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Research Project
Genetic polymorphisms and risk of coronary heart disease in Madeira. Interaction with cardiovascular risk markers and their role in prognosis.
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Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal)
Publication . Freitas, Ana I.; Mendonça, Isabel; Guerra, Graça; Brión, Maria; Reis, Roberto P.; Carracedo, Angel; Brehm, António
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.
RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population
Publication . Freitas, Ana I.; Mendonça, Isabel; Brión, Maria; Sequeira, Miguel M.; Reis, Roberto P.; Carracedo, Angel; Brehm, António
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.
Methods: ACE I/D (rs4340), ACE A11860G (rs4343), AT1R A1166C (rs5186), AGT T174M (rs4762)
and AGT M235T (rs699) gene polymorphisms were PCR-RFLP analysed in 298 CAD patients and
510 controls from Portugal. Several biochemical and behavioural markers were obtained.
Results: ACE I/D DD and ACE11860 GG genotypes are risk factors for CAD in this population.
The simultaneous presence of ACE I/D I and ACE11860 A alleles corresponds to a significant trend
towards a decrease in CAD incidence. We found several synergistic effects between the studied
polymorphisms and classical risk factors such as hypertension, obesity, diabetes and dyslipidaemia:
the presence of the DD genotype of ACE I/D (and also ACE11860 GG) increases the odds of
developing CAD when associated to each one of these classical risk factors, particularly when
considering the male and early onset CAD subgroup analysis; AGT235 TT also increases the CAD
risk in the presence of hypertension and dyslipidaemia, and AT1R1166 interacts positively with
hypertension, smoking and obesity.
Conclusion: ACE polymorphisms were shown to play a major role in individual susceptibility to
develop CAD. There is also a clear interaction between RAS predisposing genes and some
biochemical/environmental risk factors in CAD onset, demonstrating a significant enhancement of
classical markers particularly by ACE I/D and ACE11860.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
POCI
Funding Award Number
POCTI/MGI/38697/2001