Impact of Renin-Angiotensin-Aldosterone System Gene Polymorphisms on Left Ventricular Dysfunction in Coronary Artery Disease Patients

Background: Left ventricular dysfunction (LVD), followed by fall in cardiac output is one of the major complications in some coronary artery disease (CAD) patients. The decreased cardiac output over time leads to activation of the renin-angiotensin-aldosterone system which results in vasoconstriction by influencing salt-water homeostasis. Therefore, the purpose of the present study was to explore the association of single nucleotide polymorphisms (SNPs) in angiotensin I converting enzyme; ACE (rs4340), angiotensin II type1 receptor; AT1 (rs5186) and aldosterone synthase; CYP11B2 (rs1799998) with LVD

Multi-Analytic Approach Elucidates Significant Role of Hormonal and Hepatocanalicular Transporter Genetic Variants in Gallstone Disease in North Indian Population

<div><p>Objective</p><p>Cholesterol gallstone disease (CGD) is a multifactorial and multistep disease. Apart from female gender and increasing age being the documented non-modifiable risk factor for gallstones the pathobiological mechanisms underlying the phenotypic expression of CGD appear to be rather complex, and one or more variations in genes could play critical roles in the diverse pathways further progressing to cholesterol crystal formation. In the present study we performed genotyping score, Multifactor dimensionality reduction (MDR) and Classification and Regression Tree analysis (CART) to identify combinations of alleles among the hormonal, hepatocanalicular transporter and adipogenesis differentiation pathway genes in modifying the risk for CGD.</p> <p>Design</p><p>The present case-control study recruited total of 450 subjects, including 230 CGD patients and 220 controls. We analyzed common <i>ESR1, ESR2, PGR, ADRB3, ADRA2A, ABCG8, SLCO1B1, PPARγ2,</i> and <i>SREBP2</i> gene polymorphisms to find out combinations of genetic variants contributing to CGD risk, using multi-analytical approaches (G-score, MDR, and CART).</p> <p>Results</p><p>Single locus analysis by logistic regression showed association of <i>ESR1</i> IVS1-397C>T (rs2234693), IVS1-351A>G (rs9340799) <i>PGR</i> ins/del (rs1042838) <i>ADRB3</i>-190 T>C (rs4994) <i>ABCG8</i> D19H (rs11887534), <i>SLCO1B1</i> Exon4 C>A (rs11045819) and <i>SREBP2</i> 1784G>C (rs2228314) with CGD risk. However, the MDR and CART analysis revealed <i>ESR1</i> IVS1-397C>T (rs2234693) <i>ADRB3</i>-190 T>C (rs4994) and <i>ABCG8</i> D19H (rs11887534) polymorphisms as the best polymorphic signature for discriminating between cases and controls. The overall odds ratio for the applied multi-analytical approaches ranged from 4.33 to 10.05 showing an incremental risk for cholesterol crystal formation. In conclusion, our muti-analytical approach suggests that, <i>ESR1, ADRB3,</i> in addition to <i>ABCG8</i> genetic variants confer significant risk for cholesterol gallstone disease.</p> </div

Role of angiotensin II type I (AT1 A1166C) receptor polymorphism in susceptibility of left ventricular dysfunction

Background: Left ventricular dysfunction (LVD) with subsequent congestive heart failure (CHF) constitutes the final common pathway for a host of cardiac disorders. The impaired LV function develops in response to an ischemic insult followed by a fall in cardiac output that leads to activation of renin-angiotensin-system (RAS). Angiotensin II type I receptor (AT1), which mediate the vasoconstrictive and salt-conserving actions of the RAS, represent interesting candidate genes for cardiovascular diseases. Therefore, we conducted an association study between single nucleotide polymorphism (SNP) in AT1 gene and LVD in CAD patients. Methods and results: The present study recruited a total of 950 subjects including 720 angiography confirmed CAD patients and 230 healthy controls. Among 720 CAD patients, 229 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. The AT1 (A1166C, rs5186) polymorphism was determined by ARMS-PCR. Our results showed that the frequency of AT1 1166AC and CC genotypes were significantly higher in LVD patients in comparison to non-LVD (LVEF >45%) patients (p value = 0.003; OR = 1.81 and p value <0.001; OR = 4.33). Further analysis showed that AT1 A1166C polymorphism was significantly associated with LV end diastole (p-value = 0.031), end systole (p-value = 0.038) dimensions, and mean LVEF (p-value = 0.035). Moreover, on comparing the AT1 A1166C polymorphism in CAD patients with healthy controls, we did not find any association both at genotypic and allelic level (p value = 0.927; OR = 1.04 and p value = 0.219; OR = 0.83) respectively. Conclusions: Our study suggests that AT1 A1166C polymorphism may play significant role in conferring genetic susceptibility of LVD

Adipogenesis differentiation pathway.

<p>MCS = Monte Carlo Simulation; Significant values are in bold; For categorical data Cochrane Armitage trend test was used.</p

Hepatocanalicular transporter pathway.

<p>MCS = Monte Carlo Simulation; Significant values are in bold; For categorical data Cochrane Armitage trend test was used.</p

Mean G-Scores in the Selected Pathway and their Corresponding p-values.

<p>Significant values are in bold.</p

Association of High-Order Interactions with GSD Risk by MDR Analysis.

#<p>CVC: Cross Validation Consistency.</p>a<p>The model with the maximum testing accuracy and maximum CVC cross was considered as the best model. The present study calculated, the best interaction model as the four-factor model including <i>^aESR1</i> IVS1-397C>T, <i>ESR1</i> IVS1 351A>G, <i>ADRB3</i>-190T>C, <i>ABCG8</i> 145 G>C polymorphisms.</p

Demographic profile of controls and gallstone patients.

<p>Demographic profile of controls and gallstone patients.</p

Risk Estimates of CART Terminal Nodes.

<p>W = wild genotype. V = variant genotype.</p>a<p>Case rate is the percentage of gallstone patients among all individuals in each node.</p>b<p>ORs of terminal nodes were calculated by LR analysis adjusted for age and gender.</p><p>Significant values are in bold.</p

The 13-SNP G-score distribution in patients with gallstones and control subjects.

<p>The 13-SNP G-score distribution in patients with gallstones and control subjects.</p