Low HDL-C/ApoA-I index is associated with cardiometabolic risk factors and coronary artery calcium: a sub-analysis of the genetics of atherosclerotic disease (GEA) study.

BACKGROUND: The high-density lipoprotein cholesterol to apolipoprotein A-I index (HDL-C/ApoA-I) may be practical and useful in clinical practice as a marker of atherosclerosis. This study aimed to investigate the association between the HDL-C/ApoA-I index with cardiometabolic risk factors and subclinical atherosclerosis. METHODS: In this cross-sectional sub-analysis of the GEA study, 1,363 individuals, women (51.3%) and men (48.7%) between 20 and 75 years old, without coronary heart disease or diabetes mellitus were included. We defined an adverse cardiometabolic profile as excess adipose tissue metrics, non-alcoholic liver fat measured by non-contrasted tomography, metabolic syndrome, dyslipidemias, and insulin resistance. The population was stratified by quartiles of the HDL-C/Apo-AI index, and its dose-relationship associations were analysed using Tobit regression, binomial, and multinomial logistic regression analysis. RESULTS: Body mass index, visceral and pericardial fat, metabolic syndrome, fatty liver, high blood pressure, and CAC were inversely associated with the HDL-C/ApoA-I index. The CAC > 0 prevalence was higher in quartile 1 (29.2%) than in the last quartile (22%) of HDL-C/ApoA-I index (p = 0.035). The probability of having CAC > 0 was higher when the HDL-C/ApoA-I index was less than 0.28 (p < 0.001). This association was independent of classical coronary risk factors, visceral and pericardial fat measurements. CONCLUSION: The HDL-C/ApoA-I index is inversely associated with an adverse cardiometabolic profile and CAC score, making it a potentially useful and practical biomarker of coronary atherosclerosis. Overall, these findings suggest that the HDL-C/ApoA-I index could be useful for evaluating the probability of having higher cardiometabolic risk factors and subclinical atherosclerosis in adults without CAD.

Association of the rs17574 DPP4 Polymorphism with Premature Coronary Artery Disease in Diabetic Patients: Results from the Cohort of the GEA Mexican Study.

Previously, it has been reported that hypoalphalipoproteinemia (HA) is associated with rs17574 DDP4 polymorphism. Considering that in diabetic patients, HA is often present and is a risk factor for premature coronary artery disease (pCAD), the study aimed to evaluate the association of this polymorphism with pCAD in diabetic individuals. We genotyped the rs17574 polymorphism in 405 pCAD patients with T2DM, 736 without T2DM, and 852 normoglycemic individuals without pCAD and T2DM as controls. Serum DPP4 concentration was available in 818 controls, 669 pCAD without T2DM, and 339 pCAD with T2DM. The rs17574 polymorphism was associated with lower risk of pCAD (padditive = 0.007; pdominant = 0.003, pheterozygote = 0.003, pcodominant1 = 0.003). In pCAD with T2DM patients, DPP4 levels were lower when compared with controls (p < 0.001). In the whole sample, individuals with the rs17574 GG genotype have the lowest protein levels compared with AG and AA (p = 0.039) carriers. However, when the same analysis was repeated separately in all groups, a significant difference was observed in the pCAD with T2DM patients; carriers of the GG genotype had the lowest protein levels compared with AG and AA (p = 0.037) genotypes. Our results suggest that in diabetic patients, the rs17574G DPP4 allele could be considered as a protective genetic marker for pCAD. DPP4 concentrations were lower in the diabetic pCAD patients, and the rs17574GG carriers had the lowest protein levels.

The rs12617336 and rs17574 Dipeptidyl Peptidase-4 Polymorphisms Are Associated With Hypoalphalipoproteinemia and Dipeptidyl Peptidase-4 Serum Levels: A Case-Control Study of the Genetics of Atherosclerotic Disease (GEA) Cohort.

