Interleukin 6 polymorphisms are associated with cardiovascular risk factors in premature coronary artery disease patients and healthy controls of the GEA Mexican study.

BACKGROUND AND AIMS: Interleukin-6 (IL-6) is an acute-phase protein that plays an important role in the inflammatory response, vascular inflammation, and atherosclerosis process. The study aimed to establish whether IL-6 gene polymorphisms and IL-6 concentrations are associated with premature coronary artery disease (pCAD) and cardiovascular risk factors. METHODS: The IL-6 concentrations and the rs2069827, rs1800796, and rs1800795 IL-6 polymorphisms were determined in 1150 pCAD patients and 1083 healthy controls (coronary artery calcium equal to zero determined by tomography). RESULTS: The IL-6 polymorphisms studied were not associated with pCAD, but they were associated with cardiovascular risk factors in patients and controls. In controls, under the dominant model, the rs1800795 C allele and the rs2069827 T allele were associated with a low risk of central obesity (OR = 0.401, p = 0.017 and OR = 0.577, p = 0.031, respectively), hypoalphalipoproteinemia (OR = 0.581, p = 0.027 and OR = 0.700, p = 0.014, respectively) and hypertriglyceridemia (OR = 0.575, p = 0.030 and OR = 0.728, p = 0.033, respectively). In pCAD, the rs1800795 C allele was associated with an increased risk of hypoalphalipoproteinemia (OR = 1.370, padditive = 0.025) and increased C-reactive protein (CRP) concentrations (OR = 1.491, padditive = 0.007). pCAD patients had significantly higher serum IL-6 concentrations compared to controls (p = 0.002). In the total population, individuals carrying the rs1800795 GC + CC genotypes had higher levels of IL-6 than carriers of the GG genotype (p = 0.025). In control individuals carrying the C allele (CG + CC), an inverse correlation was observed between IL-6 and HDL-cholesterol levels (p = 0.003). CONCLUSIONS: In summary, the IL-6 polymorphisms were not associated with pCAD, however, they were associated with cardiovascular risk factors in pCAD patients and healthy controls. Individuals carrying the rs1800795 GC + CC genotypes had higher levels of IL-6 than carriers of the GG genotype.

The dysfunctional adiposity index is a clinical surrogate of pericardial fat in adults without premature CVD: A sub-analysis of the GEA Mexican study control group.

BACKGROUND AND AIM: The Dysfunctional Adiposity Index (DAI) is a clinical surrogate for evaluating adipose tissue functionality and cardiometabolic health. However, its association with Pericardial Fat Volume (PFV) has not been tested. The aim of this study was to evaluate DAI- PFV association, stratified by type 2 diabetes (T2D) status, and identify DAI thresholds for detecting increased PFV among patients without premature CVD. METHODS AND RESULTS: Participants from the GEA-Mexican study underwent a computed tomography scan to measure PFV. Adjusted logistic regression analyses tested the association between DAI and PFV. AUROC curves evaluated DAI's ability to identify elevated PFV (≥57.57 cm³), and the Youden method determined DAI thresholds, along with diagnostic metrics. The study analyzed 997 participants (women: 55%; mean age: 54 ± 9 years; median PFV: 42 cm³ [IQR: 29-58]), with a 13% prevalence of T2D. DAI was positively associated with elevated PFV (OR: 1.33, 95% CI: 1.07-1.70), which was more pronounced among subjects with T2D (OR: 3.01, 95% CI: 1.41-6.40). DAI thresholds were established for all participants (>1.176), individuals without T2D (>1.003), and with T2D (>1.936), yielding sensitivities of 71%, 81%, and 57%, and specificities of 48%, 38%, and 75%, respectively. The adjusted logistic regression tied DAI thresholds to a 1.68-fold elevation in PFV for all, 2.06-fold for those without T2D, and 6.81-fold for those with T2D. CONCLUSION: DAI was positively associated with increased PFV, particularly among participants with T2D. Established DAI thresholds demonstrated good diagnostic values for detecting increased PFV. DAI could serve as an accessible marker to identify PF in clinical settings.

