KCNQ1 p.D446E Variant as a Risk Allele for Arrhythmogenic Phenotypes: Electrophysiological Characterization Reveals a Complex Phenotype Affecting the Slow Delayed Rectifier Potassium Current (IKs) Voltage Dependence by Causing a Hyperpolarizing Shift and a Lack of Response to Protein Kinase A Activation.

Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, 30-fold more frequent than in public databases. We thus characterized the biophysical phenotypes of wildtype and mutant IKs co-expressing these alleles with the ß-subunit minK in HEK293 cells. KCNQ1 p.446E homozygosity significantly shifted IKs voltage dependence to hyperpolarizing potentials in basal conditions (gain of function) but failed to shift voltage dependence to hyperpolarizing potentials (loss of function) in the presence of 8Br-cAMP, a protein kinase A activator. Basal IKs activation kinetics did not differ among genotypes, but in response to 8Br-cAMP, IKs 446 E/E (homozygous) activation kinetics were slower at the most positive potentials. Protein modeling predicted a slower transition of the 446E Kv7.1 tetrameric channel to the stabilized open state. In conclusion, biophysical and modelling evidence shows that the KCNQ1 p.D446E variant has complex functional consequences including both gain and loss of function, suggesting a contribution to the pathogenesis of arrhythmogenic phenotypes as a functional risk allele.

A metagenomic study identifies a Prevotella copri enriched microbial profile associated with non-alcoholic steatohepatitis in subjects with obesity.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease. Increasing evidence indicates that the gut microbiota can play an important role in the pathophysiology of NAFLD. Recently, several studies have tested the predictive value of gut microbiome profiles in NAFLD progression; however, comparisons of microbial signatures in NAFLD or non-alcoholic steatohepatitis (NASH) have produced discrepant results, possibly due to ethnic and environmental factors. Thus, we aimed to characterize the gut metagenome composition of patients with fatty liver disease. METHODS: Gut microbiome of 45 well-characterized patients with obesity and biopsy-proven NAFLD was evaluated using shot-gun sequencing: 11 non-alcoholic fatty liver controls (non-NAFL), 11 with fatty liver, and 23 with NASH. RESULTS: Our study showed that Parabacteroides distasonis and Alistipes putredenis were enriched in fatty liver but not in NASH patients. Notably, in a hierarchical clustering analysis, microbial profiles were differentially distributed among groups, and membership to a Prevotella copri dominant cluster was associated with a greater risk of developing NASH. Functional analyses showed that although no differences in LPS biosynthesis pathways were observed, Prevotella-dominant subjects had higher circulating levels of LPS and a lower abundance of pathways encoding butyrate production. CONCLUSIONS: Our findings suggest that a Prevotella copri dominant bacterial community is associated with a greater risk for NAFLD disease progression, probably linked to higher intestinal permeability and lower capacity for butyrate production.

Effect of the Melanocortin 4-Receptor Ile269Asn Mutation on Weight Loss Response to Dietary, Phentermine and Bariatric Surgery Interventions.

The loss of function melanocortin 4-receptor (MC4R) Ile269Asn mutation has been proposed as one of the most important genetic contributors to obesity in the Mexican population. However, whether patients bearing this mutation respond differently to weight loss treatments is unknown. We tested the association of this mutation with obesity in 1683 Mexican adults, and compared the response of mutation carriers and non-carriers to three different weight loss interventions: dietary restriction intervention, phentermine 30 mg/day treatment, and Roux-en-Y gastric bypass (RYGB) surgery. The Ile269Asn mutation was associated with obesity [OR = 3.8, 95% CI (1.5-9.7), p = 0.005]. Regarding interventions, in the dietary restriction group only two patients were MC4R Ile269Asn mutation carriers. After 1 month of treatment, both mutation carriers lost weight: -4.0 kg (-2.9%) in patient 1, and -1.8 kg (-1.5%) in patient 2; similar to the mean weight loss observed in six non-carrier subjects (-2.9 kg; -2.8%). Phentermine treatment produced similar weight loss in six carriers (-12.7 kg; 15.5%) and 18 non-carriers (-11.3 kg; 13.6%) after 6 months of pharmacological treatment. RYGB also caused similar weight loss in seven carriers (29.9%) and 24 non-carriers (27.8%), 6 months after surgery. Our findings suggest that while the presence of a single MC4R loss of function Ile269Asn allele significantly increases obesity risk, the presence of at least one functional MC4R allele seems sufficient to allow short-term weight loss in response to dietary restriction, phentermine and RYGB. Thus, these three different interventions may be useful for the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.