Dipeptidyl peptidase-4 (DPP4) can influence lipid homeostasis and atherosclerosis progression. We aimed to assess the association of DPP4 gene polymorphisms with hypoalphalipoproteinemia and DPP4 serum levels, in a cohort of Mexican individuals. Five DPP4 polymorphisms (rs12617336, rs12617656, rs1558957, and rs3788979, and rs17574) were genotyped in 748 participants with and 745 without hypoalphalipoproteinemia. The associations were evaluated using logistic regression analyses. Under inheritance models adjusted for confounding variables, the rs12617336 (OR = 0.22, P heterozygote = 0.001) and rs17574 (OR = 0.78, P additive = 0.022; OR = 0.73, P dominant = 0.012; OR = 0.73, P heterozygote = 0.017; OR = 0.72, P codominant 1 = 0.014) minor alleles were associated with a low risk of hypoalphalipoproteinemia. After the correction for multiple comparisons, the associations were marginal except the association of the rs12617336 that remaining significant. Additionally, both DPP4 minor alleles were associated with protection for the presence of insulin resistance (IR) (OR = 0.17, P heterozygote = 0.019 for rs12617336 and OR = 0.75, P additive = 0.049 for rs17574). The rs12617336 minor allele was also associated with a low risk of hyperinsulinemia (OR = 0.11, P heterozygote = 0.006). Differences in DPP4 levels were observed in individuals with rs17574 genotypes, the rs17574 GG genotype individuals had the lowest levels. Our data suggest that rs12617336 and rs17574 DPP4 minor alleles could be envisaged as protective genetic markers for hypoalphalipoproteinemia, IR, and hyperinsulinemia. The rs17574 GG genotype was associated with the lowest DPP4 levels.

Metabolic control achievement in a population with premature coronary artery disease: results of the genetics of atherosclerotic disease study.

BACKGROUND AND AIMS: To the best of our knowledge, no studies have investigated the metabolic control of patients with premature coronary artery disease (CAD). The present study analyzes the metabolic control, defined as the simultaneous target in blood pressure, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and hemoglobin A1c, as well as the factors associated with its achievement in patients with premature CAD. METHODS: The study included 1206 patients with CAD diagnosed before the age of 55 and 65 years in men and women, respectively. Sociodemographic, clinical and biochemical data were collected to know the prevalence of cardiovascular risk factors, including individual components of metabolic control plus smoking cessation and body mass index (BMI) <25 kg/m2. Non-strict and strict targets were used to evaluate metabolic control. RESULTS: Participants were 54 ± 8 years old, 19.7% were women and had a median CAD evolution of 2.4 years. Non-strict and strict metabolic control was achieved by 18.4% and 6.2% of patients, respectively. Moreover, 79.8% and 67.6% met a composite of three or more cardiovascular risk factor goals using both criteria. BMI <25 kg/m2 was independently associated with 1.734 (95% confidence interval: 1.207-2.492) and 2.541 (95% confidence interval: 1.608-4.014) higher probabilities to meet non-strict or strict metabolic control. CONCLUSION: Our results show that 18.4% and 6.2% of subjects with premature CAD achieved non-strict and strict metabolic control, respectively. BMI <25 kg/m2 was found to be associated with the achievement of metabolic control. Multidisciplinary strategies including healthy lifestyle changes and pharmacological therapies could decrease the socioeconomic and clinical impact of premature CAD.