Association of TLR8 Variants in Sex-Based Clinical Differences in Patients with COVID-19.

The host immune response might confer differential vulnerability to SARS-CoV-2 infection. The Toll-like receptor 8 (TLR8), could participated for severe COVID-19 outcomes. To investigated the relationship of TLR8 rs3764879-C/G, rs3764880-A/G, and rs3761624-A/G with COVID-19 outcomes and with biochemical parameters. A cross-sectional study of 830 laboratory-confirmed COVID-19 patients was performed, and classified into mild, severe, critical, and deceased outcomes. The TLR8 rs3764879-C/G, rs3764880-A/G, and rs3761624-A/G polymorphisms were genotyped. A logistic regression analysis was performed to determinate the association with COVID-19. A stratified analysis was by alleles was done with clinical and metabolic markets. In all outcomes, men presented the highest ferritin levels compared to women (P < 0.001). LDH levels were significantly different between sex in mild (P = 0.003), severe (P < 0.001) and deceased (P = 0.01) COVID-19 outcomes. The GGG haplotype showed an Odds Ratio of 1.55 (Interval Confidence 95% 1.05-2.32; P = 0.03) in men. Among patients with severe outcome, we observed that the carriers of the GGG haplotype had lower Ferritin, C-reactive protein and LDH levels than the CAA carriers (P < 0.01). After further stratified by sex, these associations were also seen in the male patients, except for D-dimer. Interestingly, among men patients, we could observe associations between TLR8 haplotypes and Ferritin (P < 0.001), D-dimer (P = 0.04), C-reactive protein, and Lactate dehydrogenase in mild (P = 0.04) group. Our results suggest that even though TLR8 haplotypes show a significant association with COVID-19 outcomes, they are associated with clinical markers in COVID-19 severity.

Analysis of Circulating miRNA Expression Profiles in Type 2 Diabetes Patients with Diabetic Foot Complications.

Type 2 diabetes mellitus (T2DM) is associated with various complications, including diabetic foot, which can lead to significant morbidity and mortality. Non-healing foot ulcers in diabetic patients are a major risk factor for infections and amputations. Despite conventional treatments, which have limited efficacy, there is a need for more effective therapies. MicroRNAs (miRs) are small non-coding RNAs that play a role in gene expression and have been implicated in diabetic wound healing. miR expression was analyzed through RT-qPCR in 41 diabetic foot Mexican patients and 50 controls. Diabetic foot patients showed significant increases in plasma levels of miR-17-5p (p = 0.001), miR-191-5p (p = 0.001), let-7e-5p (p = 0.001), and miR-33a-5p (p = 0.005) when compared to controls. Elevated levels of miR-17, miR-191, and miR-121 correlated with higher glucose levels in patients with diabetic foot ulcers (r = 0.30, p = 0.004; r = 0.25, p = 0.01; and r = 0.21, p = 0.05, respectively). Levels of miR-17 showed the highest diagnostic potential (AUC 0.903, p = 0.0001). These findings underscore the possible role of these miRs in developing diabetes complications. Our study suggests that high miR-17, miR-191, and miR-121 expression is strongly associated with higher glucose levels and the development of diabetic foot ulcers.

DNA Methylation of the IL-17A Gene Promoter Is Associated with Subclinical Atherosclerosis and Coronary Artery Disease: The Genetics of Atherosclerotic Disease Mexican Study.

