Association of the Sirtuin and Mitochondrial Uncoupling Protein Genes with Carotid Plaque

Chuanhui Dong,Liyong Wang,David Della-Morte,Ashley Beecham,Tatjana Rundek,Mark S Mcclendon,Digna Cabral,Corneliu C Luca,Susan H Blanton,Ralph L Sacco,Stefan Kiechl

doi:10.1371/journal.pone.0027157

Abstract

ObjectiveSirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque.MethodsIn a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque.ResultsOverall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR = 1.71, 95% CI = 1.23–2.37, Bonferroni-corrected p = 0.03) and for a number of plaques (rate ratio, RR = 1.31, 1.18–1.45, Bonferroni-corrected p = 1.4×10−5), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR = 0.49, 95% CI = 0.32–0.74, Bonferroni-corrected p = 0.02) and plaque number (RR = 0.64, 95% CI = 0.52–0.78, Bonferroni-corrected p = 4.9×10−4). Some interactions with a nominal p≤0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes.ConclusionWe observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations.

Highlights

Atherosclerosis is a complex disorder and underlying cause of ischemic strokes and cardiovascular diseases (CVD) [1]
Univariate analysis showed that age, sex, race/ethnicity, smoking, hypertension, diabetes, and waist-to-hip ratio were associated with the presence of carotid plaque (Table 1)
Tcarriers of SIRT6 single nucleotide polymorphisms (SNPs) rs107251 had an increased risk for carotid plaque presence and for a number of carotid plaques (RR 1.31, 95% CI = 1.18–1.45, adjusted p = 1.461025); whereas T-carriers of UCP5 SNP rs5977238 had a decreased risk for carotid plaque presence and for a number of plaques (RR 0.64, 95% CI = 0.52–0.78, adjusted p = 4.961024)

Summary

Introduction

Atherosclerosis is a complex disorder and underlying cause of ischemic strokes and cardiovascular diseases (CVD) [1]. Presence of carotid plaque has been widely used to assess the risk of future clinical atherosclerotic disease. Atherosclerotic plaque reflects biologically distinct atherosclerotic phenotype [1]. The heritability of carotid plaque is 23–50%, indicating an important role of genetic contribution to atherosclerosis [2,3]. Genes controlling the oxidative stress, balance between production and removal of reactive oxygen species (ROS), are strongly implicated in mechanisms of atherosclerosis, stroke and cardiovascular disease (CVD) [4]. Oxidative stress plays a major role in age-dependent atherosclerosis by the enhancement of endothelial dysfunction and reduction of nitric oxide (NO) bioactivity, determining vascular aging independently of other traditional vascular risk factors [5]

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