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Leukotrienes are potent inflammatory and lipid mediators that participate in atherosclerosis. We analyzed the association of Leukotriene gene (ALOX5, ALOX5AP, LTA4H, and LTC4S) polymorphisms and plasma Leukotriene B4 (LTB4) levels with coronary artery disease (CAD) in a representative cohort of Asian Indians. In all, 136 functional single nucleotide polymorphisms (SNPs) were selected using in silico tools. Forty-five polymorphic SNPs were ranked for predicted functional effect using FastSNP. Finally, 14 functional SNPs along with 10 SNPs identified from the literature were genotyped in 340 CAD patients and 340 controls. Plasma LTB4 levels were measured in 150 cases and 150 controls. None of the 24 SNPs showed significant association with CAD. Plasma LTB4 levels were higher in cases than in controls (76.42 ± 4.46pg/mL versus 60.89 ± 2.61 pg/mL) (P = 0.003), with greater risk being associated with the top quartile as compared to the bottom quartile after adjusting for potential confounders (OR 8.94, 95% CI 2.56-31.95; P = 0.001). Four SNPs in the LTA4H gene showed significant association with LTB4 levels (P < 0.05)of which rs1978331 (P = 0.035) remained significant after correction for multiple testing. LTB4 showed strong correlation with lipids (r = 0.24-34) only in cases. Our pilot study suggests that the association between Leukotrienes gene polymorphisms and CAD risk may be modulated through plasma LTB4 levels. [ABSTRACT FROM AUTHOR]

Common single-nucleotide polymorphisms (SNPs) in genes of lipid metabolism modestly influence plasma low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD). We evaluated a panel of LDL-C–modulating SNPs for potential association with risk of CAD in Asian Indians. Fifteen SNPs of CETP, ABCB1, APOAI, CYP7A1, and HMGCR genes were genotyped in 265 CAD patients and 150 controls of North Indian origin. A proatherogenic genotype score was formulated based on number of alleles associated with LDL-C and was evaluated for association with risk of CAD. We observed 12 SNPs from CETP, APOAI, ABCB1, CYP7A1, and HMGCR genes to be associated with baseline LDL-C and high-density lipoprotein cholesterol levels and increased risk of CAD ( p < 0.05). Co-occurrence of three or more risk alleles (proartherogenic genotype score ≥3) was associated with increased risk of CAD and myocardial infarction. Analysis of epistatic interactions revealed CETPTaqIB1B1/405II/APOAI-75GA to be best model of CAD risk prediction in our population. Our study highlights synergistic association of multiple SNPs of lipid pathway with LDL-C levels and risk of CAD, and indicates that co-occurrence of proatherogenic risk alleles may provide incremental information about CAD risk beyond lipid concentrations. [ABSTRACT FROM AUTHOR]

Background: 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 multipoint 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the impact of three polymorphisms in the lipoprotein lipase gene (LPL) on coronary artery disease (CAD) susceptibility in Chinese and Asian Indian males residing in Singapore. A total of 1201 CAD patients and 841 healthy controls were recruited. The HindIII/H- and 447X alleles are associated with decreased CAD risk in both Chinese (p=0.025, 0.001, respectively) and Indians (p=0.0014, 0.008, respectively). The same effect of PvuII/P- allele was observed only in Indians (p=0.049). The most common haplotype, P+H+S, was significantly increased CAD risk in both ethnic groups (p=0.0096, 0.0011, respectively). [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]