Differential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity.

Distal and proximal colon cancers have been recognized as two different disease types in human population. The environmental factors involved in the pathogenesis of the proximal and distal tumors also differ. The main objective of this study was to determine if obesity-augmented colonic tumors differ from each other if they are located in different regions of the colonic axis. Zucker obese rats were injected with azoxymethane (AOM) 10 mg/kg body weight/week for 2 weeks. The tumors appeared within 20 weeks. The highest proportion of the tumors was in the distal colon, and the number declined towards the splenic flexure. A number of proteins previously reported to be altered in tumor tissue were assessed in the present study in tumors appearing in proximal and distal regions. Distal colonic tumors had higher TNF-α R2, NF-κB, and IκBα levels than tumors of proximal origin. In contrast, IKKß was decreased in the proximal tumors. Insulin receptor and insulin-like growth factor-1R were higher in distal tumors. The mitogen-activated protein kinase (ERK2) levels were similar in the tumor groups; however, the ERK1 was significantly higher in the distal tumor than in the proximal tumor. Our findings suggest that colon tumors induced by AOM in different colonic regions are different from each other with respect to differential expression of proteins and support the concept that these disease states could respond differently to tumor-promoting and inhibitory conditions. Moreover, these findings support the concept that cancer preventive or therapeutic agents need to be evaluated for their effectiveness on proximal as well as on distal tumors.

Genetic variants on apolipoprotein gene cluster influence triglycerides with a risk of coronary artery disease among Indians.

Apolipoprotein C3 and apolipoprotien A5 are proteins coded from the APOA1/C3/A4/A5 gene cluster. Sst I polymorphism on apolipoprotein C3 and -1131C polymorphism of apolipoprotien A5 are key variants involved in triglyceride metabolism and cause a significant cardio-metabolic risk. Here, we have evaluated these two variants for their roles in coronary artery disease in patients of the Indian population. The apolipoprotein gene cluster variants were analysed in 416 angiographically determined coronary artery disease patients and matched 416 controls using polymerase chain reaction-restriction fragment length polymorphism. The characteristics of the study subjects were analyzed statistically for their association with the polymorphisms. The alleles were combined as haplotypes and their combined risks were evaluated. The minor allele genotypes of both apolipoprotein C3 (S2) and apolipoprotien A5 (C) had a significant risk for coronary artery disease. The S2 allele genotyped patients had a significantly increased triglyceride level (P < 0.001) and increased triglycerides were observed among both patient and control CC genotype carriers. We identified the haplotype S2/C with a significant increased risk (P < 0.001) to coronary artery disease with increased levels of circulating triglycerides compared to other haplotypes in patients. We conclude that the variants on apolipoprotein C3 and apolipoprotien A5 modulate serum triglyceride levels and increase the risk of coronary artery disease.

Cardiac Troponin T (TNNT2) mutations are less prevalent in Indian hypertrophic cardiomyopathy patients.

We sought to determine the frequency of the genetic variations in the Troponin T (TNNT2) gene and its association in Indian cardiomyopathy patients. Sequencing of the entire TNNT2 gene in 162 hypertrophic cardiomyopathy (HCM) patients, along with 179 healthy controls, revealed a total of 15 variants. These included an A28V missense mutation, a novel single-nucleotide polymorphism (SNP) (g.7239;G→A) predicted to disturb the splicing significantly, three SNPs, rs3729547 (C→T), rs3729843 (G→A), rs3729842 (C→T), which were in high linkage disequilibrium, and a 5 bp polymorphism that skipped exon 4 during splicing, which was found to be significantly higher in HCM patients (del/del genotype, p=0.00011; deletion allele, p=0.00008). Further studies on the 5 bp polymorphism in 2092 randomly selected individuals belonging to 39 ethnic and endogamous populations from 19 states of India, and representing the major linguistic Indian families, revealed that the South and the Northwest Indians have a high frequency of 5 bp deletions. The missense mutations in TNNT2 are responsible for 15%-20% of familial HCM by impairing the function of the heart muscle. However, other than the 5 bp polymorphism, our comprehensive study on the Indian HCM patients have lowered the occurrence and overall prevalence of supposedly more aggressive and worst disease causing percentage of missense mutations in TNNT2 dramatically.

Haplotypes on 9p21 modify the risk for coronary artery disease among Indians.

