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.