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

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.

Association of CYP2C19*2 with hyperlipidemia in patients with the wild-type CYP2C9

“…Concerning diabetes mellitus, CYP2C9*2, *3, and CYP2C19*2 have been shown to have no association with diabetes mellitus (Semiz et al, 2010;Weise et al, 2010), which is consistent with our results. One study even showed that individuals with the CYP2C19*2 variant seem to protect against metabolic syndrome (Gaio et al, 2014). Regarding hyperlipidemia, the study by Luo et al (2005) suggested an association of CYP2C9*3 with hyperlipidemia in the female Chinese population.…”

Polymorphism of the gene eNOS G894T (Glu298Asp) in symptomatic patients with aterosclerosis

“…An important polymorphism described in the literature is the G894T (a replacement of guanine for a thymine at position 894), or Glu298Asp (a replacement of non-essential amino acid glutamate for the amino acid aspartate at codon 298). This change results in accelerated degradation and significantly reducing NO production contributing to onset of atherosclerosis (Gaio et al, 2014).…”

“…A few intronic sites have been identified presenting polymorphism and they act differently in the expression of NO within the arterial endothelium (Gaio et al, 2014). An important polymorphism described in the literature is the G894T (a replacement of guanine for a thymine at position 894), or Glu298Asp (a replacement of non-essential amino acid glutamate for the amino acid aspartate at codon 298).…”

“…A large part of these genes related to atherosclerotic disease are polymorphic. They encode proteins involved in the normal physiology of the endothelium and their variations in certain situations may contribute to the molecular etiopathogenesis in cardiovascular diseases (Gaio et al, 2014).…”

“…The gene responsible for encoding eNOS is located on the long arm of chromosome 7, region 35 to 36 (7q35®36). They present 26 exons and 25 introns, with a total of 21 kb (Gen Bank D26607), encoded by 4052 nucleotides in the mRNA, and expressed by endothelial cells from both central and peripheral vessels (Gaio et al, 2014).…”