cluster of conditions — increased blood pressure, high blood glucose level, excess body fat around the waist and abnormal cholesterol levels — that occur together. It is strongly associated with cardiovascular diseases (CVD) and Type 2 Diabetes, increasing the risk of developing these disorders 2 and 5 fold, respectively [1]. Due to the existence of multiple definitions considering different categorical cut-points, a consensus definition for MetS clinical diagnosis has been recently proposed According to this definition, MetS is diagnosed when there are present at least three of the following five MetS features: abdominal obesity, elevated blood pressure, dyslipidemia (elevated triglycerides and low levels of high-density lipoprotein cholesterol), and hyperglycemia. Medication for any of these features is considered as an indicator in the criteria for clinical diagnosis of MetS [4]

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