Francisco Rodríguez Esparragón

Relevancia de los polimorfismos génicos del sistema renina-angiotensina en la enfermedad coronaria

Introduction and objectives. Previous studies angiotensin-converting enzyme gene insertion/deletion polymorphism ACE (I/D), angiotensinogen gene polymorphism, and angiotensin II AT1 receptor polymorphism in relation to coronary heart disease controversial results. This study was designed to analyze the association between these gene polymorphisms and the first coronary event in individuals residing on Grand Canary Island, Spain. Patients and method. Case-control study. Case subjects (n=304) were recruited at the first coronary event; age-matched controls (n=315) were randomly selected from the Grand Canary population. Participants were examined for the usual risk factors. Blood samples were obtained for biochemical analyses and DNA extraction. Genotyping was performed by PCR and restriction analysis. Results. Neither ACE (I/D) nor AT1 receptor polymorphism was associated with coronary heart disease, whereas the frequency distribution of AGT M235T genotypes among patients and control subjects (TT: 29% and 19%; MT: 48% and 50%; MM: 22% and 31%, respectively) was statistically different (P=.003). Multiple logistic regression analysis identified the TT genotype of the angiotensinogen gene (OR=1.9; 95% CI 1.1-3.4), diabetes (OR=4.4; 95% CI 2.0-9.4) and hypertension (OR=2.1; 95% CI, 1.33.3) as risk factors predicting the coronary event. Conclusions. Our results provide no evidence of an association between ACE (I/D) or AT1 receptor polymorphism and coronary heart disease. However, homozygosity for the T allele of the angiotensinogen gene, diabetes and hypertension independently place individuals at higher risk of experiencing a coronary event on Grand Canary Island.Resumen Introduccion y objetivos Estudios previos sobre la relacion de la enfermedad coronaria y el polimorfismo de insercion/delecion de la enzima conversiva de la angiotensina (ECA [I/D]), el polimorfismo del gen del angiotensinogeno AGT M235T, o del receptor AT1 de la angiotensina II (A1166C) han demostrado resultados controvertidos. El objetivo de este estudio fue determinar la asociacion entre estos polimorfismos genicos y el primer acontecimiento coronario en la poblacion de Gran Canaria. Pacientes y metodo Estudio de casos y controles ajustados segun edad. Los casos (n = 304) se seleccionaron al padecer un primer acontecimiento coronario; los controles constituyen una muestra aleatoria poblacional (n = 315). Todos los sujetos fueron evaluados para los factores de riesgo clasicos. Se tomaron muestras sanguineas para determinaciones analiticas y extraccion de ADN. Las genotipificaciones se realizaron por PCR y analisis de restriccion. Resultados No se encontro asociacion entre el polimorfismo ECA (I/D), AT1R (A1166C) y la enfermedad coronaria, mientras que la distribucion de frecuencias de los genotipos del angiotensinogeno entre pacientes y controles (TT: 29 y 19%; MT: 48 y 50%; MM: 22 y 31%, respectivamente) resultaron estadisticamente diferentes (p = 0,003). El analisis multivariado identifico como factores predictores de acontecimiento coronario al genotipo TT del gen del angiotensinogeno (OR = 1,9; IC del 95%, 1,1- 3,4), la diabetes (OR = 4,4; IC del 95%, 2,0-9,4) y la hipertension (OR = 2,1; IC del 95%, 1,3-3,3). Conclusiones No se ha observado asociacion entre el polimorfismo ECA (I/D), AT1R (A1166C) y la enfermedad coronaria. Sin embargo, la homocigosis TT del gen del angiotensinogeno, la diabetes y la hipertension arterial predisponen de manera independiente a la aparicion de un primer acontecimiento coronario en la poblacion canaria.

Variantes genéticas, riesgo cardiovascular y estudios de asociación de genoma completo

Genome-wide association studies have shown an association between single nucleotide polymorphisms (SNPs) and coronary artery disease and myocardial infarction in new chromosomal regions: 1p13.1, 2q36.3, 9p21 and 10q11.21. The SNPs from the 9p21 region constitute a risk haplotype due to the strong linkage disequilibrium in this area. These SNPs have been extensively replicated in several European and Asian populations, and are associated with other pathologies such as abdominal aortic and intracranial aneurysms, and with intermediate phenotypes such as arterial stiffness and coronary calcium. The risk haplotype of 9p21 is located in a region without annotated genes, near CDKN2A and CDKN2B, known tumor suppressor genes encoding for inhibitors of cell cycle kinases. In the remaining regions the SNPs are located in genes with known roles in atherosclerosis as well as others with new roles. It has been shown that the incorporation of genetic information in the form of SNPs slightly improves the prediction of long-term cardiovascular risk estimated by the Framingham function, allowing the reclassification of individuals into more precise categories. Gene expression studies have found that expression levels of CDKN2A/CDKN2B/ANRIL are co-regulated and associated with the risk haplotype and atherosclerosis severity.

