PARP-1 Variant Rs1136410 Confers Protection against Coronary Artery Disease in a Chinese Han Population: A Two-Stage Case-Control Study Involving 5643 Subjects.

Xue-Bin Wang,Ze-Jin Liu,Shuai Zhang,Shuai Zhang,Ning-Hua Cui,Shu-Ren Guo,Liang Ming,Ze-Jin Liu

doi:10.3389/fphys.2017.00916

Abstract

Inhibition of poly(ADP-ribose) polymerase (PARP) may protect against coronary artery disease (CAD) in animal models, and rs1136410, a non-synonymous single nucleotide polymorphism (SNP) in PARP-1, has a potential impact on PARP activities in vitro. This two-stage case-control study, involving 2803 CAD patients and 2840 controls, aimed to investigate the associations of PARP-1 rs1136410 with CAD development, lipid levels, PARP activities, 8-hydroxy-2′-dexyguanosine (8-OHdG), and interleukin (IL)-6 levels in a Chinese Han population. Assuming a recessive model, the variant genotype GG of SNP rs1136410 showed a significantly inverse association with CAD risk (adjusted odds ratio (OR) = 0.73, P < 0.001), left main coronary artery (LMCA) lesions (P = 0.003), vessel scores (P = 0.003), and modified Gensini scores (P < 0.001). There were significant correlations of SNP rs1136410 with higher levels of total cholesterol (TC) and lower levels of high-density lipoprotein cholesterol (HDL-c). In gene-environment interaction analyses, participants with the variant genotype GG, but without smoking habit, type 2 diabetes mellitus, and hyperlipidemia, conferred an 84% (P < 0.001) decreased risk of CAD. The genotype-phenotype correlation analyses further supported the functional roles of SNP rs1136410 in decreasing PARP activities and 8-OHdG levels. Taken together, our data suggest that SNP rs1136410 may confer protection against CAD through modulation of PARP activities and gene-environment interactions in a Chinese Han population.

Highlights

Coronary artery disease (CAD), the major contributor to death and disability worldwide (Mozaffarian et al, 2016), is a multifactorial disease associated with predisposing genes, metabolic risk factors, and their interactions (Lanktree and Hegele, 2009)
In smooth muscle cell (SMC) and endothelial cells, hyperactivation of poly(ADP-ribose) polymerase (PARP)-1 by uncontrolled oxidative DNA damage could trigger a cellular energy crisis and irreversible cell death, which involved the pathogenesis of atherosclerosis (Oumouna-Benachour et al, 2007; Xu et al, 2014)
A previous study has suggested a dose-dependent effect of single nucleotide polymorphism (SNP) rs1136410 on PARP activities in vitro (Wang et al, 2007)

Summary

Introduction

Coronary artery disease (CAD), the major contributor to death and disability worldwide (Mozaffarian et al, 2016), is a multifactorial disease associated with predisposing genes, metabolic risk factors, and their interactions (Lanktree and Hegele, 2009). Oxidative stress, induced by extensive generation of reactive oxygen species (ROS), is a fundamental step of atherosclerosis (Harrison et al, 2003), which triggers multiple DNA lesions of coronary endothelial cells, including modified bases, single- and double- strand breaks (SSB and DSB), and chromosomal aberrations (Shah and Mahmoudi, 2015). In response to these DNA lesions, poly(ADP-ribose) polymerase 1 (PARP-1), a DNA repair sensor, is activated to initiate the base excision repair (BER) pathway by modifying PARP-1 itself and recruiting downstream BER enzymes (ElKhamisy et al, 2003; Altmeyer et al, 2009). PARP-1 deletion in mice could ameliorate lipid profiles and endothelium-dependent relaxation (Hans et al, 2009a), reduce expression of proinflammatory factors (von Lukowicz et al, 2008), and block atherosclerotic plaque regression (von Lukowicz et al, 2008; Hans et al, 2009a)

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