| Cardiovascular diseases(CVD) are the main causes of morbidity and mortality in Western countries. In the US, a 10 %increase in all CVD has been estimated from 2010 to 2030 including a 25 % increase in heart failure.Reduction of known risk factors for CAD such as hypercholesterolemia, hypertension, and smoking have been assessed in multiple randomized placebo-controlled clinical trials and is associated with30% to 40% less clinical events such as death and myocardial infarction.Epidemiological and family studies have repeatedly shown that genetic predisposition accounts for 40% to 60% of the risk for CAD. Multiple susceptibility loci have been indentured for CAD from genome-wide association(GWA) studies, with common variants being modestly associated with disease risk. Most of these studies have been performed in Europeans.Given that the substantial difference in the genetic background of European and Asian populations is well established, these associations need to be confirmed by further replication studies, particularly in other ethnic groups.ADAMTS7(a disintegrin and metalloprotease with thrombospondin motif, 7 [MIM 605009]), a metalloproteinase that belongs to A Disintegrin And Metalloprotease with Thrombo Spondin type 1 repeats(ADAMTS) family,the ADAMTS7(a disintegrin and metalloprotease with thrombospondin motif,7 [MIM 605009]) that were associated with CAD in several White cohorts.Studies in animal models have demonstrated that ADAMTS7 facilitated vascular smooth muscle cell(VSMC) migration by degrading the extracellular matrix protein thrombospondin-5(TSP5) and thereby promoted neointima formation following vascular mechanical injury [12,13]. Given that VSMC migration is an important process in atherogenesis, it is likely that ADAMTS7 can also plays an essential role during the development of atherosclerosis and restenosis, the pathology underlying the vast majority of CADThe muscle Ras(MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins,which function as signal transducers in multiple processes including cell growth and differentiation. There have been reported that four single nucleotide polymorphisms(SNPs)(rs9818870, rs2306374, rs1720819 and rs1199337) within the MRAS gene are nominally associated with genetic susceptibility for CAD in European populations, and part of results have been replicated in Saudi populations.Aldehyde dehydrogenase 2(ALDH2) is one of the 19 members of the ALDH gene family. It is the second enzyme of the major oxidative pathway of alcohol metabolism, which plays a crucial metabolic role in catalyzing the oxidation of acetaldehyde to acetic acid. ALDH2 is also a key metabolic enzyme involved in the detoxification of other reactive aldehydes such as4-hydroxy-2-nonenal(4-HNE). GWASs have discovered association between genetic variants in ALDH2 at 12q24 and CAD9. However, due to the underlying genetic heterogeneity, the association studies give quite diverse results in different ancestry groups, especially between Caucasians and Asians.Human liver has two major isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial. Most Caucasians have two major isozymes, while approximately 50% of Asians don’t have the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of disease.Part 1 ADAMTS7 Locus Confers High Cross-Race Risk for Development of Coronary Atheromatous PlaqueObjective: Coronary artery disease(CAD) has a substantial genetic component which is incompletely characterized. Genome-wide association studies of CAD have recently identi?ed a new susceptibility locus ADAMTS7 in subjects of European ancestry. This study was designed to evaluate theffect of rs3825807, a nonsynonymous variant in the prodomain of the protease ADAMTS7, on CAD risk and atherosclerosis severity in Chinese population.Methods: We performed genetic association analyses in two independent case-control cohorts. The first cohort involved 1536 patients with CAD and1609 controls. The participants were consecutively recruited from The Second Hospital of Hebei Medical University in Shijiazhuang between September2012 and September 2013. Independent replication was assessed in 5009 subjects from Tongji Hospital in Wuhan, China. The replication sample comprises 2466 cases and 2543 controls. The patients were consecutively recruited from Tongji Hospital between May 2004 and December2012.Controls matched ethnically and in terms of geographically were randomly selected from local community inhabitants participating in a community screening programme in Wuhan over the same period. Including total of 8154 participants. Additionally, the association between ADAMTS7rs3825807 genotype and the proportion of CAD patients with 3-vessel disease and 1-vessel disease was tested.Results: We found that ADAMTS7 rs3825807 was associated with susceptibility to CAD in Chinese population(OR 1.15, 95% CI 1.05-1.26, P=0.002). The association remained significant after adjusting for clinical