Association of Gut Microbiota with Atherogenic Dyslipidemia, and Its Impact on Serum Lipid Levels after Bariatric Surgery.

Gut microbiota has been suggested to modulate circulating lipids. However, the relationship between the gut microbiota and atherogenic dyslipidemia (AD), defined as the presence of both low HDL-C and hypertriglyceridemia, is not fully understood. Moreover, because obesity is among the main causes of secondary AD, it is important to analyze the effect of gut microbiota composition on lipid profiles after a weight loss intervention. We compared the microbial diversity and taxonomic composition in patients with AD (n = 41) and controls (n = 38) and sought correlations of genera abundance with serum lipid levels in 20 patients after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Gut microbiota composition was profiled using next-generation sequencing of 16S rRNA. Gut microbiota diversity was significantly lower in atherogenic dyslipidemia. Moreover, relative abundance of two genera with LDA score >3.5 (Megasphaera and LPS-producing Escherichia-Shigella), was significantly higher in AD subjects, while the abundance of four short chain fatty acids (SCFA) producing-genera (Christensenellaceae R-7, Ruminococcaceae UCG-014; Akkermansia and [Eubacterium] eligens group) was significantly higher in controls. Notably, [Eubacterium] eligens group abundance was also significantly associated with higher HDL-C levels in RYGB patients one year after surgery. Although dietary polyunsaturated fatty acid/saturated fatty acid (PUFA/SFA) ratio and PUFA intake were higher in controls than in AD subjects, of the four genera differentiated in cases and controls, only Akkermansia abundance showed a positive and significant correlation with PUFA/SFA ratio. Our results suggest that SCFA-producing bacteria promote a healthy lipid homeostasis, while the presence of LPS-producing bacteria such Escherichia-Shigella may contribute to the development of atherogenic dyslipidemia.

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.

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease.

Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study.

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25-44%; P < 3 × 10-14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10-9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10-6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10-10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.

Raet1e Polymorphisms Are Associated with Increased Risk of Developing Premature Coronary Artery Disease and with Some Cardiometabolic Parameters: The GEA Mexican Study.

In an animal model, new evidence has been reported supporting the role of raet1e as an atherosclerosis-associated gene. Our objective was to establish if raet1e polymorphisms are associated with the risk of developing premature coronary artery disease (CAD) or with the presence of cardiometabolic parameters. After an informatic analysis, five polymorphisms were chosen and determined in 1158 patients with premature CAD and 1104 controls using 5' exonuclease TaqMan genotyping assays. Standardized questionnaires were applied to all participants to obtain family medical history, demographic information, history of nutritional habits, physical activity, alcohol consumption, and pharmacological treatment. The functional effect of the rs7756850 polymorphism was analyzed by luciferase assays. Under different models, adjusted by age, gender, body mass index, current smoking, and type 2 diabetes mellitus, the rs6925151 (OR = 1.250, p heterozygote = 0.026; OR = 1.268, p codominant1 = 0.034), rs9371533 (OR = 1.255, p heterozygote = 0.024), rs7756850 (OR = 1.274, p heterozygote = 0.016; OR = 1.294, p codominant1 = 0.031), and rs9383921 (OR = 1.232, p heterozygote = 0.037) polymorphisms were associated with increased risk of premature CAD. When compared to the rs7756850 G allele, the C allele showed a decreased luciferase activity. In premature CAD patients, associations with low levels of adiponectin, with a high presence of hypertension, and with high levels of gamma-glutamyltransferase and total cholesterol were observed. In healthy controls, associations with a decrease in LDL pattern B, aspartate aminotransaminase, and hypo-α-lipoproteinemia were detected. An association of the raet1e polymorphisms with an increased risk of developing premature CAD and with cardiometabolic parameters has been shown for the first time. In addition, the functional effect of the rs7756850 polymorphism was defined.

PLA2G2A polymorphisms are associated with metabolic syndrome and type 2 diabetes mellitus. Results from the genetics of atherosclerotic disease Mexican study.