The interleukin-17 (IL-17) has a crucial role during inflammation and has been associated with cardiovascular diseases, but its role in epigenetics is still poorly understood. Therefore, the aim of this study was to evaluate the DNA methylation status of the IL-17A gene promoter to establish whether it may represent a risk factor for subclinical atherosclerosis (SA) or clinical coronary artery disease (CAD). We included 38 patients with premature CAD (pCAD), 48 individuals with SA, and 43 healthy controls. Methylation in the CpG region of the IL-17A gene promoter was assessed via methylation-specific polymerase chain reaction (MSP). Individuals with SA showed increased methylation levels compared to healthy controls and pCAD patients, with p < 0.001 for both. Logistic regression analysis showed that high methylation levels represent a significant risk for SA (OR = 5.68, 95% CI = 2.38-14.03, p < 0.001). Moreover, low methylation levels of the IL-17A gene promoter DNA represent a risk for symptomatic pCAD when compared with SA patients (OR = 0.16, 95% CI = 0.06-0.41, p < 0.001). Our data suggest that the increased DNA methylation of the IL-17A gene promoter is a risk factor for SA but may be a protection factor for progression from SA to symptomatic CAD.

Helicobacter pylori infection and DNMT3a polymorphism are associated with the presence of premature coronary artery disease and subclinical atherosclerosis. Data from the GEA Mexican Study.

BACKGROUND: The association between H. pylori infection and coronary artery disease (CAD) is well-known. Alterations in DNA methylation in CAD have been reported, which can be induced by H. pylori through the DNA demethylases (DNMTs). The objective was to analyze the association and interaction of H. pylori infection and DMNT3a gene polymorphisms with premature CAD (pCAD) and subclinical atherosclerosis (SA). METHODS: The study included 561 patients with pCAD, 318 subjects with SA, and 599 healthy controls. Antibodies against H. pylori and DNMT3a rs13420827, rs752208, and rs1550117 polymorphisms were determined. RESULTS: The pCAD group presented the highest seroprevalence of H. pylori infection (87.7%) compared to the SA (74.5%, p = 1 × 10-6) and the control group (63.1%, p = 7 × 10-23). A significant association was observed between H. pylori infection and pCAD (OR = 2.729, p = 1.0 × 10-6). The rs13420827 polymorphism was associated with a high risk of H. pylori infection in the whole population (padditive = 0.009, pdominant = 0.018, and pcodominant2 = 0.013) and in individuals with SA (padditive = 0.003, pdominant = 0.020, precessive = 0.013, and pcodominant2 = 0.005). The coexistence of H. pylori infection and the rs13420827GG genotype increases the risk of pCAD (pinteraction = 1.1 × 10-5). CONCLUSIONS: According to the model adjusted for more confounding variables, H. pylori infection was associated with almost three times the risk of developing pCAD. The rs13420827G allele was associated with an increased risk of H. pylori infection in the whole population and in individuals with SA. Individuals in whom H. pylori infection and the rs13420827GG genotype coexist are at increased risk of pCAD.

Genome-Wide Association Study Identifies a Functional SIDT2 Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease.

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.

BLK and BANK1 variants and interactions are associated with susceptibility for primary Sjögren's syndrome and with some clinical features.

BLK and BANK1 in primary Sjögren's syndrome (pSS) have scarcely been evaluated and the results are inconclusive. The aim of our study was to determine whether single nucleotide variants (SNVs) located within BLK or BANK1 are associated with susceptibility, clinical and serological features, and smoking in pSS. BLK rs13277113A/G, BANK1 rs10516487G/A and rs3733197G/A were genotyped in 203 cases and 424 controls using a TaqMan® SNP genotyping assay. The BLK rs13277113A allele showed association with pSS under the allelic (OR 1.35, p = 0.02), and recessive (OR 1.83, p = 0.003) model, while, BANK1 rs3733197G/A showed association under the dominant model (OR 2.90, p = 0.043). Interactions between BANK1 and BLK genotypes also showed association (OR 2.36, p < 0.0001). In addition, BLK rs13277113A/G was associated with protection against arthritis and BANK1 rs10516487G/A with both arthritis and keratoconjunctivitis sicca, meanwhile, BANK1 rs3733197G/A was associated with smoking in patients with pSS. This is the first study to describe an association between BLK and susceptibility to pSS in a Latin-American population. Our data also shows a first evidence of association between interactions of BLK and BANK1 in pSS, and association of BLK and BANK1with arthritis, keratoconjunctivitis sicca and smoking in patients with pSS.

