ABSTRACT
Elevated factor VII (FVII) level is a risk factor for coronary artery disease (CAD). We investigated the role of R353Q polymorphism in the F7 gene in 139 Indian families with CAD, comprising of 222 affected subjects, 105 unaffected subjects and 126 affected sibling pairs. Plasma per cent FVIIc activity (FVII.c activity) differed ignificantly across R353Q genotype (P < 0.0001). Frequency of subjects with RR and QQ genotypes were higher in 4th quartile and 1st quartile of FVII.c activity, respectively (P < 0.0001). F7 R353Q SNP was able to explain up to 7% of variation in FVII.c activity by regression analysis and an additive genetic component of variance of 28.04% by heritability analysis. Quantitative trait loci analysis showed suggestive linkage evidence of F7 SNP with per cent FVII.c activity (LOD score -1.82; P = 0.002). Individuals with RR and RQ genotypes carried an OR of 2.071 (95% c.i. = 1.506-2.850) and 2.472 (95% c.i. = 1.679-3.641), espectively, towards CAD risk. There was significant correlation of FVII.c activity with lipid markers, particularly among those with RR and RQ genotype after covariate adjustment. In conclusion, the F7 R353Q SNP appears to moderately influence plasma FVII.c activity and risk of CAD in Indians.
Subject(s)
Antigens/blood , Antigens/genetics , Asian People/genetics , Coronary Artery Disease/genetics , Factor VII/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Amino Acid Substitution/genetics , Base Sequence , Biomarkers , Case-Control Studies , Coronary Artery Disease/blood , DNA Mutational Analysis , Electrophoresis, Agar Gel , Family , Female , Genetic Association Studies , Genetic Linkage , Heterozygote , Humans , India , Male , Middle Aged , Molecular Sequence Data , Thrombosis/genetics , Thrombosis/pathologyABSTRACT
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 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. 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.
Subject(s)
Apolipoprotein A-I/genetics , Apolipoprotein C-III/genetics , Apolipoproteins A/genetics , Asian People/genetics , Coronary Artery Disease/genetics , Multigene Family/genetics , Adult , Age of Onset , Aged , Apolipoprotein A-V , Asia/ethnology , Female , Gene Frequency , Genetic Linkage , Genetic Markers , Genotype , Humans , India , Inheritance Patterns/genetics , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , Regression AnalysisABSTRACT
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 < or = 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.
