Bertha Ruiz-Madrigal

Genetic Polymorphisms of Genes Coding to Alcohol-Metabolizing Enzymes in Western Mexicans: Association of CYP2E1*c2/CYP2E1*5B Allele with Cirrhosis and Liver Function

BACKGROUND Alcoholic cirrhosis constitutes a major public health problem in the world where ADH1B, ALDH2, and CYP2E1 polymorphisms could be playing an important role. We determined ADH1B*2, ALDH2*2, and CYP2E1*c2 allele frequencies in healthy control individuals (C) and patients with alcoholic cirrhosis (AC) from western Mexico. METHODS Ninety C and 41 patients with AC were studied. Genotype and allele frequency were determined through polymerase chain reaction-restriction fragment length polymorphisms. RESULTS Polymorphic allele distribution in AC was 1.6%ADH1B*2, 0.0%ALDH2*2, and 19.5%CYP2E1*c2; in C: 6.1%ADH1B*2, 0%ALDH2*2, and 10.6%CYP2E1*c2. CYP2E1*c2 polymorphic allele and c1/c2 genotype frequency were significantly higher (p < 0.05 and p < 0.01, respectively) in patients with AC when compared to C. Patients with AC, carrying the CYP2E1*c2 allele, exhibited more decompensated liver functioning evaluated by total bilirubin and prothrombin time, than c1 allele carrying patients (p < 0.05). Cirrhosis severity, assessed by Childs Pugh score and mortality, was higher in patients carrying the c2 allele, although not statistically significant. CONCLUSIONS In this study, CYP2E1*c2 allele was associated with susceptibility to AC; meanwhile, ADH1B*2 and ALDH2*2 alleles were not. CYP2E1*c2 allele was associated with AC severity, which could probably be attributed to the oxidative stress promoted by this polymorphic form. Further studies to clearly establish CYP2E1*c2 clinical relevance in the development of alcohol-induced liver damage and its usefulness as a probable prognostic marker, should be performed. Also, increasing the number of patients and including a control group conformed by alcoholic patients free of liver damage may render more conclusive results. These findings contribute to the understanding of the influence of gene variations in AC development among populations, alcohol metabolism, and pharmacogenetics.

Association of the ε2 Allele of Apoe Gene to Hypertriglyceridemia and to Early‐Onset Alcoholic Cirrhosis

BACKGROUND The diverse incidence of alcoholic cirrhosis around the world and the fact that not all alcoholic drinkers develop liver disease indicates that genetic and environmental factors play an important role in the development of liver cirrhosis. Lipids participate in early stages of alcoholic cirrhosis. Therefore variations in the plasma lipid profile due to primary (genetic) or secondary (environmental) dyslipidemia could affect the development of liver disease. The aim of this study was to analyze the lipid profile and apolipoprotein E (APOE) polymorphism in patients with alcoholic liver cirrhosis (AC) and determine the risk associated with genotype polymorphism with the onset of alcoholic cirrhosis. METHODS In a case and control study, 86 patients with AC divided into hyperlipidemic (H) and non-hyperlipidemic (non-H) groups, and 133 healthy individuals (C) matched by age and sex were studied. Lipid profile and liver function tests were measured by enzymatic methods. The APOE genotypes were identified by PCR-RFLPs. RESULTS A statistically significant increase of the APOE*2 allele and genotypes 2/2, 2/3, and 2/4 was present in AC patients compared to C group. A hyperlipidemic state characterized by increased levels of triglycerides and apolipoprotein B (APOB) and a decrease of high density lipoprotein-cholesterol (HDL-c) was detected in young-aged patients (31.2 +/- 6.2 years old vs. 46.3 +/- 12.5 years old). In this group, hypertriglyceridemia was closely associated to APOE*2 allele and to an early onset of liver cirrhosis. By contrast, APOE*4 allele was associated with a longer duration of alcohol intake (>20 years) in the non-H group. CONCLUSIONS This study shows the association of hypertriglyceridemia and APOE allele with the early onset of alcoholic liver cirrhosis, and the interaction between environmental factors, such as duration of alcohol abuse and amount of alcohol intake, and genetic factors (APOE*2 allele) on the hypertriglyceridemic process.