Are functional variants of the microRNA-146a gene associated with primary knee OA? Evidence in Mexican mestizo population.

MicroRNA-146a (miR-146a) is an inflammatory response regulator whose expression is deregulated in osteoarthritis (OA); variations in the miR-146a gene could affect OA risk. This study aimed to analyze the association between two functional variants of the miR-146a gene and primary knee OA in Mexican mestizo population. Methods and Results. A case-control study was conducted with cases defined as individuals aged ≥ 40 years with primary knee OA grade ≥ 2, according to the Kellgren-Lawrence system. Controls were volunteers with no primary knee OA with radiographic grade < 2. TaqMan allelic discrimination assays genotyped the rs2910164 and rs57095329. Allelic and genotypic frequencies, as well as the Hardy-Weinberg equilibrium (HWE), were calculated. The genetic association was tested under codominant, dominant, and recessive models. Non-conditional logistic regressions were carried out to estimate the association magnitude. We included 310 cases and 379 controls. Despite rs2910164 being in HWE, there was no association under codominant, dominant, and recessive models. In women with OA grade 2, the codominant model found a trend between the CC genotype and increased risk [OR (95% CI) 1.6 (0.7-3.5)]; the same trend was found in OA grade 4 in the codominant and recessive models [1.8 (0.6-5.4) and 2.0 (0.7-5.9)]. Conversely, in men with OA grade 4, the CC genotype tended to be associated with a lower risk in the codominant and recessive models [0.6 (0.1-6.0) and 0.5 (0.1-5.1)]. Conclusion. Our results show that miR-146a gene variants are not significantly associated with primary knee OA in Mexican mestizos.

Influence of COMT polymorphism in cognitive performance on dementia in community-dwelling elderly Mexican (SADEM study).

There is an inconsistent finding about the relationship of catechol-O-methyltransferase (COMT) with dementia susceptibility, as well as with cognitive impairment. To substantiate this, we examined COMT genotype effects in certain cognitive domains in dementia. To evaluate the effects of COMT Val158Met on cognitive performance, we used The Mini-Mental State Examination (MMSE), the cognitive subscale of the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) and the Syndrome Kurz Test (SKT). The results show COMT Val/Met, Val/Val genotype polymorphisms had a significant effect on cognition performance (OR = 1.75 (95 %CI 1.22-2.54) and (OR = 2.76 (95 %CI 1.78-4.26), p < 0.001), and with adjustment for all cognitive test scores together, Val/Val (OR = 4.98 (95 % CI 1.47-16.86) and Val/Met (OR = 3.62 (95 % CI 1.37-9.56) had effect. Our study allows us to understand the role of COMT in cognitive performance in dementia, as well as interaction with other known risk factors for this pathology. This data might help in developing new therapeutic targets for cognitive impairment, main symptom of dementia. Other risk genotypes or haplotypes should be evaluated to determine the association with cognitive decline in dementia.

Trp Fluorescence Redshift during HDL Apolipoprotein Denaturation Is Increased in Patients with Coronary Syndrome in Acute Phase: A New Assay to Evaluate HDL Stability.