Concerning the Significance of Paraoxonase-1 and SR-B1 Genes in Atherosclerosis

High-density lipoprotein (HDL) is an independent protective factor against cardiovascular disease. The enzyme paraoxonase-1 (PON-1) contributes to the anti-atherogenic effects of HDL. In vitro studies have demonstrated that paraoxonases substrates are highly heterogeneous and that some contribute to the development of atherosclerotic lesions. The atheroprotective role of PON-1 was established in genetically engineered animal models. In humans, the PON-1 Gln192Arg and Met55Leu polymorphisms appear to be associated with increased susceptibility to cardiovascular disease and with different PON-1 activity levels and concentrations. The CLA-1 (CD36 and Lysosomal integral membrane protein-II Analogous-1) gene is the human homologue of the murine SR-B1 (Scavenger Receptor class B type 1) gene. SR-B1 was the first high-affinity HDL receptor to be identified at the molecular level. The CLA-1 receptor plays a pivotal role in HDL-mediated reverse cholesterol transport by mediating the selective uptake of free cholesterol as well as of native and oxidized cholesteryl esters. Its atheroprotective role has also been established in transgenic mice studies. Several polymorphic variants of the CLA-1 gene have been described, some of which are associated with phenotypic changes in plasma lipoproteins. Both genes participate in the complex HDL metabolic pathway and, presumably, also in defense mechanisms against oxidative stress.

Sobre los genes paraoxonasa-1 y SR-B1, y su importancia en la aterosclerosis

La lipoproteina de alta densidad (HDL) constituye un factor de proteccion independiente de enfermedad cardiovascular. La enzima paraoxonasa-1 (PON-1) contribuye a las propiedades antiaterogenicas asociadas al HDL. Estudios in vitro muestran que posee una gran heterogeneidad de sustratos, algunos de los cuales participan en la progresion de las lesiones ateroscleroticas. Se han desarrollado modelos animales que muestran su papel ateroprotector. En humanos, las variantes PON-1 Gln192Arg y Met55Leu parecen asociarse con una mayor susceptibilidad cardiovascular, con diferentes actividades y concentracion de la proteina PON-1. El gen CLA-1 (CD36 and Lysosomal integral membrana protein-II Analogous-1) es el homologo humano del gen SR-B1 (Scavenger Receptor class B type 1) y constituye el primer receptor de alta afinidad de HDL bien caracterizado. El receptor CLA-1 participa en el transporte reverso de colesterol a traves de la entrada selectiva de esteres de colesterol nativos y oxidados, y su papel ateroprotector se ha deducido de los estudios en animales geneticamente manipulados. En humanos, el gen CLA-1 es polimorfico y algunas de sus variantes han sido previamente asociadas con cambios fenotipicos en lipoproteinas plasmaticas. Ambos genes participan en el complejo metabolismo del HDL y, presumiblemente, en los mecanismos de defensa frente a estres oxidativo.

Replication of Relevant SNPs Associated with Cardiovascular Disease Susceptibility Obtained from GWAs in a Case-Control Study in a Canarian Population

Recent genome-wide single nucleotide polymorphism (SNP) association studies (GWAS) have identified a number of SNPs that were significantly associated with coronary artery disease (CAD) and myocardial infarction (MI). We tested for replication of the previously described association with CAD in our case-control datasets of SNPs variants located at 1p13.1, 2q33.1, 10q11.1, 9p21, and 21q22. We observed a small significant risk associated of the SNP rs10757274 with CAD in the PROCAGENE study. Besides, the multilocus combination rs10757274 and rs1333048 gave a near significant result. We confirmed that the SNP rs10757274 showed association with CAD in the PROCAGENE study, although after applying the Bonferroni correction was not longer significant. Independent replication studies in other populations are needed to unequivocally confirm the association.