| I. Association and gene-gene interaction study of coronary artery disease among Type 2 diabetes mellitus patients on Hp-CD163-HO-1 pathwayBackground:Patients with Type 2 diabetes mellitus (T2DM) have an increased risk of developing macrovascular disease, like coronary artery disease (CAD), which is more complicated and severe. Also, there is also an increased incidence of restenosis after stenting, as well as the rate of mortality in total. Haptoglobin (Hp) is an acute phase protein, which plays an important role in reducing oxidative damage via its combination with serum free hemoglobin (Hb). The formation of Hp-Hb complex is decomposed by endocytosis CD163 after intake. There exists three major Hp genetypes, Hp1-1, Hp2-1 and Hp2-2, all of which were reported associated with CAD risk in T2DM patients. The Hp-CH163-HO-1 pathway is efficient in Hb clearance. But the evidence is weak when it comes to the SNPs association studies with CAD based on this pathway, as well as the gene-gene interaction effect.Objective:This study aims at the analysis of the gene-gene interaction effect between tagSNPs on Hp-CD163-HO-1 pathways and CAD risk and severity in T2DM patients.Method:Hapmap, Haploreg V2 and SNP Function Prediction were used to determine the tagSNPs in Hp-CD163-HO-1 pathway. Hp was genotyped by polymerase chain reaction (PCR). TagSNPs was genotyped by rt-PCR. Participants in this study were T2DM patients who admitted in Fuwai Hospital for percutaneous coronary angiography diagnosis (CAG) from 2011 to 2015. Diagnosis of CAD was based on significant stenosis ≥50% in at least one major coronary artery determined by CAG. Additionally, participants without PCI or CABG history were set into Syntax group to further discuss the influence of genetics on the progression of CAD in T2DM patients. Plink was used to analyze the association between SNPs and CAD, GMDR was used to analyze the gene-gene interaction.Results:1. Among the selected SNPs, Hp, rs2071748, and rs2070874 showed deviation of Hardy-Weinberg equilibrium (P<0.05), and were excluded from followed analysis. After adjusting covariates, like sex, age, smoking, BMI, hypertention, hyperlipidemia, atherosclerosis, insulin, and HbAlc, rs743811(HMOX1) was associated with CAD risk in T2DM patients (0R1.41, 95%CI 1.09,1.86). Genotypic analysis suggested that rs11054072 (CD163) GA:AA (0R0.69 95%CI 0.47,1.00), rs3756074 (IL4) TT:CC (OR2.06 95%CI 1.13,3.75) were associated with CAD risk in T2DM patients.2. Among the selected SNPs, Hp was deviated from Hardy-Weinberg equilibrium (P<0.05), and was excluded from followed analysis. After adjusting covariates, like sex, age, smoking, BMI, hypertention, hyperlipidemia, atherosclerosis, insulin, and HbA1c, rs3790622 (IL10) was associated with SYNTAX score in CAD patients (β4.95,95%CI 0.88,9.02). Genotypic analysis suggested that rs743811 (HMOX1) TC:CC (0-0.48,95%CI-7.680,-0.48), rs2069705 (IFN γ) AG:GG (β-3.92 95%CI-7.39,-0.45) was associated with SYNTAX score.3. GMDR results indicated that the interactions of rs2069705 (IFN γ) and rs3790622 (IL10), as well as rs1800796 (IL6), rs743811 (HMOX1) and rs1800871 (IL10)are likely play an essential role in the development of CAD in T2DM patients.Conclusions:SNP association studies indicated that rs743811 (HMOX1), rs11054072 (CD163) and rs3756074 (IL4) were associated with CAD risk in T2DM patients, while rs743811 (HMOX1), rs3790622 (IL10) and rs2069705 (IFN γ) were associated with CAD severity in T2DM patients. Gene-gene interaction analysis showed that rs743811 (HMOX1) and rs3756074 (IL4), as well asrs1800796 (IL6), rs743811 (HMOX1) and rs1800871 (IL10) may play a role in CAD severity in T2DM patients.Ⅱ. Association and gene-gene interaction study of coronary arterydisease among Type 2 diabetes mellitus patients on SNPsBackground:The mechanisms of Type 2 diabetes mellitus(T2DM) complications are hyperglycemia, insulin resistance, obesity, dyslipidemia, hemodynamic instability, oxidative stress and inflammatory reaction, etc. This study focusses on the current knowledge of the genetic and epigenetic basis of coronary artery disease (CAD) in T2DM patients. Ultimately, identification of genes or genetic loci, structural variants and epigenetic changes contributing to risk of or protection from CADwill help uncover the complex mechanism(s) underlying CAD, with crucial implications for the development of personalized medicine for diabetes mellitus and its complications.Objective:To analyze the association of SNPs and different pathways and gene-gene interaction effect with CAD risk and severity of T2DM patients.Methods:Based on the Pudmed database,139 SNPs which were reported with T2DM cardiovascular complications was selected. SNP Function Prediction and Haploreg V2 was used to screening the