Background: Several polymorphisms within the renin-angiotensin system cluster of genes have been associated with the advent of coronary artery disease (CAD) or related pathologies. We investigated the distribution of 5 of these polymorphisms in order to find any association with CAD development and distinguish if any of the biochemical and behavioural factors interact with genetic polymorphisms in the advent of the disease.
Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.
Introduction:
Previous studies consistently reported statistically significant relative risk for coronary artery disease (CAD) with multiple genes. The utility of genetic risk scores (GRS) as additive risk predictors to standard stratification like Framingham risk score (FS) remains inconclusive.
Objectives:
To evaluate the ability of a
multiloci
GRS to provide additive value to 10 year risk FS subgroups (low risk <5%, intermediate risk 5-20%, high risk >20%) in a south European sample.
Methods:
Case-control study of 2555 individuals, 1321 (51.7%) coronary patients and 1234 (48.3%) of controls without coronary disease with a mean age of 52±8.3 years divided in three groups according to FS (FS<5, n=403, 53.3% male, FS 5-20, n=1657, 78% male and FS>20, n= 495, 89.7% male). The
multiloci
GRS was determined with specific
primers
of 29 different genetic variants associated to atherosclerotic/CAD disease. A multiplicative model was used based on risk multiplication (odds ratio - OR) of each genotype. Multivariate analysis and respective ROC curves and area under curve (AUC) were performed for each Framingham risk subgroup. The analysis was repeated adding GRS and pairwise comparison of the two ROC Curve was done by the DeLong test.
Results:
By multivariate analysis GRS was an independent predictor for CAD (OR=2.05; 1.66-2.54, p<0.0001). Diabetes, arterial hypertension, dyslipidemia and smoking (OR= 3.07 (2.47-3.80); OR=2.07 (1.73-2.49); OR=3.1 (2.37-4.07); OR=3.11 (2.58-3.74); all p<0.0001) were also independent CAD predictors. GRS added significant predictive value to Framingham score across the intermediate (0.70 to 0.73 (p<0.0001) and high risk group from 0.68 to 0.72 (p=0.005).
Conclusion:
GRS proved to add significant incremental value only in intermediate and high risk subgroups. In these subgroups, the inclusion of genotyping may be considered to better clarify cardiovascular risk.
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