Chia (Salvia hispanica)-supplemented diet ameliorates non-alcoholic fatty liver disease and its metabolic abnormalities in humans.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a public health problem lacking an approved pharmacological treatment. Omega-3 fatty acids have shown to reverse NAFLD. Chia is a seed rich in α-linolenic acid (ALA), antioxidants, and fiber; therefore, it could be useful to treat NAFLD. METHODS: In a single arm experimental design study, the effect of 25 g/day of milled chia was assessed in 25 patients with NAFLD. After two weeks of dietary stabilization (basal condition) and eight weeks of a chia-supplemented isocaloric diet, liver:spleen attenuation index and visceral abdominal fat (VAF) were measured by computed tomography. Lipids, lipoproteins, free fatty acids (FFA), and ALA plasma concentrations were also determined. RESULTS: Dietary chia supplementation induced an increase in plasma ALA concentration (75%) and dietary fiber (55%) consumption. After chia supplementation, VAF (9%), body weight (1.4%), total cholesterol (2.5%), non-high density lipoprotein cholesterol (3.2%), and circulating FFA (8%) decreased. Furthermore, NAFLD regressed in 52% of the treated patients (P < 0.05 for all). CONCLUSIONS: The results of the present study show that 25 g/day of milled chia ameliorates NAFLD. Chia is an accessible vegetal source of omega-3 fatty acids, antioxidants, and fiber, which could have the potential to prevent metabolic abnormalities in NAFLD patients. Considering that there is no pharmacological treatment approved for NAFLD, the findings of the present study suggest that a chia-supplemented diet could be an innovative alternative to control this disease. RETROSPECTIVELY REGISTERED: https://clinicaltrials.gov/show/NCT03942822.

Common Variants in IL-20 Gene are Associated with Subclinical Atherosclerosis, Cardiovascular Risk Factors and IL-20 Levels in the Cohort of the Genetics of Atherosclerotic Disease (GEA) Mexican Study.

Inflammation has been involved in the development of atherosclerosis, type 2 diabetes mellitus, insulin resistance, and obesity. Interleukin 20 is a pro-inflammatory cytokine encoded by a polymorphic gene located in chromosome 1. The aim of the study was to evaluate the association of two IL-20 polymorphisms (rs1400986 and rs1518108) with subclinical atherosclerosis (SA), cardiovascular risk factors and IL-20 levels in a cohort of Mexican individuals. The polymorphisms were determined in 274 individuals with SA and 672 controls. Under different models, rs1400986 (OR = 0.51, Pcodominant1 = 0.0001; OR = 0.36, Pcodominant2 = 0.014; OR = 0.49, Pdominant = 0.0001 and OR = 0.55, Padditive = 0.0001) and rs1518108 (OR = 0.62, Pcodominant2 = 0.048 and OR = 0.79, Padditive = 0.048) were associated with a lower risk of SA. These polymorphisms were associated with cardiovascular risk factors in individuals with SA and controls. Controls with the rs1400986 TT genotype presented high levels of IL-20 (p = 0.031). In individuals with the rs1400986 CC genotype, we observed a negative correlation between IL-20 levels and total abdominal tissue (TAT), visceral abdominal tissue (VAT) and subcutaneous abdominal tissue (SAT). Our results indicate that the IL-20 rs1400986 and rs1518108 polymorphisms were associated with decreased risk of developing SA and with some cardiovascular risk factors in individuals with SA and healthy controls. Negative correlation between BMI and VAT/SAT ratio in individuals with rs1400986 CC genotype and among IL-20 levels and TAT, VAT and SAT was observed.

Association of Adiponectin with Subclinical Atherosclerosis in a Mexican-Mestizo Population.

BACKGROUND AND AIMS: Adiponectin (ADPN) is a cardioprotective adipocytokine, and its association with atherosclerosis development is controversial. The aim of the present study was to assess the association of low ADPN plasma levels with the presence of subclinical atherosclerosis in a Mexican-Mestizo population without history of diabetes or coronary artery disease (CAD). METHODS: In 818 subjects (53.4 ± 9 years; 49.9% women) anthropometry, subcutaneous and visceral adipose tissue, lipids, glucose, C-reactive protein (CRP), insulin, and ADPN levels were determined. Carotid artery intima-media thickness (CIMT) was measured with ultrasound in B mode and the sex-age specific value higher than 75th percentile defined the presence of subclinical atherosclerosis. Low ADPN was considered when plasma concentrations were lower than 25th percentile (8.67 µg/mL in women, 5.30 µg/mL in men). RESULTS: Prevalence of low ADPN was 43.6% (42.9% in women and 44.4% in men; p = 0.66) and elevated CIMT (eCIMT) was 23.8% (25.8% in women and 21.9% in men; p = 0.184). In addition to their higher prevalence of low ADPN, subjects with eCIMT had higher values of body mass index, blood pressure, total cholesterol, triglycerides, glucose, insulin, and CRP. Multivariate analysis revealed that independent of these factors, low ADPN was associated with eCIMT (OR [95% CI]: 1.505 [1.051-2.153]). CONCLUSIONS: In the studied population, low adiponectin concentrations are associated with a higher prevalence of subclinical atherosclerosis, independent of traditional cardiovascular risk factors.