common potential functional SNPs without linkage equilibrium. A total of 50 SNPs was genotyped used Sequenom MassArry method. Participants in this study were T2DM patients who admitted in Fuwai Hospital for percutaneous coronary angiography diagnosis (CAG) from 2011 to 2014. Diagnosis of CAD was based on significant stenosis ≥50% in at least one major coronary artery determined by CAG. Additionally, participants without PCI or CABG history were set into Syntax group to further discuss the influence of genetics on the progression of CAD in T2DM patients. Plink was used to analyze the association between SNPs and CAD, GMDR was used to analyze the gene-gene interaction.Results:1. Among the selected SNPs, rs20417 was deviated from Hardy-Weinberg equilibrium (P<0.05), and were excluded from followed analysis. After adjusting covariates, like sex, age, smoking, BMI, hypertention, hyperlipidemia, atherosclerosis, insulin, and HbAlc, rs10120688 (CDKN2BAS) (OR0.63,95%CI0.40-0.98), rs10920531 (ADIPOR1) (OR1.64,95%CI1.07-2.50), rs12733285 (ADIPOR1) (OR0.33,95%CI0.13-0.83) and rs7539542 (ADIPOR1) (OR1.83,95%CI1.20-2.78) indicated association with CAD risk in T2DM patients. For the genotypic analysis, rs10920531 (ADIPOR1) CC:AA (OR2.75,95%CI1.14,6.65); rs1342387 (ADIPOR1) AA:GG (OR0.45,95%CI0.24,0.86); rs2066826 (COX2) AA:GG (OR0.26,95%CI0.07,0.93); rs7539542 (ADIPOR1) CC:GG (OR3.06,95%CI 1.27,7.41) and CG:GG(OR 2.14,95% CI 1.13,4.08) showed association with CAD risk in T2DM patients.2. Among the selected SNPs, rs1883025 and rs20417 were deviated from Hardy-Weinberg equilibrium (P<0.05), and were excluded from followed analysis. After adjusting covariates, like sex, age, smoking, BMI, hypertention, hyperlipidemia, atherosclerosis, insulin, and HbAlc, rs1535045 (CD40) (β-3.58,95%CI-6.59,-0.58), rs7756935 (PLA2G7)(β 5.09, 95%CI1.34,8.85) and rs3917782 (SELP) (β-10.73,95%CI-20.74,-0.72) indicated association with CAD severity in T2DM patients. For the genotypic analysis, rs1342387 (ADIPOR1) AA:GG (β-7.00,95%CI-13.51,-0.48), rs1535045 (CD40) TT:CC(β-6.75.95%CI-13.11,-0.38) showed association with CAD severity in T2DM patients.3. After covariates adjusting, rs1535045 (CD40) and rs2066826 (COX2), as well as rs1131882 (TBXA2R),rs1535045 (CD40) and rs2502448 (RGS7) showed interaction effecton severity of CAD in T2DM patients.Conclusions:SNP association studies indicated that rs10120688 (CDKN2BAS), rs10920531 (ADIPOR1), rs12733285 (ADIPOR1), rs1342387 (ADIPOR1), rs2066826 (COX2), and rs7539542 (ADIPOR1)were associated with CAD risk in T2DM patients, whilers1535045 (CD40), rs7756935 (PLA2G7), rs3917782 (SELP), rs1342387 (ADIPOR1), and rs1535045 (CD40) were associated with CAD severity in T2DM patients. Gene-gene interaction analysis showed thatrs1535045 (CD40) and rs2066826 (COX2), as well as rs1131882 (TBXA2R), rs1535045 (CD40) and rs2502448 (RGS7) may play a role in CAD severity in T2DM patients.Background:Atherosclerosis is a common pathological basis of a variety of vascular disease, including coronary heart disease. And it is related to thrombus formation caused by cardiovascular and cerebrovascular events, which is currently the main reason of death and disability in developed countries. Dyslipidemia plays an indispensable role in the occurrence and development of atherosclerosis. Statins competitive inhibit acetyl coenzyme A, as well as inhibit the conversion of acetyl CoA to mevalonic acid, thereby inhibiting the formation of cholesterol and isoamyl diene compound and reduce the content of total cholesterol in serum, that is, the improvement of dyslipidemia. And statins were also many clinical trials have proven that by improving endothelial function, reduce platelet adhesion, reduce oxidative stress, promoting plaque stability, anti-inflammatory and direct cardioprotective effect, statin can prevent coronary heart disease, and improve clinical prognosis. With the wide use of statins in clinical practice and the deepening of clinical research, the adverse reactions have been paid enough attention.Objective:To analyze the clinical outcomes of statin-induced myopathy.Method:The reports of statin-induced myopathy were reported as adverse drug reaction (ADR) to the Beijing Center for ADR Monitoring during January 2007 to December 2012. The above reports are defined as the general level of myopathy group and rhabdomyolysis group, according to whether rhabdomylysis was identified. The clinical characteristic, medication history, outcomes were discussed. Differences of these issues were also analyzed. The Chi-square test, T-test and Spearman correlative analysis was used for data analysis.Results:160 statin-induced myopathy cases were collected from the database. The average age of them were 64.22±13.55,51.2% of which were male (n=82), and 