The secretory phospholipase A2 II A (sPLA2-IIA) encoded by PLA2G2A gene hydrolyzes phospholipids liberating free fatty acids (FFAs) and lysophospholipids. If lipolysis exceeds lipogenesis, the free fatty acids undergo a continuous release into circulation. A sustained excessive increase in this release contributes to metabolic disease. The aim of the present study was to evaluate the role of PLA2G2A gene polymorphisms as susceptibility markers for metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) in Mexican population. Three PLA2G2A gene polymorphisms (rs876018, rs3753827 and rs11573156) were genotyped by 5' exonuclease TaqMan assays in a group of 338 patients with T2DM, 460 individuals with MetS and 366 healthy controls. Under codominant 1(codom1), dominant (dom) and additive (add) models adjusted by age, gender, body mass index (BMI), smoking habit, and hypertension, the rs876018T allele was associated with increased risk of MetS [Odds Ratio (OR)=1.66, Pcodom1=0.005; OR=1.67, Pdom=0.003; OR=1.49, Padd=0.005] as compared to controls. On the other hand, under several models adjusted by the same variables, the rs3753827A (OR=1.52, Pcodom1=0.039 and OR=1.49, Pdom=0.039) and rs11573156C alleles (OR=6.46, Pcodom1=0.013; OR=6.70, Pcodom2=0.009; OR=6.65, Pdom=0.009) were associated with increased risk of T2DM when compared with controls. In addition, the rs876018T allele was associated with hypercholesterolemia (Pdom=0.017, Padd=0.009) and risk of subclinical atherosclerosis (SA) (Pdom=0.041) in MetS when compared with controls. Also, this allele was associated with SA in T2DM patients (Pdom=0.007). The TAG haplotype was significantly associated with increased risk of MetS (OR=1.54, P=0.006). Results suggest that PLA2G2A polymorphisms are involved in the risk of developing MetS and T2D and are associated with SA in this group of patients.

Receptor-interacting protein 2 (RIP2) gene polymorphisms are associated with increased risk of subclinical atherosclerosis and clinical and metabolic parameters. The Genetics of Atherosclerotic Disease (GEA) Mexican study.

The receptor-interacting protein 2 (Rip2) is a serine/threonine kinase involved in multiple nuclear factor-κB (NFκB) activation pathways and is a key regulator of cellular lipid metabolism and cardiovascular disease. The aim of the present study was to evaluate the role of RIP2 gene polymorphisms as susceptibility markers for subclinical atherosclerosis (SA). Using an informatics analysis, four RIP2 gene polymorphisms with predicted functional effects (rs2293808, rs43133, rs431264, and rs16900627) were selected. The polymorphisms were genotyped in 405 individuals with SA (calcium score>0 assessed by computed tomography) and 1099 controls (calcium score=0). Clinical, anthropometric, tomographic and biochemical traits were measured. The association between the RIP2 polymorphisms and SA was evaluated using logistic regression analyses. Pair wise linkage disequilibrium (LD, D') estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 4:1. Under different models adjusted by age, gender, body mass index, hypertension, diabetes mellitus, smoking habit, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride levels, rs43133 (OR=1.43, 95% CI: 1.05-1.94, P=0.022), and rs16900627 (OR=1.59, 95% CI: 1.00-2.54, Pdom=0.048 and OR=1.60, 95% CI: 1.05-2.54, Padd=0.028) were associated with increased risk of developing SA. Moreover, rs2293808, and rs431264 were associated with clinical or metabolic parameters in SA individuals and in healthy controls. The four polymorphisms were in high linkage disequilibrium and the GAAG haplotype was associated with increased risk of developing SA (OR=1.47, P=0.027). This study shows for the first time, that RIP2 polymorphisms are associated with increased risk of SA and with some clinical and metabolic parameters.

Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects.

BACKGROUND AND AIM: Abnormal cholesterol metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH) and fibrosis. miR-33 and miR-144 regulate adenosine triphosphate binding cassette transporter (ABCA1) and other target genes involved in cholesterol efflux, fatty acid oxidation and inflammation. We explored relationships between non-alcoholic fatty liver disease (NAFLD) and the hepatic expression of ABCA1/ABCG1, as well as other target genes regulated by miR-33 (carnitine O-octanoyltransferase, CROT and hydroxyacyl-CoA-dehydrogenase ß-subunit, HADHB) and miR-144 (toll-like receptor-2, TLR2). Moreover, we evaluated whether the expression of these genes is correlated with miR-33a/b and miR-144 expression in Mexican individuals with morbid obesity. METHODS: Eighty-four morbidly obese subjects undergoing bariatric surgery were included in this study. Liver biopsies were obtained to measure hepatic triglyceride and free cholesterol contents, as well as ABCA1, ABCG1, CROT, HADHB, TLR2, miR-33a/b and miR-144 expression. RESULTS: Hepatic free cholesterol content was significantly increased in NASH as compared to non-NASH subjects, while ABCA1 and ABCG1 protein levels significantly decreased with NASH and fibrosis progression. The relative expression of miR-33a and miR-144 correlated inversely with ABCA1 but not with ABCG1 protein levels. Moreover, both miRNAs increased significantly in NASH individuals. miR-33 target genes CROT and HADHB correlated inversely with miR-33a. However, the expression of these genes was not associated with NASH. CONCLUSIONS: miR-33a/144 and their target gene ABCA1 may contribute to the pathogenesis of NASH in morbidly obese subjects.

SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women.

BACKGROUND AND AIMS: Secreted frizzled-related protein 5 (SFRP5) was recently described as a new adipokine protective for hepatic steatosis and other obesity-related complications in the mouse model. To date, SFRP5 expression in non-alcoholic fatty liver disease (NAFLD) has not been fully assessed in humans. We measured circulating SFRP5 levels and its expression in liver and adipose tissue, and evaluated its association with NAFLD in morbidly obese women. MATERIAL AND METHODS: Fifty-four morbidly obese women undergoing bariatric surgery were included in the study. Liver biopsies were used for histology and hepatic triglyceride content quantification. Circulating SFRP5 levels were measured through enzyme-linked immunoabsorbent assay, and SFRP5 expression was performed in hepatic and adipose tissue (subcutaneous and visceral). RESULTS: Although circulating SFRP5 levels showed a tendency to decrease with NAFLD progression, no significant differences were observed among non-alcoholic steatosis, steatohepatitis, and control subjects. Hepatic SFRP5 expression showed a negative correlation with hepatic triglyceride content (r = -0.349, P = 0.016 for mRNA and r = -0.291, P = 0.040 for SRFP5 protein) and ALT serum levels (r = -0.437, P = 0.001 for SRFP5 protein). In addition, hepatic SFRP5 protein levels were significantly lower in NASH than in control subjects (P = 0.006). CONCLUSION: This is the first study reporting an association of hepatic SFRP5 expression with NAFLD in humans.

Interleukin-17A gene haplotypes are associated with risk of premature coronary artery disease in Mexican patients from the Genetics of Atherosclerotic Disease (GEA) study.

AIM: The role of interleukin 17A (IL-17A) in the inflammatory process has caused interest in the potential significance of IL-17A as a biomarker for coronary artery disease (CAD). The aim of the present study was to evaluate the role of IL-17A gene polymorphisms as susceptibility markers for CAD in the Mexican population. METHODS: Four IL-17A gene polymorphisms (rs8193036, rs3819024, rs2275913 and rs8193037) were genotyped by 5' exonuclease TaqMan assays in a group of 900 patients with premature CAD and 667 healthy controls (with negative calcium score by computed tomography), seeking associations with CAD and other metabolic and cardiovascular risk factors using logistic regression analyses. RESULTS: No single IL-17A polymorphism was associated with premature CAD, however two haplotypes (CAGG and TAGA) were significantly associated with increased risk of premature CAD (OR = 1.35, 95% CI: 1.00-1.84, P = 0.018 and OR = 2.09, 95% CI: 1.16-3.76, P = 0.003, respectively). Moreover, rs3819024 was associated with increased levels of visceral abdominal fat (P = 0.002) and rs8193036 was significantly associated with risk of central obesity (P = 0.020), hypertriglyceridemia (P = 0.027), and metabolic syndrome (P = 0.027) in the premature CAD group, under dominant models adjusted by age, gender, BMI, smoking history, alcohol consumption, and treatment. CONCLUSION: The results suggest that IL-17A haplotypes are involved in the risk of developing premature CAD and some IL-17A polymorphisms are associated with cardiovascular risk factors in Mexican individuals with premature CAD.

Muerte súbita cardiaca en el corazón estructuralmente normal: una actualización / Sudden cardiac death in individuals with normal hearts: an update

La muerte súbita (MS) es un evento trágico que representa un grave problema de salud. Se estima que causa cerca de 4-5 millones de decesos por año en todo el mundo. La MS se define como la muerte ocurrida en el lapso de 1 h en una persona sin signos previos de fatalidad; puede denominarse «recuperada¼, cuando el paciente afectado sobrevive al episodio potencialmente fatal ya sea por reanimación cardiopulmonar o desfibrilación efectiva. Las canalopatías arritmogénicas son alteraciones funcionales de los canales iónicos del corazón, generalmente condicionados por mutaciones en los genes que los codifican y dan lugar a diversos tipos de arritmias que pueden culminar en MS, el deceso ocurre normalmente antes de los 40 años y el corazón en estudio de autopsia suele ser estructuralmente normal. En la presente revisión presentamos las principales causas de MS en el contexto del corazón estructuralmente normal y discutimos el abordaje que se debe dar a los pacientes y familiares de víctimas que han experimentado éste trágico evento.