High-density lipoproteins' (HDL) stability is a determinant of their residence times in plasma and consequently an important parameter that influences the beneficial properties of these lipoproteins. Since there are no accessible procedures for this purpose, here, we describe the methodological conditions to assess the stability of the HDL based on the redshift of the fluorescence spectrum of tryptophans contained in the structure of HDL-apolipoproteins during incubation with urea 8M. Along the HDL denaturation kinetics, the main variations of fluorescence were observed at the wavelengths of 330, 344, and 365 nm at room temperature. Therefore, HDL denaturation was estimated using the tryptophan (Trp)-ratio of fluorescence intensity (rfi) at such wavelengths. By setting 100% of the measurable denaturation at 26 h, HDL reached 50% after 8 h of incubation with urea. Then, for further analyses we determined the percentage of HDL denaturation at 8 h as an estimation of the stability of these lipoproteins. To explore the potential usefulness of this test, we analyzed the stability of HDL isolated from the plasma of 24 patients diagnosed with acute coronary syndrome (ACS). These HDL presented significantly higher percentages of denaturation (64.9% (58.7-78.4)) than HDLs of healthy individuals (23.3% (20.3-27.0)). These results indicate that HDL in ACS are less stable than in control subjects. Moreover, the percentage of denaturation of HDL correlated with body mass index and aspartate transaminase plasma activity. Furthermore, apo-I, HDL-cholesterol, HDL-triglycerides, and apo A-I-to-triglycerides ratio correlated with the percentage of HDL denaturation, suggesting that the lipoprotein composition is a main determinant of HDL stability. Finally, the percentage of HDL denaturation is the parameter that predicted the presence of ACS as determined by a machine learning procedure and logistic regression analysis. In conclusion, we established the methodological conditions to assess the stability of HDL by a fluorescence-based method that merits exploration in prospective studies for evaluating the coronary artery disease risk.

Epstein-Barr virus-induced gene 3 (EBI3) single nucleotide polymorphisms and their association with central obesity and risk factors for cardiovascular disease: The GEA study.

Obesity, a chronic low-grade inflammation metabolic abnormality, is related to high proinflammatory cytokines concentrations. Epstein-Barr virus-induced gene 3 (EBI3) encodes for the EBI3 beta subunit that constitutes interleukin (IL) 27 and 35. Our objective was to assess the association of three EBI3 single nucleotide polymorphisms (SNPs) with the presence of central obesity in a group of Mexican subjects. The rs428253, rs4740, and rs4905 EBI3 SNPs were genotyped in 1323 individuals (1092 central obese and 231 non-central obese). We also analyzed IL-6, IL-27, and IL-35 concentrations. Under different models, the rs4740 (OR = 0.384, Precessive = 0.010; OR = 0.404, Pcodominant 2 = 0.019) and rs4905 (OR = 0.380, Precessive = 0.009; OR = 0.404, Pcodominant 2 = 0.018) were related with a low risk of central obesity. In central obese subjects, the SNPs were related to lower risk of hypoalphalipoproteinemia (rs4740) and with high IL-6 concentrations (rs428253, rs4740, and rs4905), whereas in non-central obese individuals, the rs428253 was related with low risk of increased visceral abdominal fat and hypertriglyceridemia. Interleukin-6, IL-27 and IL-35 concentrations were similar in both groups and no relation was noticed with the studied genotypes. Our results suggest an association of EBI3 SNPs with a low risk of central obesity and with a few risk factors for cardiovascular disease in individuals with and without central obesity.

Microencapsulated Pomegranate Modifies the Composition and Function of High-Density Lipoproteins (HDL) in New Zealand Rabbits.

Previous studies demonstrated that pomegranate, which is a source of several bioactive molecules, induces modifications of high-density lipoproteins (HDL) lipid composition and functionality. However, it remains unclear whether the beneficial effects of pomegranate are related to improvement in the lipid components of HDL. Therefore, in this placebo-controlled study, we characterized the size and lipid composition of HDL subclasses and assessed the functionality of these lipoproteins after 30 days of supplementation with a pomegranate microencapsulated (MiPo) in New Zealand white rabbits. We observed a significant decrease in plasma cholesterol, triglycerides, and non-HDL sphingomyelin, as well as increases in HDL cholesterol and HDL phospholipids after supplementation with MiPo. Concomitantly, the triglycerides of the five HDL subclasses isolated by electrophoresis significantly decreased, whereas phospholipids, cholesterol, and sphingomyelin of HDL subclasses, as well as the HDL size distribution remained unchanged. Of particular interest, the triglycerides content of HDL, estimated by the triglycerides-to-phospholipids ratio, decreased significantly after MiPo supplementation. The modification on the lipid content after the supplementation was associated with an increased resistance of HDL to oxidation as determined by the conjugated dienes formation catalyzed by Cu2+. Accordingly, paraoxonase-1 (PON1) activity determined with phenylacetate as substrate increased after MiPo. The effect of HDL on endothelial function was analyzed by the response to increasing doses of acetylcholine of aorta rings co-incubated with the lipoproteins in an isolated organ bath. The HDL from rabbits that received placebo partially inhibited the endothelium-dependent vasodilation. In contrast, the negative effect of HDL on endothelial function was reverted by MiPo supplementation. These results show that the beneficial effects of pomegranate are mediated at least in part by improving the functionality of HDL, probably via the reduction of the content of triglycerides in these lipoproteins.

