SIRT1 Gene Polymorphisms Affect the Protein Expression in Cardiovascular Diseases

Ulkan Kilic,Omer Uysal,Birsen Elibol-Can,Muzeyyen Izmirli,Ozlem Gok,Ahmet Bacaksiz,Robert Lafrenie

doi:10.1371/journal.pone.0090428

Ulkan Kilic, Omer Uysal + Show 5 more

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https://doi.org/10.1371/journal.pone.0090428

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Journal: PloS one	Publication Date: Feb 28, 2014
Citations: 119	License type: CC BY 4.0

Affiliation: Bezmiâlem Vakıf Üniversitesi

Abstract

Cardiovascular disease (CVD), the leading cause of death worldwide, is related to gene-environment interactions due to epigenetic factors. SIRT1 protein and its downstream pathways are critical for both normal homeostasis and protection from CVD-induced defects. The aim of this study was to investigate the association between SIRT1 single nucleotide polymorphisms (SNPs) (rs7895833 A>G in the promoter region, rs7069102 C>G in intron 4 and rs2273773 C>T in exon 5 silent mutation) and SIRT1 and eNOS (endothelial nitric oxide synthase) protein expression as well as total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) in CVD patients as compared to controls. The frequencies of mutant genotypes and alleles for rs7069102 and rs2273773 were significantly higher in patients with CVD compared to control group. The risk for CVD was increased by 2.4 times for rs7069102 and 1.9 times for rs2273773 in carriers of mutant allele compared with carriers of wild-type allele pointing the protective role of C allele for both SNPs against CVD. For rs7895833, there was no significant difference in genotype and allele distributions between groups. SIRT1 protein, TAS, TOS and OSI levels significantly increased in patients as compared to control group. In contrast, level of eNOS protein was considerably low in the CVD patients. An increase in the SIRT1 expression in the CVD patients carrying mutant genotype for rs7069102 and heterozygote genotype for all three SNPs was observed. This is the first study reporting an association between SIRT1 gene polymorphisms and the levels of SIRT1 and eNOS expressions as well as TAS, TOS and OSI.

Highlights

Cardiovascular disease (CVD), the leading cause of death worldwide, is related gene-environment interaction due to epigenetic factors [1] such as smoking, hyperlipidemia, hypertension, age, family history, diabetes mellitus, and obesity
Pearson’s correlation test showed a positive correlation between SIRT1 expression with total antioxidant status (TAS) level (p = 0.008) and age (p = 0.014) in patients (Table 4), there was no significant correlation between SIRT1 activity with endothelial nitric oxide synthase (eNOS) protein, total oxidant status (TOS), oxidative stress index (OSI) levels in patients and in control group (p. 0.05)
Because it may be thought to affect the CVD phenotype by associating body mass index and obesity, glucose tolerance and diabetes, blood pressure, cholesterol metabolism and coronary artery calcification, we performed our experiments on rs7895833 A.G in the promoter, rs7069102 C.G in intron and rs2273773 C.T in exon regions of SIRT1 gene

Summary

Introduction

Cardiovascular disease (CVD), the leading cause of death worldwide, is related gene-environment interaction due to epigenetic factors [1] such as smoking, hyperlipidemia, hypertension, age, family history, diabetes mellitus, and obesity. In the previous candidate gene, linkage analysis, and genomewide association studies, more than a dozen of genes and genetic loci related with CVD were determined [3,4,5]. SIRT1 protein, a NAD-dependent histone deacetylase, is expressed in many tissue and organ systems such as liver, spleen, kidney, brain, heart, pancreas, endothelial tissue, skeletal muscle and white adipose tissue [8,9,10,11]. While it is expressed in both the cytoplasm and nucleus, it is dominantly located in the nucleus. It acts as a transcription factor and cofactor in addition to being a target for histone and non-histone proteins [7,8]

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