Insulin Resistance in Adipose Tissue but Not in Liver Is Associated with Aortic Valve Calcification.

Background. Insulin resistance is involved in the pathogenesis of cardiovascular disease, but its relationship with cardiovascular calcification has yielded conflicting results. The purpose of the present study was to investigate the role of hepatic and adipose tissue insulin resistance on the presence of coronary artery (CAC > 0) and aortic valve calcification (AVC > 0). Methods. In 1201 subjects (52% women, 53.6 ± 9.3 years old) without familiar and personal history of coronary heart disease, CAC and AVC were assessed by multidetector-computed tomography. Cardiovascular risk factors were documented and lipid profile, inflammation markers, glucose, insulin, and free fatty acids were measured. Hepatic insulin resistance (HOMA-IR) and adipose tissue insulin resistance (Adipo-IR) indices were calculated. Results. There was a significant relationship between HOMA-IR and Adipo-IR indices (r = 0.758, p < 0.001). Participants in the highest quartiles of HOMA-IR and Adipo-IR indices had a more adverse cardiovascular profile and higher prevalence of CAC > 0 and AVC > 0. After full adjustment, subjects in the highest quartile of Adipo-IR index had higher odds of AVC > 0 (OR: 2.40; 95% CI: 1.30-4.43), as compared to those in the lowest quartile. Conclusions. Adipo-IR was independently associated with AVC > 0. This suggests that abnormal adipose tissue function favors insulin resistance that may promote the development and progression of AVC.

Dietary fat and carbohydrate modulate the effect of the ATP-binding cassette A1 (ABCA1) R230C variant on metabolic risk parameters in premenopausal women from the Genetics of Atherosclerotic Disease (GEA) Study.

BACKGROUND: Although the R230C-ATP-binding cassette A1 (ABCA1) variant has been consistently associated with HDL-C levels, its association with diabetes and other metabolic parameters is unclear. Estrogen and dietary factors are known to regulate ABCA1 expression in different tissues. Thus, we aimed to explore whether gender, menopausal status and macronutrient proportions of diet modulate the effect of this variant on various metabolic parameters. METHODS: One thousand five hundred ninety-eight controls from the GEA study were included (787 men, 363 premenopausal women and 448 menopausal women), previously assessed for anthropometric and biochemical measurements and visceral to subcutaneous abdominal fat (VAT/SAT) ratio on computed tomography. Taqman assays were performed for genotyping. Diet macronutrient proportions were assessed using a food frequency questionnaire validated for the Mexican population. Multivariate regression models were constructed to assess the interaction between the proportion of dietary macronutrients and the R230C polymorphism on metabolic parameters. RESULTS: All significant interactions were observed in premenopausal women. Those carrying the risk allele and consuming higher carbohydrate/lower fat diets showed an unfavorable metabolic pattern [lower HDL-C and adiponectin levels, higher VAT/SAT ratio, homeostasis model assessment for insulin resistance (HOMA-IR) and higher gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels]. Conversely, premenopausal women carrying the risk allele and consuming lower carbohydrate/higher fat diets showed a more favorable metabolic pattern (higher HDL-C and adiponectin levels, and lower VAT/SAT ratio, HOMA-IR, GGT and ALP levels). CONCLUSION: This is the first study reporting a gender-specific interaction between ABCA1/R230C variant and dietary carbohydrate and fat percentages affecting VAT/SAT ratio, GGT, ALP, adiponectin levels and HOMA index. Our study confirmed the previously reported gender-specific ABCA1-diet interaction affecting HDL-C levels observed in an independent study. Our results show how gene-environment interactions may help further understand how certain gene variants confer metabolic risk, and may provide information useful to design diet intervention studies.