CORONARY ARTERY CALCIUM IS ASSOCIATED WITH LPA GENE VARIANT RS7765803-C IN MEXICAN MESTIZO POPULATION. THE GEA PROJECT.

BACKGROUND: Lipoprotein(a) [Lp(a)] levels are genetically determined; high levels are a risk factor for coronary disease, although their association with coronary artery calcium (CAC) is controversial. Objective: The objective of the study was to assess the association of LPA gene polymorphisms with CAC in a Mexican Mestizo population. METHODS: We included 1594 subjects 35-70 years old. Six polymorphisms of the LPA gene were analyzed. CAC score was determined by tomography and Lp(a) serum levels by immunonephelometry. The association of LPA polymorphism with CAC and Lp(a) was evaluated by logistic regression. RESULTS: The prevalence of Lp(a) ≥30 mg/dL was 10%, and of CAC >0 was 26.9%. Three polymorphisms were associated with high Lp(a) levels: rs10455872-G (p = 0.013), rs6907156-T (p = 0.021), and rs7765803-C (p = 0.001). Homozygotes (CC) for the rs7765803 variant compared with the G allele (CG + GG) carriers had higher Lp(a) levels (8.9 [3.3-23.9] vs. 4.9 [2.3-11.2] mg/dL; p = 0.015) and higher prevalence of CAC >0 (36.5% vs. 26.3%, p = 0.045) and were associated with CAC > 0 (odds ratio = 1.7, 95% confidence interval: 1.06-2.7; p < 0.026). The other polymorphisms were not associated with CAC. CONCLUSIONS: This is the first study to demonstrate in a Mexican Mestizo population that carriers of the rs7765803-C allele of LPA gene have 2.6 times greater risk for high Lp(a) values and 1.7 times higher risk for coronary artery disease.

THE BRANCHED-CHAIN AMINO ACID TRANSAMINASE 1 -23C/G POLYMORPHISM CONFERS PROTECTION AGAINST ACUTE CORONARY SYNDROME.

BACKGROUND: Previous studies have shown an association between polymorphisms of the BAT1-NF-κB inhibitor-like-1 (NFKBIL1)-LTA genomic region and susceptibility to myocardial infarction and acute coronary syndrome (ACS). OBJECTIVE: The objective of the study was to study the role of three polymorphisms in the BAT1, NFKBIL1, and LTA genes on the susceptibility or protection against ACS; we included a group of cases-controls from Central Mexico. METHODS: The BAT1 rs2239527C/G, NFKBIL1 rs2071592T/A, and LTA rs1800683G/A polymorphisms were genotyped using a 5' TaqMan assay in a group of 625 patients with ACS and 617 healthy controls. RESULTS: Under a recessive model, the BAT1 -23C/G (rs2239527) polymorphism showed an association with protection against ACS (odds ratio = 0.56, and p-corrected = 0.019). In contrast, the genotype and allele frequencies of the NFKBIL1 rs2071592T/A and LTA rs1800683G/A polymorphisms were similar between ACS patients and controls and no association was identified. CONCLUSION: Our data suggest an association between the BAT1 -23C/G polymorphism and protection against ACS in Mexican patients.

Interleukin 27 polymorphisms, their association with insulin resistance and their contribution to subclinical atherosclerosis. The GEA Mexican study.

