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Advisor(s)
Abstract(s)
A doença coronária (DC) é a principal causa
de mortalidade nos países desenvolvidos. O
aumento da peroxidação lipídica está associado
com a progressão acelerada da arteriosclerose.
A Paraoxonase (PON1) é uma
enzima antioxidante, que protege contra a
peroxidação lipídica e a DC. A actividade
da PON1 está sob controlo genético e a sua
base molecular consiste num polimorfismo
do gene da PON1 que apresenta duas isoformas
comuns: a forma nativa, Q (192 Gln)
com elevada capacidade de protecção das
LDL da peroxidação lipídica in vitro, e a
isoforma mutada R (192 Arg) com baixa
capacidade de protecção.
Objectivo: O objectivo deste trabalho foi
investigar a interacção entre o alelo R do
gene da PON 1 e os níveis plasmáticos
baixos de colesterol HDL, no risco do
aparecimento da DC.
Métodos: Participaram no estudo 818 indivíduos,
298 doentes coronários com idade
média 55.0±10.3 anos, 78.9% do sexo masculino,
e 520 controlos, com uma idade
média de 53.3±11, 7 anos, 72, 5% do sexo
masculino, tendo casos e controlos sido
emparelhados por idade e sexo. Foi considerado
um valor <de 40 mg/dl (0,90
mmol/L), nos homens e <de 50 mg/dl (1,11
mmol/L), nas mulheres como um nível baixo
de Colesterol HDL. As comparações
genotípicas, entre casos e controlos, foram efectuadas pelo teste do Chi-quadrado. A
significância estatística foi aceite para valores
de p <0,05. Para determinar o risco
relativo de DC, em relação ao genótipo RR
e aos níveis baixos de colesterol HDL, foi
usada uma análise univariada e foram utilizadas
as tabelas epidemiológicas 4x2 e
medidas de sinergismo (modelo aditivo - SI
e multiplicativo - SIM) para determinar a
interacção entre o genótipo RR e os níveis
baixos de colesterol HDL. Foi finalmente
calculado o excesso de risco relativo (RERI)
e proporção atribuída à interacção (AP).
Resultados: A PON 1 192 RR está associada
à DC [OR=1,61; p=0,043] para toda a população.
A associação de níveis baixos de
HDL com o genótipo 192 RR mostrou um
aumento do risco de DC (OR=17,38; p
<0,0001) comparada aos níveis normais de
HDL associados ao mesmo genótipo
(OR=1,39; p=0,348) e aos níveis baixos de
HDL sem o genótipo RR (OR=7,79; p
<0,0001). Índices de Sinergismo: SI= 2,3;
SIM = 1.6; RERI=9,2; AP=0,53.
Conclusão: Estes dados sugerem a existência
de um efeito sinérgico entre o genótipo
192 RR da PON1 e os valores baixos de
colesterol HDL, na emergência de DC, pois
este genótipo aumentou o risco de DC, em
especial, na população com níveis plasmáticos
baixos de colesterol HDL. A proporção
de DC que pode ser atribuída a esta interacção
(AP) foi de 0,53 significando que
53% da DC que surgiu nestes indivíduos,
foi explicada por esta interacção.
