Population differences in allele frequencies at the OLR1 locus may suggest geographic disparities in cardiovascular risk events.

Abstract Background: Several studies have demonstrated a link between cardiovascular disease (CVD) susceptibility and the genetic background of populations. Endothelial activation and dysfunction induced by oxidized low-density lipoprotein (ox-LDL) is one of the key steps in the initiation of atherosclerosis. The oxidized low density lipoprotein (lectin-like) receptor 1 (OLR1) gene is the main receptor of ox-LDL. We have previously characterized two polymorphisms (rs3736235 and rs11053646) associated with the risk for coronary artery disease (CAD) and acute myocardial infarction (AMI). Aim: Given their clinical significance, it is of interest to know the distribution of these variants in populations from different continents. Subjects and methods: A total of 1229 individuals from 17 different African, Asian and European populations was genotyped for the two considered markers. Results: The high frequencies of ancestral alleles in South-Saharan populations is concordant with the African origin of our species. The results highlight that African populations are closer to Asians, and clearly separated from the Europeans. Conclusion: The results confirm significant genetic structuring among populations and suggest a possible basis for varying susceptibility to CVD among groups correlated with the geographical location of populations linked with the migrations out of Africa, or with different lifestyle

Role of genomics in cardiovascular medicine

As all branches of science grow and new experimental techniques become readily accessible, our knowledge of medicine is likely to increase exponentially in the coming years. Recently developed technologies have revolutionized our analytical capacities, leading to vast knowledge of many genes or genomic regions involved in the pathogenesis of congenital heart diseases, which are often associated with other genetic syndromes, coronary artery disease and non-ischemic cardiomyopathies and channelopathies. The knowledge-base of the genesis of cardiovascular diseases is likely going to be further revolutionized in this new era of genomic medicine. Here, we review the advances that have been made over the last several years in this field and discuss different genetic mechanisms that have been shown to underlie a variety of cardiovascular diseases

Association between OLR1 K167N SNP and Intima Media Thickness of the Common Carotid Artery in the General Population.

BACKGROUND AND PURPOSE: The lectin-like oxidised LDL receptor-1 (OLR1) gene encodes a scavenger receptor implicated in the pathogenesis of atherosclerosis. Although functional roles have been suggested for two variants, epidemiological studies on OLR1 have been inconsistent. Methods - We tested the association between the non-synonymous substitution K167N (rs11053646) and intima media thickness of the common carotid artery (CCA-IMT) in 2,141 samples from the Progression of Lesions in the Intima of the Carotid (PLIC) study (a prospective population-based study). RESULTS: Significantly increased IMT was observed in male carriers of the minor C (N) allele compared to GC and GG (KN and KK) genotype. Functional analysis on macrophages suggested a decreased association to Ox-LDL in NN carriers compared to KN and KK carriers which is also associated with a reduced OLR1 mRNA expression. Macrophages from NN carriers present also a specific inflammatory gene expression pattern compared to cells from KN and KK carriers. CONCLUSIONS: These data suggest that the 167N variant of LOX-1 receptor affects the atherogenic process in the carotid artery prior to evidence of disease through an inflammatory process

IDOL N342S variant, atherosclerosis progression and cardiovascular disorders in the italian general population

Inducible degrader of the low density lipoprotein receptor (IDOL), is an E3 ubiquitin ligase that negatively modulates low density lipoprotein receptor (LDL-R) expression. Genome-wide association studies (GWAS) indicated that genetic variants in IDOL gene contributes to variation in LDL-C plasma levels and the detailed analysis of a specific locus resulted in the identification of the functional common single nucleotide polymorphism (SNP) rs9370867 (c. G1025A, p.N342S) associates with increased LDL-R degradation and increased LDL-C levels. These findings, however, were not confirmed in two other independent cohorts and no data about the impact of this variant on atherosclerosis progression and cardiovascular risk are available. Aim of this study was to investigate the association between a functional variant in IDOL and atherosclerosis progression in an Italian general population. 1384 subjects enrolled in the PLIC study (Progression of Lesions in the Intima of Carotid) were genotyped by Q-PCR allelic discrimination and the association with anthropometric parameters, plasma lipids and the carotid intima media thickness (cIMT) and the impact on cardiovascular disease (CVD) incidence were investigated. The N342S variant was not associated with changes of the plasma lipid profile am ong GG, AG or AA carriers, including total cholesterol (249±21, 249±19 and 248±21 mg/dl respectively), LDL-C (158±25, 161±22 and 160±23 mg/dL), cIMT (0.74±0.14, 0.75±0.17 and 0.77±0.15 mm) and CVD incidence. In agreement, the expression of LDLR and the uptake of LDL was similar in macrophages derived from GG and AA carriers. Taken together our findings indicate that the N342S variant does not impact plasma lipid profile and is not associated with atherosclerosis progression and CVD in the general population, suggesting that other variants in the IDOL gene might be functionally linked with cholesterol metabolism

-374 T/A RAGE Polymorphism Is Associated with Chronic Kidney Disease Progression in Subjects Affected by Nephrocardiovascular Disease

Background: Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease. Methods: 174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6-9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease. Results: Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03) Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline. Conclusions: -374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression. © 2013 Baragetti et al