covariates(adjusted OR 1.12, 95% CI 1.02-1.24, P=0.02). Among 3741 angiographically documented CAD patients, the risk allele of rs3825807 showed a signi?cant association with disease severity(P = 0.04, Trend P =0.02). Additionally, 3-vessel disease demonstrated a strong, direct association with ADAMTS7 rs3825807 gene dosage(P = 0.02).Conclusions: ADAMTS7 is an important susceptibility locus that not only confers high cross-race risk for development of CAD but also predicts the degree of coronary atheromatous burden.Part 2 Genetic Insight Into the Role of MRAS in Coronary Artery Disease RiskObjective: The muscle Ras(MRAS) gene polymorphisms have beenreported to be associated with coronary artery disease(CAD) in white Europeans. The aim of this study was to ascertain the role of MRAS gene polymorphisms in conferring susceptibility to CAD, and to explore the effect on severity of CAD in Chinese population.Methods: We genotyped 5009 Chinese individuals(2466 CAD cases and2543 controls) for eight single nucleotide polymorphisms(SNPs) around MRAS and used logistic regression analysis to determine whether they were associated with CAD. The association of the SNP loci on severity of CAD was analyzed using a logistic and linear regression analysis, respectively.Results: Our results revealed that an intron SNP, rs1199337, tend to have the same direction of the association with CAD as previously reported in Caucasians(nominal P = 0.01, OR 1.10, 95% CI 1.01-1.20). However, this association was lost after applying Bonferroni’s correction for multiple testing(corrected P=0.08). Multivariate analysis demonstrated no association between any other SNP loci with CAD(nominal P > 0.05), not even before correcting for multiple testing. Additionally, we also conducted the genetic analyses under a dominant and recessive model(Supplementary Table 1). However,none of SNPs showed an association with CAD under a dominant or recessive genetic model(all P value >0.05). We further performed haplotype analysis for associations between CAD and multiple SNPs. Unfortunately, none of the constructed haplotype confers the risk for CAD. We did not observe any significant association between the SNPs and severity of CAD(all P values>0.05).Conclusions: The MRAS gene loci might have minor effect in conferring susceptibility to CAD in Chinese population.Part 3 Aldehyde dehydrogenase 2 genetic variants increased risk of coronary artery diseaseObjective: Impacts of Aldehyde dehydrogenase 2 genetic variants on atherosclerosis has been reported, while common variants on vascular outcomes in CVD patients has not been extensively studied.Methods: In this study, we used two cohorts with a mean follow-upperiod of 41.44±19.71 months to investigate impacts of Aldehyde dehydrogenase 2 genetic variants on vascular outcomes. The initial cohort comprises 1920 CAD patients and 1920 ethnically and geographically matched control subjects. All cases were recruited from Tongji Hospital in Wuhan(Hubei, People’s Republic of China). The healthy subjects were recruited from two communities in Wuhan.Results: Most of the polymorphisms were not associated with CAD under additive model. Only one variant rs671 in Tongji cohorts was significantly associated with CAD(OR=1.26, 95%CI: 1.13–1.40, P < 0.001),as shown in table 2. After adjustment for traditional risk factors(including age,sex, body mass index(BMI), Waist to Hip Ratio(WHR), hypertension,hyperlipidemia, diabetes mellitus, smoking and drinking status), the results remain unchanged(OR=1.26, 95%CI: 1.07-1.48, P = 0.004). The results were similar under recessive model(Crude OR=1.37, 95%CI: 1.21-1.56, P < 0.001,and Adjusted OR=1.34, 95%CI: 1.10-1.64, P=0.004,). However, these associations were not found in Shijiazhuang cohorts. The results show that the common variant rs671 in ALDH2 is associated with an increased risk of CAD in South Chinese(OR=1.34, 95%CI: 1.10-1.64, P =0.004), while not in North Chinese(OR=0.99, 95%CI: 0.84-1.17, P =0.92). Our findings didn’t provide evidence that ALDH2 genotypes may influence the outcome of CAD(HR=1.11, 95%CI: 0.892-1.38, P=0.346).We define myocardial infarction,stroke, heart failure and rehospitalisation during the follow up as the endpoint.During the 41.44±19.71 months follow-up period, endpoint was reached in410 subjects among the followed patients. After adjusted for sex, age, age,gender, BMI, WHR, smoke and drinking status, no significant difference were found between the GG and GA+AA genotypes(HR=1.11, 95%CI: 0.892-1.38,P=0.346, Figure 2). There was no significant difference between the GG and GA+AA genotypes in myocardial infarction, stroke, heart failure and rehospitalisation during the follow up as well.Conclusions: The common variants rs671 in ALDH2 is associated with an increased risk of CAD in South Chinese, while not in North Chinese.RS671 genotypes may not influence the outcome of CVD. |
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