48.8% were female (n=78). The ADR occurred from the first medication time to 4 years after medication. Observed clinical features were myalgia, Myositis, Symptom less creatine kinase (CK) elevation or rhabdomyolysis.54 cases of rhabdomyolysis group (33.8%) and 106 cases of the general level of myopathy group (66.3%) were identified from the 160 cases. The average age were (68.54±15.41) year and (62.02±12.41) year, respectively (P=0.004). The occupation of male and female in the two groups was 25 cases:29 cases (46.3%:53.7%) vs 57 cases:49 cases (53.8%:46.2%), respectively (P=0.406). Meanwhile,24 cases (44.4%) of rhabdomyolysis were in a high dose statin treatment, while 26 cases (16.5%) were in the general level of myopathy group, (X2=16.45, P<0.001). Moreover, the cases of simvastatin taken in the two group were 38 (70.4%) and 34 (32.1%), respectively (X2=21.20, P<0.001). Correlation analysis showed that age, high-dose statin taken and simvastatin taken were all positively correlated with rhabdomylysis (P<0.001), and the Correlation Coefficients (r) were 0.305,0.290 and 0.364, respectively. Four patients died because of ADR, aged between 71-85. All of these 4 patients were taken high-dose statin before ADR occurrence, and 3 of them were detailed in medical records with complex combined disease, acute history and complex associated drug history.Conclusions:Severe statin-induced myopathy, like rhabdomyolysis, may more likely occur when patients are older, taking high-dose statin or simvastatin.Background:Left ventricular thrombus (LVT) is reported to be a common complication in acute myocardial infarction (AMI) patients. And it occurs more frequently in acute anterior myocardial infarction, especially in extensive anterior myocardial infarction. And it has the potential to cause systemic embolism in cerebra, spleen and kidney, which may result in severe damage in the organs. Thus, it is important to prevent, to predict and to diagnose LVT in clinical practice. However, previous studies differ in the percentage, as well as the risk factors of LVT.Objective:This retrospective study was to present the current situation of LVT in clinical practice, as well as to evaluate the clinical characteristics and the risk factors of LVT after AMI.Methods:LVT cases (n=96) were identified from 13,732 AMI patients in Fuwai Hospital’s electronic medical records system from January 2003 to January 2013. The controls (n=192) were gender-and age-matched AMI patients without LVT during this period. A conditional logistic regression (fitted by the Cox model) was performed to identify the independent risk factors.Results:1. Clinical characteristics:Based on the analysis, the rate of LVT was 0.7%. Sex, age, BMI, smoking status, combined diseases (hypertension, diabetes mellitus, hyperlipidemia, stroke, or deep venous thrombus (DVT), etc.), duration from symptoms onset to admission, and the timing of the 1st imaging exam were not insignificant (P>0.05) between LVT group and AMI group. Eleven patients in the LVT group and twenty patients in the AMI group were admitted into the hospital within 24 hrs after AMI symptoms onset, while the other patients were intended to further therapy within one month after receiving brief treatment for AMI. The rates of triple vessel disease had no significant difference(P>0.05) between the two groups. One patient experienced abdominal pain and limb hemiplegia 20 days after thrombolysis. After cerebral magnetic resonance imaging detection, emboli exfoliation to the brain was diagnosed. And a superior mesenteric arterial embolism was also diagnosed due to the typical symptoms.2. Risk Factors:The results indicate that the infarction location show a statistically significant difference between the two groups in both anterior wall and extensive anterior wall. And the LVEF%, severe regional wall motion abnormality (RWMA), moderate to high levels of mitral reflux (MR), pericardial effusion and aneurysm were all analyzed. The results demonstrate that the LVEF%, LVEF≤40%, severe RWMA, pericardial effusion, as well as aneurysm were all significantly different (P<0.05). After the analyzed by the conditional logistic regression model, which was fitting by the Cox multivariate model, with the statistically significant factors mentioned above, the independent risk factors of LVT after AMI are as followed,1) lower LVEF%(OR 0.891,95%CI 0.828-0.960),2) extensive anterior myocardial infarction (OR=6.403,95%CI 1.769-23.169),3) severe RWMA (OR=7.348,95%CI 1.323-40.819),4) aneurysm (OR=6.955,95%CI 1.673-28.921).Conclusions:This study indicated that 1) lower LVEF%,2) extensive anterior myocardial infarction,3) severe RWMA, and 4) aneurysm were independent risk factors of LVT after AMI. |
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