Our previous data suggest that the heterodimeric interleukin-27 (IL-27) could participate in the developing of insulin resistance (IR). Our aim was to assess the participation of IL-27p28 gene single nucleotide polymorphisms (SNPs) as markers for IR, subclinical atherosclerosis (SA) and cardiovascular risk factors in a Mexican population. Five IL-27p28 SNPs (rs153109, rs40837, rs17855750, rs26528 and rs181206) were genotyped in 856 individuals with IR and 644 participants without IR. Under inheritance models adjusted for confounding factors, the rs153109A (0.78[0.64-0.94] Padditive = 0.008, 0.58[0.41-0.82] Precessive = 0.002, 0.57[0.38-0.83] Pcodominant2 = 0.004), rs26528T (0.78[0.64-0.94] Padditive = 0.008, 0.61[0.43-0.88] Precessive = 0.007, 0.57[0.38-0.84] Pcodominant2 = 0.004) and rs40837A (0.76[0.63-0.92] Padditive = 0.004; 0.60[0.42-0.86] Precessive = 0.005; 0.54[0.37-0.80] Pcodominant2 = 0.002) alleles were related with a decreased risk of IR. Moreover, AAATA haplotype that contains the protector alleles was related with 17% lower risk of presenting IR (0.83 [0.71-0.98], P = 0.023). After adjusting for potential confounding variables, IL-27p28 SNPs were not associated with SA. However, some SNPs were associated with hypertension (rs26528 and rs40837) and increased total abdominal fat (rs17855750) in non-IR individuals, whereas in IR subjects we observed an association of rs26528 and rs40837 with hypoadiponectinemia. Our evidence suggests that rs40837A, rs153109A, and rs26528T alleles could be envisaged as protective markers for IR. Some polymorphisms showed an association with hypertension, low adiponectin levels, and increased total abdominal fat.

miR-196a2 (rs11614913) polymorphism is associated with coronary artery disease, but not with in-stent coronary restenosis.

OBJECTIVE: The aim of the study was to evaluate the association of miRNA-146a G/C (rs2910164), and miRNA-196a2 C/T (rs11614913) polymorphisms with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent. MATERIALS AND METHODS: The polymorphisms were determined in 218 patients with CAD who underwent coronary artery stenting (66 with restenosis and 152 without restenosis) and 611 healthy controls using 5' exonuclease TaqMan assays. RESULTS: The distribution of both polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under co-dominant, dominant and additive genetic models, the T allele of the miRNA-196a2 C/T (rs11614913) polymorphism was associated with increased risk of CAD (OR = 2.18, Pco-dom = 0.006, OR = 1.86, Pdom = 0.002, and OR = 1.52, Padd = 0.002, respectively). All models were adjusted for age, type 2 diabetes mellitus, dyslipidemia, hypertension and smoking habit. The "GT" haplotype was associated with increased risk of developing CAD (OR = 1.36, P = 0.046). CONCLUSIONS: Our data suggests that the T allele of the miRNA-196a2 C/T (rs11614913) polymorphism is associated with the risk of developing CAD, but no association with restenosis was observed.

Atorvastatin and Fenofibrate Increase the Content of Unsaturated Acyl Chains in HDL and Modify In Vivo Kinetics of HDL-Cholesteryl Esters in New Zealand White Rabbits.

Previous studies demonstrated modifications of high-density lipoproteins (HDL) structure and apolipoprotein (apo) A-I catabolism induced by the atorvastatin and fenofibrate combination. However, it remains unknown whether such structural and metabolic changes of HDL were related to an improvement of the HDL-cholesteryl esters (HDL-CE) metabolism. Therefore, we determined the structure of HDL and performed kinetic studies of HDL-CE radiolabeled with tritium in rabbits treated with atorvastatin, fenofibrate, and a combination of both drugs. The atorvastatin and fenofibrate combination increased the HDL size and the cholesterol and phospholipid plasma concentrations of the largest HDL subclasses. Moreover, the relative amount of unsaturated fatty acids contained in HDL increased, in detriment of saturated fatty acids as determined by gas chromatography-mass spectrometry. The transfers of cholesteryl esters (CE) from HDL to very low-density lipoproteins/low-density lipoproteins (VLDL/LDL) and vice versa were enhanced with atorvastatin, alone or in combination. Moreover, the direct elimination of CE from plasma via VLDL/LDL decreased with fenofibrate, whereas the direct elimination of CE via HDL augmented with the combination treatment. Taken together, the rise of unsaturated fatty acid content and the size increase of HDL, suggest that atorvastatin and fenofibrate induce more fluid HDL particles, which in turn favor an enhanced CE exchange between HDL and VLDL/LDL. Our results contribute to a better understanding of the relationship between the structure and function of HDL during the use of anti-dyslipidemic drugs.

