Genetic variants of PON1, GSTM1, GSTT1, and locus 9p21.3, and the risk for premature coronary artery disease in Yucatan, Mexico.

OBJECTIVE: Genetic variants of PON1, rs70587, rs662, rs854560, GSTM1, and GSTT1 and two single nucleotide polymorphisms (SNP) at 9p21.3 locus, rs1333049, and rs2383207; were evaluated in association with the risk for premature coronary artery disease (CAD) in a population of Yucatan, Mexico. These genes are involved in the inactivation of pro-oxidants and pro-inflammatory mediators, lipid and xenobiotic metabolism, detoxification of reactive oxygen species, and regulation of cellular proliferation playing key roles in the pathogenesis of atherosclerosis. METHODS: We conducted a matched case-control study with 98 CAD cases and 101 healthy controls. Genotyping of PON1 and 9p21.2 SNP was performed by real time-PCR and for GSTM1 and GSTT1 with multiplex-PCR. Odds ratios (OR) were calculated to estimate association and generalized multifactor dimensionality reduction (GMDR) algorithm to identify gene-gene and gene-environment interactions. RESULTS: The distribution of all allele/genotype frequencies in controls was within Hardy-Weinberg expectations (p > .05) except for GSTM1. The allele/genotype frequencies of the GSTT1 null were significantly higher in CAD cases than in controls, suggesting association with higher risk for developing CAD. The other SNPs did not show any significant independent association with premature CAD. GMDR revealed a significant interaction between GSTT1 and LL55 genotype. Likewise, the body mass index (BMI) and smoking also showed an interaction with GSTT1. CONCLUSION: The GSTT1 null allele/genotype is associated with an increased risk of developing premature CAD, the effect of which is not modified by cardiovascular risk factors in the population of Yucatan.

Análisis de epistasia de polimorfismos de genes metabólicos asociados a cardiopatía isquémica en Yucatán / Epistasis analysis of metabolic genes polymorphisms associated with ischemic heart disease in Yucatan

Objetivo: La epistasia es un tipo de interacción genética que podría explicar gran parte de la variabilidad fenotípica que muestran las enfermedades complejas. En este trabajo se determinó el efecto de la epistasia de genes metabólicos y los factores de riesgo cardiovascular en la susceptibilidad al desarrollo de cardiopatía isquémica en Yucatán. Métodos: Estudio de casos y controles en 79 pacientes yucatecos con cardiopatía isquémica y 101 controles sanos pareados por edad y origen con los casos. Se genotipificaron los polimorfismos -108CT, Q192R, L55M (paraoxonasa 1, PON1), C677T, A1298C (5,10 metilentetrahidrofolato reductasa, MTHFR) y la presencia/ausencia del gen glutatión S-transferasa T1 (GSTT1). El análisis de epistasia se realizó con el método de reducción dimensional multifactorial (MDR). El mejor modelo de predicción de riesgo se seleccionó con base en la precisión (%), la significación estadística (p < 0,05) y la consistencia de la validación cruzada. Resultados: Se encontró asociación independiente del genotipo nulo GSTT1*0/0 (OR = 3,39; IC: 1,29-8,87; p = 0,017) y el alelo nulo (OR = 1,86; IC: 1,19-2,91; p = 0,007) con la cardiopatía isquémica. La deleción GSTT1*0 y el genotipo 677TT (MTHFR) se identificaron de alto riesgo cardiovascular, mientras que el genotipo silvestre GSTT1*1 y la variante CC677 se clasificaron de bajo riesgo. La interacción gen-ambiente identificó al gen GSTT1, al polimorfismo C677T (MTHFR) y a la hipertensión arterial como los factores que mejor explican la cardiopatía isquémica en la población estudiada. Conclusiones: La interacción de los genes GSTT1 y MTHFR conjuntamente con la hipertensión arterial puede constituir un modelo de predicción de riesgo para el inicio temprano de cardiopatía isquémica en la población de Yucatán

