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1.  Network Analysis of Inflammatory Genes and Their Transcriptional Regulators in Coronary Artery Disease 
PLoS ONE  2014;9(4):e94328.
Network analysis is a novel method to understand the complex pathogenesis of inflammation-driven atherosclerosis. Using this approach, we attempted to identify key inflammatory genes and their core transcriptional regulators in coronary artery disease (CAD). Initially, we obtained 124 candidate genes associated with inflammation and CAD using Polysearch and CADgene database for which protein-protein interaction network was generated using STRING 9.0 (Search Tool for the Retrieval of Interacting Genes) and visualized using Cytoscape v 2.8.3. Based on betweenness centrality (BC) and node degree as key topological parameters, we identified interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), interleukin-1 beta (IL-1B), tumor necrosis factor (TNF) and prostaglandin-endoperoxide synthase 2 (PTGS2) as hub nodes. The backbone network constructed with these five hub genes showed 111 nodes connected via 348 edges, with IL-6 having the largest degree and highest BC. Nuclear factor kappa B1 (NFKB1), signal transducer and activator of transcription 3 (STAT3) and JUN were identified as the three core transcription factors from the regulatory network derived using MatInspector. For the purpose of validation of the hub genes, 97 test networks were constructed, which revealed the accuracy of the backbone network to be 0.7763 while the frequency of the hub nodes remained largely unaltered. Pathway enrichment analysis with ClueGO, KEGG and REACTOME showed significant enrichment of six validated CAD pathways - smooth muscle cell proliferation, acute-phase response, calcidiol 1-monooxygenase activity, toll-like receptor signaling, NOD-like receptor signaling and adipocytokine signaling pathways. Experimental verification of the above findings in 64 cases and 64 controls showed increased expression of the five candidate genes and the three transcription factors in the cases relative to the controls (p<0.05). Thus, analysis of complex networks aid in the prioritization of genes and their transcriptional regulators in complex diseases.
PMCID: PMC3988072  PMID: 24736319
2.  Integrative Bioinformatics Analysis of Genomic and Proteomic Approaches to Understand the Transcriptional Regulatory Program in Coronary Artery Disease Pathways 
PLoS ONE  2013;8(2):e57193.
Patients with cardiovascular disease show a panel of differentially regulated serum biomarkers indicative of modulation of several pathways from disease onset to progression. Few of these biomarkers have been proposed for multimarker risk prediction methods. However, the underlying mechanism of the expression changes and modulation of the pathways is not yet addressed in entirety. Our present work focuses on understanding the regulatory mechanisms at transcriptional level by identifying the core and specific transcription factors that regulate the coronary artery disease associated pathways. Using the principles of systems biology we integrated the genomics and proteomics data with computational tools. We selected biomarkers from 7 different pathways based on their association with the disease and assayed 24 biomarkers along with gene expression studies and built network modules which are highly regulated by 5 core regulators PPARG, EGR1, ETV1, KLF7 and ESRRA. These network modules in turn comprise of biomarkers from different pathways showing that the core regulatory transcription factors may work together in differential regulation of several pathways potentially leading to the disease. This kind of analysis can enhance the elucidation of mechanisms in the disease and give better strategies of developing multimarker module based risk predictions.
PMCID: PMC3585295  PMID: 23468932
3.  Pathogen burden, cytomegalovirus infection and inflammatory markers in the risk of premature coronary artery disease in individuals of Indian origin 
Coronary artery disease (CAD) occurs at an earlier age in South Asians compared with other ethnic groups. Infection and inflammation show a positive association with the disease.
To investigate the association of infection and inflammatory markers with premature CAD in the Indian Atherosclerosis Research Study population.
Antibody titres for Chlamydia pneumoniae, cytomegalovirus (CMV), Helicobacter pylori, herpes simplex virus and levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen and secretory phospholipase A2, were measured in 866 individuals (433 CAD patients and matched controls). All individuals were followed-up for recurrent cardiac events for four years. ANOVA was used to study the association of infection and inflammation with CAD.