The chromosomal region 9p21 has been reported to be associated with myocardial infarction, coronary artery disease (CAD), diabetes, and many other related multifactorial diseases in humans. Although the genome-wide association studies have identified a limited number of single-nucleotide polymorphisms (SNPs) at 9p21 for CAD risk, the role of flanking SNPs has not been studied so far. Therefore, in the present work, we studied the role of flanking SNPs with respect to that of the previously identified SNPs rs10757278 and rs2383207 at 9p21 among the Indian subjects found to have CAD (n = 414) along with age- and sex-matched control subjects (n = 408). Our study replicated the association of genome-wide association studies that had identified SNPs rs2383207 (p = 4.7 × 10(-5)) and rs10757278 (p = 5.5 × 10(-5)) among Indians with CAD. Further, we evaluated nine additional SNPs, of which two SNPs flanking rs2383207 (rs1537375 [p = 2.4 × 10(-5)] and rs1537374 [p = 5.6 × 10(-5)]) were also strongly associated with CAD. The haplotypes constructed using four risk SNPs revealed that the haplotypes with combinations of rs10757278 showed CAD risks, whereas the minor alleles of rs2383207, rs1537375, and rs1537374 in combinations reduce the CAD risks substantially. Our study demonstrates that the variation in the chromosomal region 9p21 is involved in modifying progression toward CAD among Indians and the risk may be variable, contributed by the SNPs that are flanking previously identified SNPs.

An association study of thrombospondin 1 and 2 SNPs with coronary artery disease and myocardial infarction among South Indians.

INTRODUCTION: Thrombospondin 1 and 2 are multidomain calcium-binding extracellular glycoproteins and they play a role in platelet aggregation, inflammatory response and assembly of connective tissue extracellular matrix. The association of thrombospondins (TSP) in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI) is well established. The association of the TSP-1 (Asn700Ser, 2210A → G, rs2228262) and TSP-2 un-translated region (UTR) (3949T → G, rs8089) gene variations among South Indian CAD and MI patients has been examined in the present study. MATERIALS AND METHODS: We analyzed the thrombospondin polymorphisms in unrelated CAD patients (n = 511) and a subgroup with an event of MI (n = 173) compared with controls (n = 522). The polymorphisms were assessed using polymerase chain reaction, restriction fragment length analysis and the circulating TSP concentration were measured using enzyme linked immune-sorbent assay. RESULTS: The prevalence of TSP-1 and TSP-2 alleles did not show any significant difference statistically, when compared controls against CAD/MI patients. The rare GG genotype of the N700S polymorphism was not observed among the studied population. Further, multiple regression analysis revealed that there was no significant risk for CAD (OR = 1.68; 95% CI 0.927 - 3.055; p = 0.087) or MI (OR = 1.84; 95% CI 0.846 - 4.007; p = 0.124) for the GA genotype. The GA genotype showed no impact on clinical characteristics of the CAD patients and their circulating TSP-1 levels. A similar non-association was observed for the TSP-2 in 3949T → G polymorphism (GG genotype) for CAD (OR = 0.64; 95% CI 0.278 - 1.455; p = 0.636) and MI (OR = 0.53; 95% CI 0.166 - 1.675; p = 0.278). CONCLUSIONS: Our data suggests that the presence of thrombospondin-1 (rs2228262) and thrombospondin-2 (rs8089) variants need not be considered a risk for coronary artery disease or myocardial infarction among South Indians.

Associations for lipoprotein lipase and peroxisome proliferator-activated receptor-gamma gene and coronary artery disease in an Indian population.

BACKGROUND AND AIMS: Peroxisome proliferator activated receptor-gamma (PPARgamma) and lipoprotein lipase (LPL) genes are important in pathways of triglyceride metabolism, insulin resistance and adipogenesis. We hypothesized that polymorphisms of PPARgamma Pro12Ala, LPL HindIII and LPL Ser447X influence severity of coronary artery disease (CAD) in an Indian population. METHODS: PPARgamma Pro12Ala, LPL HindIII and LPL Ser447X polymorphisms were genotyped in 414 patients with CAD and matched with 424 controls. The study subjects were inducted after standard diagnostic procedures and analyzed statistically for the association of polymorphisms with clinical characteristics. RESULTS: We found that PPARgamma alleles were not associated with CAD among Indians although proline carriers had significantly higher levels of HDL-cholesterol (p = 0.03) among CAD patients. The LPL HindIII also had no significant correlations for CAD or for any clinical characteristics. The Ser447X polymorphism (p = 0.015) influenced lower triglyceride levels among CAD patients with significant associations (OR = 0.66, 95% CI 0.483-0.915, p = 0.012). This protective effect of the 447X allele was more pronounced among the CAD patients without the risk factor of diabetes (OR = 0.60, 95% CI 0.403-0.907, p = 0.014) along with less progression of a severe atherosclerotic disease. CONCLUSIONS: PPARgamma and LPL have intractable roles in pathways that lead to CAD, but their gene polymorphisms associate differently. Our results imply a significant correlation of Ser447X polymorphism and its protective effect on Indians against severity of CAD modified by the risk of diabetes, than LPL HindIII and PPARgamma Pro12Ala.