Objective: Epistasis is a type of genetic interaction that could explain much of the phenotypic variability of complex diseases. In this work, the effect of epistasis of metabolic genes and cardiovascular risk on the susceptibility to the development of ischemic heart disease in Yucatan was determined. Methods: Case-control study in 79 Yucatecan patients with ischemic heart disease and 101 healthy controls matched by age and origin with cases. The polymorphisms -108CT, Q192R, L55M (paraoxonase 1; PON1), C677T, A1298C (methylenetetrahydrofolate reductase; MTHFR), and the presence/absence of the glutathione S-transferase T1 (GSTT1) gene were genotyped. Epistasis analysis was performed using the multifactorial dimensional reduction method. The best risk prediction model was selected based on precision (%), statistical significance (P<0.05), and cross-validation consistency. Results: We found an independent association of the null genotype GSTT1*0/0 (OR=3.39, CI: 1.29-8.87, P=0.017) and the null allele (OR=1.86, CI: 1.19-2.91, P=0.007) with ischemic heart disease. The GSTT1*0 deletion and the 677TT genotype (MTHFR) were identified as being at a high cardiovascular risk, whereas the GSTT1*1 wild type genotype and the CC677 variant were at low risk. The gene-environment interaction identified the GSTT1 gene, C677T polymorphism (MTHFR), and hypertension as the factors that best explain ischemic heart disease in the study population. Conclusions: The interaction of the MTHFR, GSTT1 and hypertension may constitute a predictive model of risk for early onset ischemic heart disease in the population of Yucatan

Epistasis analysis of metabolic genes polymorphisms associated with ischemic heart disease in Yucatan. / Análisis de epistasia de polimorfismos de genes metabólicos asociados a cardiopatía isquémica en Yucatán.

OBJECTIVE: Epistasis is a type of genetic interaction that could explain much of the phenotypic variability of complex diseases. In this work, the effect of epistasis of metabolic genes and cardiovascular risk on the susceptibility to the development of ischemic heart disease in Yucatan was determined. METHODS: Case-control study in 79 Yucatecan patients with ischemic heart disease and 101 healthy controls matched by age and origin with cases. The polymorphisms -108CT, Q192R, L55M (paraoxonase 1; PON1), C677T, A1298C (methylenetetrahydrofolate reductase; MTHFR), and the presence/absence of the glutathione S-transferase T1 (GSTT1) gene were genotyped. Epistasis analysis was performed using the multifactorial dimensional reduction method. The best risk prediction model was selected based on precision (%), statistical significance (P<0.05), and cross-validation consistency. RESULTS: We found an independent association of the null genotype GSTT1*0/0 (OR=3.39, CI: 1.29-8.87, P=0.017) and the null allele (OR=1.86, CI: 1.19-2.91, P=0.007) with ischemic heart disease. The GSTT1*0 deletion and the 677TT genotype (MTHFR) were identified as being at a high cardiovascular risk, whereas the GSTT1*1 wild type genotype and the CC677 variant were at low risk. The gene-environment interaction identified the GSTT1 gene, C677T polymorphism (MTHFR), and hypertension as the factors that best explain ischemic heart disease in the study population. CONCLUSIONS: The interaction of the MTHFR, GSTT1 and hypertension may constitute a predictive model of risk for early onset ischemic heart disease in the population of Yucatan.

Polimorfismos G894T del gen NOS3 y G1958A del gen MTHFD1 y riesgo de cardiopatía isquémica en Yucatán, México / G894T (NOS3) and G1958A (MTHFD1) gene polymorphisms and risk of ischemic heart disease in Yucatan, Mexico

Introducción y objetivos: La medicina cardiovascular actual está dirigida a la búsqueda de marcadores de riesgo genético con valor predictivo y/o pronóstico. Entre las variantes de interés se encuentran los polimorfismos G894T en el gen óxido nítrico sin tasa endotelial y G1958A en el gen metilentetrahidrofolato deshidrogenasa 1. El objetivo de este estudio fue determinar la posible asociación entre estos polimorfismos y la cardiopatía isquémica (CI) en el sureste de México (Yucatán). Métodos: Estudio de casos y controles con pareamiento por edad, sexo y lugar de nacimiento. Se estudiaron 98 pacientes con CI y 101 controles. Todos los participantes fueron evaluados para los factores de riesgo tradicionales. Los polimorfismos se identificaron utilizando la reacción en cadena de la polimerasa mediante análisis de la longitud de los fragmentos de restricción. Se obtuvo el consentimiento informado de todos los participantes. Resultados: Los polimorfismos G894T y G1958A no mostraron asociación con la CI. Sin embargo, la estratificación según la manifestación clínica mostró que el genotipo TT (G894T) se asoció con la angina (OR = 10,2; IC 95%, 1,51-68,8; p = 0,025). Se observó mayor frecuencia del genotipo GT en los pacientes con historia familiar de enfermedad coronaria. El análisis de regresión logística identificó al tabaquismo (OR = 5,21; IC 95%, 2,1-12,9; p = 0,000), la hipertensión arterial (OR = 3,54; IC 95%, 1,47-8,56; p = 0,005) y la obesidad (OR = 1,16; IC 95%, 1,1-1,27; p = 0,001) como factores predictores de CI. Conclusiones: Los polimorfismos G894T y G1958A no mostraron asociación con la CI. Sin embargo, la homocigosis del alelo 894T (NOS3) confiere riesgo para el desarrollo de angina en Yucatán