The present study found that the odds of CAD occurrence was 2.42 (95% CI 1.26 to 4.64; P<0.008), with all four infections and increased in the presence of hsCRP (OR 4.67 [95% CI 1.43 to 15.25]); P=0.011). Only anti-CMV antibody levels were a significant risk factor for CAD occurrence (OR 2.23 [95% CI 1.20 to 4.15]; P=0.011) and recurrent cardiac events (OR 1.94 [95% CI 0.85 to 4.45]; P=0.015). Mean values of the inflammatory biomarkers IL-6 (P=0.035), fibrinogen (P=0.014), hsCRP (P=0.010) and secretory phospholipase A2 (P=0.002) increased with CMV antibody levels. Incorporating hsCRP and IL-6 in the risk prediction models significantly increased the OR to 2.56 (95% CI 1.16 to 5.63; P=0.019) with a c statistic of 0.826.
Pathogen burden, especially CMV infection in combination with inflammatory markers, is a significant predictor of CAD risk in the young Indian population.
PMCID: PMC3395457  PMID: 22826649
Coronary artery disease; C-reactive protein; Cytomegalovirus; Inflammatory markers; Pathogen burden
4.  Understanding the expression of Toll-like receptors in Asian Indians predisposed to coronary artery disease 
Toll-like receptors (TLRs) are an important link between innate and adaptive immunity.
Material and methods
Expression of TLR-2, TLR-4, and TLR-9 genes was assessed in 60 coronary artery disease (CAD) patients and 79 controls by SYBR Green 1 based real time PCR assay.
Expression of the TLR-2 gene was found to be significantly elevated in cases (1.295 ±0.09) compared to the controls (1.033 ±0.08) (p = 0.015) whereas expression of the TLR-9 gene was significantly lower in cases (1.522 ±0.18) than in the controls (2.165 ±0.16) (p = 0.032). There was no difference in TLR-4 expression levels (p = 0.174). A significant correlation of TLR-2 was observed with TLR-4 (r = 0.803, p<0.0001) and TLR-9 (r = 0.264, p = 0.003) as well as between TLR-4 and TLR-9 (r = 0.303, p = 0.001). A significant association was seen between TLR 2 (OR 3.94, 95% CI 1.73-8.99, p = 0.001) and TLR-9 (OR 0.297, 95% CI 0.131-0.672, p = 0.004) with CAD after adjustment for age and gender. Statins did not affect TLR gene expression.
The TLR-2, TLR-4 and TLR-9 genes exhibit a differential pattern of expression between CAD patients and controls in this Asian Indian cohort. This observation warrants further investigation, keeping in mind the infectious and inflammatory elements in perspective, in order to understand the true implications of TLR in the aetiopathology of CAD and consequent therapeutic implications.
PMCID: PMC3258818  PMID: 22291822
Toll-like receptors; gene expression; coronary artery disease; Asian Indians
5.  Usefulness of C-Reactive Protein as a Marker for Prediction of Future Coronary Events in the Asian Indian Population: Indian Atherosclerosis Research Study 
Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 (r = .373; P = <.0001), sPLA2 (r = .544; P = <.0001) as also with fibrinogen (r = .579; P = <.0001). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP (>3.58 mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population.
PMCID: PMC2989863  PMID: 21152190
6.  Implications of Genetic Polymorphisms in Inflammation-Induced Atherosclerosis 
Inflammation is the mainstay of atherosclerosis and is an important governing factor at all stages of the disease process from lesion formation to plaque build-up and final end-stage rupture and thrombosis. An overview of the numerous clinico-epidemiological studies on the association between inflammatory gene polymorphisms and Cardiovascular disease (CVD) and its co-morbidities have shown that the risk associated with any single genotype is modest while the haplotypes, especially those defined on the basis of tag-SNP approach, have better coverage of the gene and show moderately higher impact on disease risk. Nevertheless, even these associations have been inconsistent with low cross-race repeatability. This has been attributed to many plausible causes such as clinical heterogeneity, sample selection criteria, variable genetic landscapes across different ethnic groups, confounding effect of co-morbidities etc. On the other hand, unbiased studies such as the family-based linkage and case-control based associations that have taken into account, thousands of genotypic markers spanning the whole genome, have had the ability to identify novel genetic loci for coronary artery disease. These studies have shown that many inflammatory genes are involved in the regulation of specific biomarkers of inflammation that collectively contribute to the disease-associated risk. In addition, there appears to be considerable cross talk between the different biochemical and metabolic processes. Therefore, consideration of all these factors can build towards an ‘atherosclerotic bionetwork’ that can refine our quest for developing a robust risk stratification tool for cardiovascular disease.