The ACE I/D polymorphism is associated with nitric oxide metabolite and blood pressure levels in healthy Mexican men / El polimorfismo I/D de la ECA se asocia con los niveles de metabolitos óxido nítrico y de presión arterial en hombres mexicanos sanos

The I/D insertion/deletion polymorphism of the angiotensin-converting enzyme has been related to hypertension. This polymorphism also seems to have gender related implications. Angiotensin II contributes to the production and release of oxygen reactive species that react with nitric oxide, inactivating its effects. Objective: To establish whether the ACE I/D polymorphism correlates with nitric oxide plasma metabolites in healthy men and women. Methods: Among 896 subjects between 18 and 30 years of age range, 138 fulfilled inclusion criteria. The polymorphism was identified by polymerase chain reaction, and blood nitric oxide metabolites were analyzed following the method described by Bryan. Results: Both systolic and diastolic arterial pressures were higher in men than in women (107/67 vs. 101/65 mmHg, p < 0.001). In terms of the ACE gene, there were differences in the concentration of nitric oxide metabolites in men with the I/D and D/D genotypes when compared to carriers of the I/I genotype (33.55 and 29.23 vs. 53.74 pmol/ml; p = <0.05), while there were no significant differences in women when compared by genotype. Men with the D/D genotype had higher systolic blood pressure than I/D carriers (111 vs. 104 mmHg, p < 0.05). We observed no arterial blood pressure differences in women when grouped by ACE genotype. Conclusions: The ACE D/D genotype was associated with nitric oxide metabolite levels and systolic blood pressure in clinically healthy men while it had no effect in women.

El polimorfismo inserción/deleción del gen de la enzima convertidora de la angiotensina (polimorfismo I/D de la ECA), se relaciona con hipertensión y sus efectos podrían estar asociados al género. La angiotensina II contribuye a la producción y liberación de especies reactivas de oxígeno, que reaccionan con el óxido nítrico (ON), inactivándolo. Objetivo: Conocer si existen diferencias en la concentración de metabolitos de ON en hombres y mujeres sanos que puedan estar influidas por el polimorfismo I/D de la ECA. Métodos: De 896 sujetos de entre 18 y 30 años, 138 cumplieron los criterios de inclusión. El polimorfismo fue identificado usando reacción en cadena de la polimerasa y los metabolitos de ON fueron analizados en sangre usando el método de Bryan. Resultados: Las presiones sistólica y diastólica fueron más elevadas en hombres que en mujeres (107/67 vs. 101/65 mmHg p < 0.001). En relación con el genotipo, existieron diferencias significativas en la concentración de metabolitos de ON en los hombres con genotipos I/D, D/D comparados con los portadores del genotipo I/I (33.55 y 29.23 vs. 53.74 pmol/ml, respectivamente; p = <0.05). No hubo diferencias significativas en las mujeres portadoras de los diferentes genotipos. Respecto a la presión arterial, los hombres con genotipo D/D presentaron mayor presión arterial sistólica que aquellos portadores de I/D (111 vs. 104 mmHg, p < 0.05). En las mujeres no se observaron diferencias significativas comparándolas por genotipo. Conclusiones: El genotipo D/D de la ECA está asociado con el nivel de metabolitos de ON en plasma y la presión arterial sistólica en hombres clínicamente sanos; esta asociación no se observa en las mujeres.

The ACE I/D polymorphism is associated with nitric oxide metabolite and blood pressure levels in healthy Mexican men.