The rs10455872-G allele of the LPA gene is associated with high lipoprotein(a) levels and increased aortic valve calcium in a Mexican adult population.

Polymorphisms in the LPA gene have been associated with aortic valve calcification (AVC). There are wide differences in the allelic frequencies, Lp(a) levels, and the association with AVC among ethnic groups. The aim of this study was to determine the association of the LPA gene polymorphisms with Lp(a) levels and risk of developing AVC, in Mexican-Mestizos population. Six LPA polymorphisms (rs10455872, rs7765803, rs6907156, rs1321195, rs12212807 and rs6919346) were genotyped by TaqMan assays in 1,265 individuals without premature coronary artery disease. The presence of AVC was determined by computed tomography. The association of the LPA polymorphisms with AVC, Lp(a), and other cardiovascular risk factors (CVRF) was evaluated using logistic regression analysis. Compared to AA genotype, subjects with AG+GG genotypes had high prevalence of Lp(a) ≥ 30 mg/dL (7.1% vs. 23.7%, p<0.001) and AVC (19.0% vs. 29.4%, p=0.007). In a model adjusted for several CVRF, the LPA rs10455872-G allele was associated with high Lp(a) levels and AVC. Carriers of G allele had a high risk of Lp(a) ≥ 30 mg/dL (OR= 3.86, CI 95%: 2.2 - 6.7, p=0.001) and AVC (OR= 2.54, CI 95%: 1.56 - 4.14, p=0.001), independently of other CVRF. In this population, carriers of rs10455872-G allele had 3.86 and 2.54 higher risk of Lp(a) ≥ 30 mg/dL or presence of AVC, respectively.

POLYMORPHISMS IN ß-ADRENERGIC RECEPTORS ARE ASSOCIATED WITH INCREASED RISK TO HAVE A POSITIVE HEAD-UP TILT TABLE TEST IN PATIENTS WITH VASOVAGAL SYNCOPE.

BACKGROUND: Vasovagal syncope (VVS) is a frequent clinical condition in which a genetic background seems to be implicated. Considering that the adrenergic receptors (ARs) may play a role in VVS, the present study has as principal aim to determine if the α- and ß-AR (ADRA and ADRB) gene polymorphisms are associated with an increased risk to have a positive head-up tilt table (HUTT) test in patients with VVS. Methods: Nine polymorphisms in the ADRA1A (rs1048101, rs1383914, rs574584, and rs573542), ADRB1 (rs1801252 and rs1801253), ADRB2 (rs1042713 and rs1042714), and ADRB3 (rs4994) genes were analyzed using the 5' exonuclease TaqMan genotyping assay in a group of 134 patients with VVS. RESULTS: Under different models, the rs1801252 (OR = 8.63, 95% CI: 0.95-78.72, Precessive = 0.02), rs1042713 (OR = 1.94, 95% CI: 1.02-3.66, Padditive = 0.04), and rs4994 (OR = 2.46, 95% CI: 1.01-6.01, Pdominant = 0.042 and OR = 2.62, 95% CI: 1.04-6.63, Pover-dominant = 0.03) polymorphisms were associated with increased risk for a positive HUTT. All models were adjusted for statistically significant covariates. CONCLUSION: These results suggest that some polymorphisms of the ß-AR genes could contribute to a positive tilt test in patients with VVS.