PMCID: PMC2840586  PMID: 21804639
Inflammation; Biomarkers; Genes; Single Nucleotide Polymorphisms; Atherosclerosis.
7.  Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease 
The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history.
Methods & results
Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h2 48% – 70%; P < 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi-point analysis (LOD score 7.42, P < 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (P < 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (P < 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (P < 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis.
The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians.
PMCID: PMC2556320  PMID: 18801202
8.  Prevalence and component analysis of metabolic syndrome: An Indian atherosclerosis research study perspective 
Asian Indians have a high predisposition to metabolic syndrome (MS) and coronary artery disease (CAD). The present study aimed to estimate MS prevalence in 531 Asian Indian families comprising of 2318 individuals. Anthropometrics and lipid profile were assessed. MS prevalence was estimated using standard Adult Treatment Panel III (ATP-III) and World Health Organisation (WHO) criteria and modified definitions which included lowered cut-offs for waist circumference (WC) (≥90 cm for men and ≥80 cm for women], body mass index (BMI) (≥23 kg/m2) and impaired fasting glucose (IFG) levels. ATP-III criteria identified a significantly higher proportion of people with MS (N = 933; 40.3%) compared with WHO (N = 708; 30.6%; p < 0.0001) while modified ATP-III showed maximum gain in percent prevalence among the revised criteria (17.3%; p = 0.0056). The IDF criteria identified similar proportion of subjects with MS (N = 809; 34.9%) as the revised WHO criteria (N = 792; 34.2%). The number of MS subjects was highest in the 50–59 years age group. MS was diagnosed a decade earlier in unaffected subjects compared with those with CAD/diabetes using the modified MS criteria. WC correlated significantly with BMI and waist–hip ratio (WHR) (p = 0.000). Among MS components, high density lipoprotein cholesterol and BMI contributed significantly in males (71.4% and 85.9%) and females (86.8% and 88.8%), respectively. The higher percentage contribution of WC among males and WHR among females indicates the influence of gynecoid/android pelvis on WHR measures. In conclusion, the revision of definition criteria for MS with lowered cut-offs for WC and BMI is critical for the accurate assessment of MS among Asian Indians.
PMCID: PMC2464750  PMID: 18629355
9.  Adult nontwin sib concordance rates for type 2 diabetes, hypertension and metabolic syndrome among Asian Indians: The Indian Atherosclerosis Research Study 
Vascular Health and Risk Management  2007;3(6):1063-1068.
Diabetes (DM), hypertension (HTN), and metabolic syndrome (MS) are established cardiovascular risk factors with a complex etiology. The aim of the present study was to estimate the rates of concordance for the above coronary risk factors between siblings in Asian Indian families with premature coronary artery disease (CAD). Spouse concordance rates were used to evaluate the relative contribution of shared genes and lifestyle towards these traits. A total of 508 families comprising of 1250 sib-pairs and 463 corresponding spouse-pairs were analyzed. Concordance rates were manually determined. Plasma lipids were estimated by standard enzymatic assay. The concordance rates among sib-pairs for DM, HTN, and MS was 11% (N = 136), 14% (N = 174), and 23% (N = 287), while the corresponding concordance for spouse-pairs was 2.8% (N = 13), 6.3% (N = 29), and 28.1% (N = 130), respectively. Employing Chi-square test, sib-pairs showed significantly higher concordance for diabetes (p ≤ 0.0001) and hypertension (p < 0.0001) while spouse-pairs had higher concordance for metabolic syndrome (p = 0.033) in our study. These findings suggest a probable dominant genetic component in the causation of DM and HTN and a predominantly nongenetic component for metabolic syndrome among Asian Indians.
PMCID: PMC2350127  PMID: 18200825
sib-pairs; spouse-pairs; type 2 diabetes; hypertension; metabolic syndrome; concordance; CAD; Asian Indians

Results 1-9 (9)