| The first part:Common genetic variations in pre-miRNAs and the risk of coronary heart disease in a Chinese Han populationBackgrounds and objectives:MicroRNAs (miRNAs) have been found to play pervasive roles in various basic biological and pathological processes. Common single nucleotide polymorphisms (SNPs) in pre-miRNAs may function as regulatory factors to alter miRNA expression so as to affect disease susceptibility. Several SNPs in pre-miRNAs have been found to be associated with susceptibility to human cancers. However, the association between miRNA related SNPs and coronary heart disease (CHD) remains uncertain. The objective of this study is to examine the association between common SNPs in pre-miRNAs and CHD in Chinese Han population.Subjects and Methods:We designed a two-stage case-control study to investigate whether common SNPs in pre-miRNAs are associated with CHD in a Chinese Han population. A total of5560subjects (2772CHD cases and2788controls) were included in this study. Six SNPs including hsa-mir-196a2rs11614913, hsa-mir-27a rs895819, hsa-mir-499rs3746444, hsa-mir-146a rs2910164, hsa-mir-423rs6505162and hsa-mir-492rs2289030, were selected using bioinformatic method. Genotypes of selected SNPs were determined by TaqMan SNP allelic discrimination. In stage1, all the SNPs were genotyped in a case-control sample (853CHD cases and948controls). The associations between SNPs and CHD risk were examined. In stage2, the SNPs significantly associated with CHD were further genotyped in another large case-control sample (1919CHD cases and1840controls). The statistical analysis was then performed in the total5560subjects. Odds ratios (OR) were estimated by logistic regression model adjusted for multivariates. Stratified analysis method was used to investigate association between SNPs and CHD in the subjects with different clinical traits, and further detect the possible interactive effects between such clinical traits and SNPs on CHD risk.Results:In stage1, among six SNPs, including rs11614913, rs3746444, rs2910164, rs895819, rs2289030and rs6505162, only rs11614913T>C in pre-miRNA-196a2 showed a marginal significant association with CHD (P=0.05). In stage2, the marker rs11614913remained significantly associated with the increased CHD risk under dominant genetic model after multivariate adjustment, with adjusted OR1.17(95%CI1.01-1.36). Stratified analysis showed that SNP rs11614913was significantly associated with the risk of CHD in smokers or hypertension patients, with adjusted ORs1.23(95%CI1.03-1.47) and1.23(95%CI1.02-1.49), respectively. No siginificant association was found in nonsmokers or normotensive groups. The rs11614913C allele significantly increased the risk of CHD among smokers or hypertension patients in Chinese Han population.Conclusions:Our study indicates that the common genetic variant rs11614913T>C in pre-miRNA-196a2is associated with an increased risk of CHD. These results may provide a novel genetic susceptibility marker for CHD and lead to a better understanding of CHD pathophysiology. The second part:Combined effect of elevated total cholesterol level and hypertension on the risk of fatal cardiovascular disease:a cohort study in Chinese steelworkersBackground and objective:Increased blood pressure and elevated total cholesterol (TC) level are two most important modifiable risk factors of cardiovascular disease (CVD) in the world. Hypertension and hypercholesterolemia co-exist more often than would be expected. Whether there is a synergistic impact on fatal CVD between elevated TC and hypertension need to be further examined in Chinese population.Subjects and Methods:We conducted a cohort study which recruited5092Chinese male steelworkers aged18-74years in1974-1980and followed up for an average of20.84years. The follow-up study was carried out in2001, with CVD death as the end point of observation in this study. Fatal CVD outcomes included deaths caused by acute myocardial infarction, cardiac arrest, heart failure, stroke and other CVD deaths (ICD-9390.9to398.9,401.0to429.9, and430.0to438.9) among the participants without history of CVD. Totally302fatal CVD outcomes were documented by the year of2001. Cox proportional hazards regression models were undertaken to adjust for baseline variables with fatal CVD as the outcome variable. Additive interaction model was used to evaluate the interaction between elevated TC and hypertension.Results:Hypercholesterolemia and hypertension were significantly associated with an increased hazard ratio (HR) of fatal CVD,1.67(95%CI1.18-2.38,P=0.004) and2.91(95%CI2.23-3.80,P<0.001) respectively. Compared to participants with normotension and TC<240mg/dl, the HR was1.11(95%CI0.56-2.21, P=0.767) for hypercholesterolemia,2.74(95%CI2.07-3.64, P<0.001) for hypertension, and5.51(95%CI3.58-8.46, P<0.001) for participants with both risk factors, respectively. There was an additive interaction with a2.65(95%CI0.45-4.85) relative excess risk due to the interaction (RERI) between hypercholesterolemia and hypertension on fatal CVD. The attributable proportion (AP) was48.2(95%CI23.7%-72.7%), and the synergy index (SI) was2.43(95%CI1.25-4.71). When the cut point of TC level decreased from240mg/dl to220mg/dl, the RERI, AP and SI decreased to the1.86(95%CI0.46-3.26),42.6(95%CI20.1%-65.2%) and2.24(95%CI1.21-4.13) respectively. When the cut point of TC level decreased to200mg/dl, no significantly additive interaction was found between TC>200mg/dl group and hypertensionConclusions:Our study identified an additive interaction due to elevated TC level and hypertension on the risk of fatal CVD, besides a conventional main effect derived from either of them. These results highlights that the prevention and treatment of both risk factors might improve the individual risk profile thus reduce the CVD mortality. The third part:Association between variants in the peroxisome proliferator-activated receptor gamma coactivator1alpha gene and type2diabetes mellitus:a meta-analysisBackground and objective:The association between polymorphisms in the peroxisome proliferator-activated receptor gamma coactivator1alpha gene (PPARGClA) and type2diabetes mellitus (T2DM) has been investigated in several studies, but these studies rendered contradictory results. We conducted a meta-analysis to assess the association between three polymorphisms (Gly482Ser, Thr394Thr, and Thr612Met) in PPARGClA gene and T2DM.Subjects and Methods:Literature-based searching was conducted to collect data. The additive model was chosen to investigate the association between three polymorphisms and T2DM. Random effects model was used if there was heterogeneity between studies. In addition, subgroup meta-analyses were made according to the ethnic groups.Results:Twenty-three studies were enrolled in this meta-analysis (7539cases and9562controls for Gly482Ser,1818cases and2376controls for Thr394Thr,2042cases and1289controls for Thr612Met). In the combined analysis of all eligible studies, a significant association was found between Gly482Ser, Thr394Thr and T2DM with pooled ORs1.19(95%CI1.05-1.34) and1.33(95%CI1.04-1.70), respectively, but large heterogeneity was found between studies. In the subgroup meta-analyses, we found that Gly482Ser and Thr394Thr polymorphisms were associated with the risk of T2DM, and the pooled ORs were1.66(95%CI1.28-2.15) and1.72(95%CI1.45-2.03) in Indian population, respectively, but no significant evidence was found in either Caucasian or East Asian population.Conclusions:This meta-analysis indicated that Gly482Ser and Thr394Thr polymorphisms of PPARGClA were significantly associated with the risk of T2DM, especially in Indian population. No such relationship was found between the Thr612Met and risk of T2DM.
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