Sudden death (SD) is a tragic event and a world-wide health problem. Every year, near 4-5 million people experience SD. SD is defined as the death occurred in 1 h after the onset of symptoms in a person without previous signs of fatality. It can be named «recovered SD¼ when the case received medical attention, cardiac reanimation effective defibrillation or both, surviving the fatal arrhythmia. Cardiac channelopathies are a group of diseases characterized by abnormal ion channel function due to genetic mutations in ion channel genes, providing increased susceptibility to develop cardiac arrhythmias and SD. Usually the death occurs before 40 years of age and in the autopsy the heart is normal. In this review we discuss the main cardiac channelopathies involved in sudden cardiac death along with current management of cases and family members that have experienced such tragic event.

Single nucleotide polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals.

AIM: To explore the role of the ACE gene polymorphisms in the risk of essential hypertension in Mexican Mestizo individuals and evaluate the correlation between these polymorphisms and the serum ACE levels. METHODS: Nine ACE gene polymorphisms were genotyped by 5' exonuclease TaqMan genotyping assays and polymerase chain reaction (PCR) in 239 hypertensive and 371 non- hypertensive Mexican individuals. Haplotypes were constructed after linkage disequilibrium analysis. ACE serum levels were determined in selected individuals according to different haplotypes. RESULTS: Under a dominant model, rs4291 rs4335, rs4344, rs4353, rs4362, and rs4363 polymorphisms were associated with an increased risk of hypertension after adjusting for age, gender, BMI, triglycerides, alcohol consumption, and smoking. Five polymorphisms (rs4335, rs4344, rs4353, rs4362 and rs4363) were in strong linkage disequilibrium and were included in four haplotypes: H1 (AAGCA), H2 (GGATG), H3 (AGATG), and H4 (AGACA). Haplotype H1 was associated with decreased risk of hypertension, while haplotype H2 was associated with an increased risk of hypertension (OR = 0.77, P = 0.023 and OR = 1.41, P = 0.004 respectively). According to the codominant model, the H2/H2 and H1/H2 haplotype combinations were significantly associated with risk of hypertension after adjusted by age, gender, BMI, triglycerides, alcohol consumption, and smoking (OR = 2.0; P = 0.002 and OR = 2.09; P = 0.011, respectively). Significant elevations in serum ACE concentrations were found in individuals with the H2 haplotype (H2/H2 and H2/H1) as compared to H1/H1 individuals (P = 0.0048). CONCLUSION: The results suggest that single nucleotide polymorphisms and the "GGATG" haplotype of the ACE gene are associated with the development of hypertension and with increased ACE enzyme levels.

Carbohydrate intake modulates the effect of the ABCA1-R230C variant on HDL cholesterol concentrations in premenopausal women.

The R230C variant of the ATP-binding cassette transporter A1 (ABCA1) gene has been consistently associated with decreased HDL-cholesterol (HDL-C) concentrations in several studies in the Mexican mestizo population. However, information on how diet composition modifies the effect of the ABCA1-R230C variant on HDL-C concentrations is very scarce. The aim of the present study was to analyze whether the effect of ABCA1-R230C on HDL-C concentrations is modulated by dietary factors in a nationwide population sample of 3591 adults from the National Health and Nutrition Survey conducted by the State's Employees' Social Security and Social Services Institute. All participants answered a validated questionnaire to assess health status and weekly food consumption. Fasting blood samples were drawn for biochemical analysis and DNA extraction, and the ABCA1-R230C variant was genotyped using TaqMan assays. Statistical analyses consisted of simple linear and multiple regression modeling adjusting for age, BMI, smoking, and alcohol consumption. The overall C risk allele frequency was 9.3% and the variant was significantly associated with low HDL-C concentrations in both sexes. A significant negative correlation between carbohydrate consumption and HDL-C concentrations was observed in women bearing the R230C variant (P = 0.021) and a significant gene-diet interaction was found only in premenopausal women (P = 0.037). In conclusion, the effect of the ABCA1-R230C gene variant on HDL-C concentrations is modulated by carbohydrate intake in premenopausal women. This finding may help design optimized dietary interventions according to sex and ABCA1-R230C genotype.