Elsevier

Clinical Biochemistry

Volume 46, Issues 16–17, November 2013, Pages 1668-1672
Clinical Biochemistry

Methionine sulfoxide reductase A rs10903323 G/A polymorphism is associated with increased risk of coronary artery disease in a Chinese population

https://doi.org/10.1016/j.clinbiochem.2013.07.011Get rights and content

Highlights

  • We studied the association between MSRA and VEGFA polymorphisms and CAD risk.

  • Genotyping was done using MALDI-TOF MS in 435 CAD patients and 480 controls.

  • We found MSRA rs10903323 G/A polymorphism was associated with CAD development.

Abstract

Objective

Coronary artery disease (CAD) is a complex disease resulting from a combination of environmental and genetic factors. We hypothesized that polymorphisms in methionine sulfoxide reductase A (MSRA: rs10903323 G/A) and vascular endothelial growth factor A (VEGFA: rs699947 C/A, rs2010963 G/C, and rs3025039 C/T) contribute to CAD susceptibility.

Designs and methods

We examined the association between the four polymorphisms and the risk of CAD in a Chinese population of 435 CAD patients and 480 controls. Genotyping was performed using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF-MS).

Results

When the MSRA rs10903323 GG homozygous genotype was used as the reference group, the GA and GA/AA genotypes were associated with a significantly increased risk of CAD (GA vs GG: adjusted OR = 1.36, 95% CI = 1.02–1.82, p = 0.038; GA/AA vs GG: adjusted OR = 1.33, 95% CI = 1.01–1.76, p = 0.042). The AA homozygous genotype was not associated with a risk of CAD. In the recessive model, when the MSRA rs10903323 GG/GA genotypes were used as the reference group, the AA homozygous genotype was not associated with a risk of CAD. Logistic regression analyses revealed that the VEGFA rs699947 C/A, VEGFA rs2010963 G/C, and VEGFA rs3025039 C/T polymorphisms were not associated with a risk of CAD.

Conclusions

These findings suggest that the functional MSRA rs10903323 G/A polymorphism is associated with CAD development. However, our results allow only a preliminary conclusion, which must be validated with a larger study of a more diverse ethnic population.

Introduction

Coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide [1], [2], [3]. CAD has a complex etiology and both environmental and genetic influences are major risk factors for CAD [2].

Methionine sulfoxide reductase A (MSRA) acts as a scavenger of reactive oxygen species (ROS) and protects proteins from oxidation [4]. MSRA is located on chromosome 8p23.1 and the protein catalyzes the reversible oxidation–reduction of methionine sulfoxide in proteins to methionine [5]. The lack of MSRA in cardiac myocytes reduces the capacity of myocardial cells to withstand stress stimuli and may cause cardiac cell dysfunction. Previous studies have observed associations between single-nucleotide polymorphisms (SNPs) in MSRA and the risk of obesity [6]. The MSRA rs10903323 G/A polymorphism is also associated with an increased risk of cardiovascular disease in patients with rheumatoid arthritis (RA) [7].

The downregulation of MSRA expression results in the upregulation of vascular endothelial growth factor A (VEGFA), which promotes local vascular hyperplasia [8]. VEGFA is one of the most potent endothelial cell mitogens and plays a crucial role in both lymphogenesis and angiogenesis [9]. Angiogenesis refers to the development of new blood vessels from preexisting vascular structures. VEGFA production is a response to stimulation by the proinflammatory cytokines interleukin 1, interleukin 6, tumor necrosis factor α, and transforming growth factor β expressed by perivascular cells [10], [11].

The VEGFA gene is located on chromosome 6p12.3. It consists of eight exons and its transcript is alternatively spliced to produce a family of proteins [12]. The human VEGFA gene is highly polymorphic and there is considerable variation in its expression between individuals [13]. A number of SNPs have been reported to be associated with the differential expression of VEGFA in vitro [14]. SNP rs699947 (− 2578C > A) is located in the VEGFA promoter region, SNP rs2010963 (− 634G > C, also denoted G + 405C) is in exon 1, and SNP rs3025039 (+ 936C > T) is in exon 8, corresponding to the 3′ untranslated region [15]. VEGFA polymorphisms are associated with several different kinds of diseases [16], [17], [18], [19].

Few studies have focused on the effects of the MSRA rs10903323 G/A, VEGFA rs699947 C/A, VEGFA rs2010963 G/C, and VEGFA rs3025039 C/T polymorphisms on the susceptibility to CAD. Therefore, we performed a hospital-based case–control study to genotype a cohort of 435 CAD patients and 480 controls from a Chinese population.

Section snippets

Study population

This case–control study included 435 consecutive patients with CAD from Tianjin TEDA International Cardiovascular Hospital between November 2011 and July 2012 and 480 CAD-free controls, the controls were inpatients which exclude CAD by quantitative coronary angiography (QCA) in Tianjin TEDA International Cardiovascular Hospital. All 435 CAD patients and 480 inpatients received QCA with a Cardiovascular Measurement System (Philips Integris and Philips Allura Xper) shortly after being admitted to

Characteristics of the study population

The demographic and clinical characteristics of all subjects are summarized in Table 1. The subjects were adequately matched for age (p = 0.383) and sex (p = 0.398) for CAD cases and controls in Tianjin. The average body mass index (BMI) was not significantly different between CAD cases and the controls. For the family disease history, 98 (22.5%) cases had family history of CAD which was significantly higher than that of the controls (13.1%), there were more hypertension and diabetes mellitus in

Discussion

We determined the association between the MSRA rs10903323 G/A, VEGFA rs699947 C/A, VEGFA rs2010963 G/C, and VEGFA rs3025039 C/T polymorphisms and the risk of CAD in a Chinese population. We found that the MSRA rs10903323 G/A polymorphism may be associated with an increased risk of CAD.

Methionine oxidation increases the pathological impact of myocardial infarction [21]. A deficiency of MSRA can increase the sensitivity of the heart to oxidative stress, resulting in cardiac dysfunction and

Conflict of interest

None of the authors has any potential financial conflict of interest related to this manuscript.

Acknowledgments

We appreciate all patients who participated in this study.

References (23)

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    Association of the methionine sulfoxide reductase A rs10903323 gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis

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  • Cited by (0)

    Grant support: This study was supported in part by the National Natural Science Foundation of China (No.30901230, 30900630 and 81101889).

    1

    Haiyong Gu and Weiqiang Chen contributed equally to this work.

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