A synergistic association of ACE I/D and eNOS G894T gene variants with the progression of immunoglobulin A nephropathy - a pilot study.

BACKGROUND: Individual variability in the natural history and response to therapy of immunoglobulin A nephropathy (IgAN) suggests a complex multifactorial pathogenesis. We investigated whether single nucleotide polymorphisms (SNPs) involved in the non-immunologic progression of renal disease are related with disease progression. METHODS: This is a pilot historic cohort study of 64 Caucasian patients with biopsy-proven IgAN and a median follow-up of 70 months. Three SNPs of the renin-angiotensin system genes (angiotensin I converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT(1)R) 1166A/C), 2 of the endothelial nitric oxide synthase (eNOS), 4a/b and G894T, and 1 of the bradykinin 1 receptor, G-699C, were genotyped. The primary outcome was 'kidney survival' defined as a 30% decrease of baseline creatinine clearance; annualized decrease of glomerular filtration rate was also calculated. RESULTS: Proteinuria, histological lesions, and mean arterial pressure were related to an unfavorable outcome. The simultaneous presence of the DD and GG variants of the ACE and eNOS genes was related to an unfavorable outcome as compared with other combinations [hazard ratio ranging from 4.7 (95% CI 1.52-14.33) to 8.4 (95% CI 2.45-29.10)] after controlling for proteinuria, mean arterial pressure and baseline histological lesions. CONCLUSION: This study suggests that in our population with IgAN, an interaction between ACE and eNOS polymorphisms may be a prognostic factor for renal function deterioration.

[Concerning the significance of paraoxonase-1 and SR-B1 genes in atherosclerosis]. / Sobre los genes paraoxonasa-1 y SR-B1, y su importancia en la aterosclerosis.

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 paraoxonase's 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 / Concerning the significance of paraoxonase-1 and SR-B1 genes in atherosclerosis

La lipoproteína de alta densidad (HDL) constituye un factor de protección independiente de enfermedad cardiovascular. La enzima paraoxonasa-1 (PON-1) contribuye a las propiedades antiaterogénicas asociadas al HDL. Estudios in vitro muestran que posee una gran heterogeneidad de sustratos, algunos de los cuales participan en la progresión de las lesiones ateroscleróticas. 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 concentración de la proteína PON-1. El gen CLA-1 (CD36 and Lysosomal integral membrana protein-II Analogous-1) es el homólogo 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 través de la entrada selectiva de ésteres de colesterol nativos y oxidados, y su papel ateroprotector se ha deducido de los estudios en animales genéticamente manipulados. En humanos, el gen CLA-1 es polimórfico y algunas de sus variantes han sido previamente asociadas con cambios fenotípicos en lipoproteínas plasmáticas. Ambos genes participan en el complejo metabolismo del HDL y, presumiblemente, en los mecanismos de defensa frente a estrés oxidativo

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 paraoxonase's 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

Allelic variants of the human scavenger receptor class B type 1 and paraoxonase 1 on coronary heart disease: genotype-phenotype correlations.

OBJECTIVE: The antioxidant properties of high-density lipoprotein (HDL) have been attributed to paraoxonase (PON) enzyme activity. Human scavenger receptor class B type 1 (SR-BI; CD36 and lysosomal integral membrane protein-II analogous-1 [CLA-1]) plays a central role in HDL-mediated native and oxidized cholesteryl ester uptake. We tested for a significant contribution of common variant of these genes to coronary heart disease (CHD) risk and hypothesized that genetic-mediated PON activity and CLA-1/SR-BI receptor functional properties jointly reduce plasma oxidation status. METHODS AND RESULTS: We studied 304 cases and 315 controls. Polymorphisms were analyzed by polymerase chain reaction-restriction fragment analysis. CLA-1/SR-BI-relative expression levels and mRNA stability were analyzed by the comparative threshold cycle method. There was a significant difference in the male genotype distribution of the CLA-1/SR-BI exon 8 (C8/T8) variant between groups with an odds ratio of 1.7 (95% CI, 1.16 to 2.51). This significant risk was restricted to those subject carriers of Arg (R) and Leu (L) allele of the PON1 192 and 55 variants and was confirmed in multiple logistic regression analysis. CLA-1/SR-BI mRNA expression levels differed according to CLA-1/SR-BI genotypes. CONCLUSIONS: These data suggest a plausible genetic interaction between the CLA-1 exon 8 gene polymorphism and the risk of CHD in males.

Peroxisome proliferator-activated receptor-gamma2-Pro12Ala and endothelial nitric oxide synthase-4a/bgene polymorphisms are associated with essential hypertension.

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) belongs to the family of the nuclear hormone receptors and has been recently implicated in vascular biology. PPARgamma2(Pro12Ala) gene polymorphism is associated with obesity, body mass index and diabetes mellitus. The endothelial nitric oxide synthase (eNOS) (4a/b) gene polymorphism contributes to coronary heart disease and hypertension risk. We tested whether both polymorphic variants were associated with hypertension risk, and their inter-relationship with plasma homocysteine. DESIGN: A case-control study was conducted selecting 235 subjects with arterial hypertension and 223 normotensive matched controls. METHODS: Genotyping for the PPARgamma2(Pro12Ala) and the eNOS(4a/b) were performed by mutagenically separated polymerase chain reaction and by polymerase chain reaction. Glucose, lipid profile, plasma creatinine, homocysteine and microalbuminuria were measured. RESULTS We found a significant contribution of the PPARgamma2(Pro12Ala) and eNOS(4a/b) gene polymorphisms to hypertensive risk in our population (odds ratio, 1.9 and 1.6, respectively), confirmed by multiple logistic regression analysis. Those subjects with normal plasma homocysteine values had an increased hypertensive risk with an odds ratio of 2.6 for the PP genotype of the PPARgamma2 gene and an odds ratio of 1.8 for the a allele of the eNOS gene. CONCLUSIONS: Both analyzed polymorphisms were associated in a synergistic manner with hypertension. This effect manifested only in those subjects with normal homocysteine plasma values. Our findings suggest complex genotype-environmental interactions on hypertensive risk.