Introduction and objectives: Cardiovascular medicine is focused on the search for genetic risk markers with predictive and/or prognostic value. Among the genetic variants of interest are G894T endothelial nitric oxide synthase and G1958A methylenetetrahydrofolate dehydrogenase 1 gene polymorphisms. The aim of this study was to determine the possible association between these polymorphisms and ischemic heart disease in patients from Southern of Mexico (Yucatán). Methods: Case-control study matched by age, sex and origin was designed. We studied 98 patients with coronary disease and 101 controls. Participants were evaluated for the usual risk factors. The polymorphisms were identified using the polymerase chain reaction/restriction fragment length polymorphism analysis. Informed consent was obtained from all participants. Results: The G894T and G1958A polymorphisms were not associated with ischemic heart disease, however, the TT genotype (G894T) was associated with the angina (OR = 10.2; 95% CI, 1.51-68.8; p = 0.025). The genotype GT (G894T) was the most frequent in patients with family history of coronary artery disease. Multiple logistic regression analysis identified smoking (OR = 5.21; 95% CI, 2.1-12.9; p = 0.000), hypertension (OR = 3.54; 95% CI, 1.47-8.56; p = 0.005) and obesity (OR = 1.16; 95% CI, 1.1-1.27; p = 0.001) as risk factors predicting the ischemic heart disease. Conclusions: The G894T and G1958A polymorphisms showed not association with ischemic heart disease. However, homozygosis for the 894T allele (NOS3) confers at risk to develop angina on Yucatán

[G894T (NOS3) and G1958A (MTHFD1) gene polymorphisms and risk of ischemic heart disease in Yucatan, Mexico]. / Polimorfismos G894T del gen NOS3 y G1958A del gen MTHFD1 y riesgo de cardiopatía isquémica en Yucatán, México.

INTRODUCTION AND OBJECTIVES: Cardiovascular medicine is focused on the search for genetic risk markers with predictive and/or prognostic value. Among the genetic variants of interest are G894T endothelial nitric oxide synthase and G1958A methylenetetrahydrofolate dehydrogenase1 gene polymorphisms. The aim of this study was to determine the possible association between these polymorphisms and ischemic heart disease in patients from Southern of Mexico (Yucatán). METHODS: Case-control study matched by age, sex and origin was designed. We studied 98 patients with coronary disease and 101 controls. Participants were evaluated for the usual risk factors. The polymorphisms were identified using the polymerase chain reaction/restriction fragment length polymorphism analysis. Informed consent was obtained from all participants. RESULTS: The G894T and G1958A polymorphisms were not associated with ischemic heart disease, however, the TT genotype (G894T) was associated with the angina (OR=10.2; 95%CI, 1.51-68.8; p=0.025). The genotype GT (G894T) was the most frequent in patients with family history of coronary artery disease. Multiple logistic regression analysis identified smoking (OR=5.21; 95%CI, 2.1-12.9; p=0.000), hypertension (OR=3.54; 95%CI, 1.47-8.56; p=0.005) and obesity (OR=1.16; 95%CI, 1.1-1.27; p=0.001) as risk factors predicting the ischemic heart disease. CONCLUSIONS: The G894T and G1958A polymorphisms showed not association with ischemic heart disease. However, homozygosis for the 894T allele (NOS3) confers at risk to develop angina on Yucatán.