UNLABELLED: The I/D insertion/deletion polymorphism of the angiotensin-converting enzyme has been related to hypertension. This polymorphism also seems to have gender related implications. Angiotensin II contributes to the production and release of oxygen reactive species that react with nitric oxide, inactivating its effects. OBJECTIVE: To establish whether the ACE I/D polymorphism correlates with nitric oxide plasma metabolites in healthy men and women. METHODS: Among 896 subjects between 18 and 30 years of age range, 138 fulfilled inclusion criteria. The polymorphism was identified by polymerase chain reaction, and blood nitric oxide metabolites were analyzed following the method described by Bryan. RESULTS: Both systolic and diastolic arterial pressures were higher in men than in women (107/67 vs. 101/65 mm Hg, p<0.001). In terms of the ACE gene, there were differences in the concentration of nitric oxide metabolites in men with the I/D and D/D genotypes when compared to carriers of the I/I genotype (33.55 and 29.23 vs. 53.74 pmol/ml; p=<0.05), while there were no significant differences in women when compared by genotype. Men with the D/D genotype had higher systolic blood pressure than I/D carriers (111 vs. 104 mm Hg, p<0.05). We observed no arterial blood pressure differences in women when grouped by ACE genotype. CONCLUSIONS: The ACE D/D genotype was associated with nitric oxide metabolite levels and systolic blood pressure in clinically healthy men while it had no effect in women.

Association of fatty liver with cardiovascular risk factors and subclinical atherosclerosis in a Mexican population.

INTRODUCTION: Individuals with fatty liver (FL) have an increased risk of coronary artery disease (CAD) probably due to its association with cardiometabolic risk factors (CMRF). OBJECTIVE: To know the prevalence of FL and analyze its association with CMRF and subclinical atherosclerosis, in a sample of Mexican Mestizo population. MATERIAL AND METHODS: This study included 846 subjects from the Genetic of Atherosclerosis Disease (GEA) study (53 ± 9 years, 50.7% women) without diabetes and no personal or family history of premature CAD. Blood samples were taken for measurements of lipids profile, uric acid, and insulin. The presence of FL was identified by computed tomography. Carotid intima media thickness (CIMT) was measured by B mode ultrasound, using the > 75 percentile as cutoff value to define subclinical atherosclerosis. RESULTS: The general prevalence of FL was 32.4%. In men, FL was associated with hyperuricemia, whereas in women, hyperuricemia, low level of high density lipoprotein cholesterol, and metabolic syndrome were the factors associated with this hepatic alteration. In women, FL was associated with a 66% higher probability of having high CIMT, independently of age, hypertension, dyslipidemia, and waist circumference, but not of HOMA-IR. CONCLUSIONS: In women, FL was associated with the presence of subclinical atherosclerosis independently of traditional CMRF. Our study suggests that, in women, insulin resistance could be a mediator of metabolic abnormalities and of subclinical atherosclerosis.

The ABCA1 gene R230C variant is associated with decreased risk of premature coronary artery disease: the genetics of atherosclerotic disease (GEA) study.

BACKGROUND: ABCA1 genetic variation is known to play a role in HDL-C levels and various studies have also implicated ABCA1 variation in cardiovascular risk. The functional ABCA1/R230C variant is frequent in the Mexican population and has been consistently associated with low HDL-C concentrations. Although it has been associated with other cardiovascular risk factors such as obesity and type 2 diabetes mellitus, it is not known whether it is associated with coronary artery disease (CAD). AIM: The purpose of the study was to analyze whether the ABCA1/R230C variant is associated with premature CAD in a case-control association study (GEA or Genetics of Atherosclerotic Disease), and to explore whether BMI modulates the effect of the C230 allele on other metabolic traits using a population-based design. RESULTS: The C230 allele was significantly associated with both lower HDL-C levels and a lower risk of premature CAD as compared to controls (OR = 0.566; P(add) = 1.499×10(-5)). In addition, BMI modulated the effect of R230C on body fat distribution, as the correlation between BMI and visceral to subcutaneous adipose tissue (a metric of the propensity to store fat viscerally as compared to subcutaneously) was negative in RR homozygous individuals, but positive in premenopausal women bearing the C230 allele, with a statistically significant interaction (P = 0.005). BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036). CONCLUSION: This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. C230 was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C interactions were observed for different metabolic traits. These interactions may help explain inconsistencies in associations, and underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise and other environmental factors.