INTRODUCTION: Coronary artery disease (CAD) is the main cause of mortality in developed countries. Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidant enzyme bound to high-density lipoprotein (HDL), which protects against lipid peroxidation and coronary artery disease. PON1 activity is under genetic control and its molecular basis is a polymorphism in the PON1 gene that shows two common isoforms: the wild Q form (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and the mutated R (Arg) form with lower ability. AIM: To explore the interaction of the R allele of the paraoxonase gene and low HDL-cholesterol concentrations in CAD risk. METHODS: The study population consisted of 818 individuals, 298 coronary patients, aged 55.0 +/- 10.3 years, 78.9% male, and 520 age and gender matched healthy controls, aged 53.3 +/- 11.7 years, 72.5% male. Low HDL-cholesterol was defined as < 0.90 mmol/l in men and < 1.11 mmol/l in women. Comparisons of genotypes between cases and controls were performed by a chi-square test. Statistical significance was accepted at p < 0.05. Odds ratios and 95% confidence intervals for the RR genotypes and HDL-deficient subjects were computed using univariate analysis (2 x 2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used 4 x 2 epidemiologic tables and synergy measures: the additive model (Rothman's synergy index, SI) and multiplicative model (Khoury's synergy index, SIM). The relative excess risk due to interaction (RERI) and the attributable proportion (AP) due to interaction (Rothman) were calculated. RESULTS: The PON1 RR192 polymorphism was associated with coronary heart disease (OR = 1.61; p = 0.043) in the whole population. HDL-deficient subjects with the RR192 genotype showed increased risk for CAD (OR = 17.38; p < 0.0001) compared to those with normal HDL and RR192 (OR = 1.39; p = 0.348) and HDL-deficient subjects not carrying the RR genotype (OR = 7.79; p < 0.0001). Synergy measures were SI = 2.3, SIM = 1.6; RERI = 9.2. CONCLUSION: These data suggest the existence of a synergistic effect of the PON1 RR192 genotype (with lower antioxidant ability) and HDL-deficient subjects in risk for development of CAD. The AP due to this interaction was 0.53, meaning that 53% of CAD was explained by this interaction.
INTRODUCTION: Coronary artery disease (CAD) is the main cause of mortality in developed countries. Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidant enzyme bound to high-density lipoprotein (HDL), which protects against lipid peroxidation and coronary artery disease. PON1 activity is under genetic control and its molecular basis is a polymorphism in the PON1 gene that shows two common isoforms: the wild Q form (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and the mutated R (Arg) form with lower ability. AIM: To explore the interaction of the R allele of the paraoxonase gene and low HDL-cholesterol concentrations in CAD risk. METHODS: The study population consisted of 818 individuals, 298 coronary patients, aged 55.0 +/- 10.3 years, 78.9% male, and 520 age and gender matched healthy controls, aged 53.3 +/- 11.7 years, 72.5% male. Low HDL-cholesterol was defined as < 0.90 mmol/l in men and < 1.11 mmol/l in women. Comparisons of genotypes between cases and controls were performed by a chi-square test. Statistical significance was accepted at p < 0.05. Odds ratios and 95% confidence intervals for the RR genotypes and HDL-deficient subjects were computed using univariate analysis (2 x 2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used 4 x 2 epidemiologic tables and synergy measures: the additive model (Rothman's synergy index, SI) and multiplicative model (Khoury's synergy index, SIM). The relative excess risk due to interaction (RERI) and the attributable proportion (AP) due to interaction (Rothman) were calculated. RESULTS: The PON1 RR192 polymorphism was associated with coronary heart disease (OR = 1.61; p = 0.043) in the whole population. HDL-deficient subjects with the RR192 genotype showed increased risk for CAD (OR = 17.38; p < 0.0001) compared to those with normal HDL and RR192 (OR = 1.39; p = 0.348) and HDL-deficient subjects not carrying the RR genotype (OR = 7.79; p < 0.0001). Synergy measures were SI = 2.3, SIM = 1.6; RERI = 9.2. CONCLUSION: These data suggest the existence of a synergistic effect of the PON1 RR192 genotype (with lower antioxidant ability) and HDL-deficient subjects in risk for development of CAD. The AP due to this interaction was 0.53, meaning that 53% of CAD was explained by this interaction.
Description
Keywords
Polimorfismos Paraoxonase 1 Factores de Risco Colesterol HDL Doença Coronária Polymorphisms Risk factors HDL-cholesterol Coronary disease. Portugal Madeira
Citation
Mendonca, M. I., Dos, R. R., Freitas, A. I., Pereira, A., Sousa, A. C., Freitas, S., ... & Araujo, J. J. (2010). Interaction of paraoxonase-192 polymorphism with low HDL-cholesterol in coronary artery disease risk. Revista portuguesa de cardiologia: orgao oficial da Sociedade Portuguesa de Cardiologia= Portuguese journal of cardiology: an official journal of the Portuguese Society of Cardiology, 29(4), 571-580.
Publisher
Elsevier España