Polymorphism of the β3-adrenergic receptor and lipid profile in patients with rheumatoid arthritis and systemic lupus erythematosus treated with chloroquine

We investigated the effect of beta 3-adrenergic receptor (β3AR) polymorphism on lipid profiles in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) treated with chloroquine. One hundred sixty-eight subjects were classified into three groups: 61 RA patients, 57 SLE patients, and 50 healthy subjects. All patients fulfilled the 1987 and 1982 classification criteria for RA and SLE, respectively, of the American College of Rheumatology. Demographic data and clinical characteristics of the patients were registered. Fasting lipid profile determination and leukocyte genomic DNA isolation from peripheral blood was performed in all the participants. Screening of the β3-AR gene polymorphic region (exon 1) was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Quantitative and qualitative variables were analyzed using analysis of variance (ANOVA) with the LSD and χ2 tests, respectively. An association between the arg64/arg64 β3-AR genotype and high levels of triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-c) was found in three RA patients (P=0.01), two of them taking chloroquine. Arg64/arg64 β3-AR polymorphism may contribute to increased TG and VLDL-c in RA patients, independently of chloroquine treatment.

Effect of Ala54Thr polymorphism of FABP2 on anthropometric and biochemical variables in response to a moderate-fat diet

OBJECTIVE To analyze the effect of the fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism on anthropometric and biochemical variables in response to a moderate-fat diet in overweight or obese subjects. METHODS One hundred nine subjects with a body mass index ≥ 25 kg/m(2) were studied. Participants underwent a dietary intervention that consisted of 30% fat (saturated fat <7% of total calories), 15% protein, and 55% carbohydrates. The FABP2 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Anthropometric and biochemical data were measured at baseline, 1 mo, and 2 mo of nutritional intervention. RESULTS The mean age was 38.6 ± 11.3 y and the mean body mass index 32.7 ± 6.1 kg/m(2), with 20 men (18%) and 89 women (82%). Fifty-three patients (48.6%) had genotype Ala54Ala (wild-type group) and 56 patients had genotype Ala54Thr/Thr54Thr (51.4%, mutant group). At baseline, no significant difference was found between the FABP2 genotypes groups, except for the carbohydrate intake and resting metabolic rate, which were higher in the Ala54Thr/Thr54Thr group (P < 0.05). At 2 mo, participants had lost 6.8% of their initial weight. The Ala54Thr/Thr54Thr group compared with the Ala54Ala group showed significant decreases in the parameters of weight (-7.5 versus -4.2 kg), body mass index (-2.1 versus -1.2 kg/m(2)), waist circumference (-7.6 versus -5.2 cm), waist-to-hip ratio (-0.04 versus -0.02), and C-reactive protein (-1.4 versus -0.76 mg/L), respectively (P < 0.05). After the resting metabolic rate was adjusted, the decreases in waist circumference, waist-to-hip ratio, and C-reactive protein remained significant between the two groups. CONCLUSIONS This study showed that the Thr54 allele carriers responded better to a moderate-fat diet.

Association of the T54 allele of the FABP2 gene with cardiovascular risk factors in obese Mexican subjects

Genetic predisposition to cardiovascular risk may vary between different ethnic groups. We studied the effect of the FABP2 A54T polymorphism on biochemical and anthropometric cardiovascular risk factors in 114 obese Mexican subjects. The mean age of the patients studied was 36.8±13.3 years. Insulin resistance was present in 47%, hypercholesterolaemia in 49% and hyper-triglyceridaemia in 45%. Frequency of the FABP2 genotype was 39% AA, 54.8% AT and 6.2% TT. The AT/TT group showed an increase in body mass index (34±7.1 vs. 31±4.8 kg/m2), waist circumference (101±15.7 vs. 96.5±15.8 cm), triglycerides (145±60.8 vs. 127±79.4 mg/dL; 1.64±0.67 vs. 1.43±0.89 mmol/L), total cholesterol (176±39.4 vs. 164±38.2 mg/dL; 4.55±1.02 vs. 4.24±0.99 mmol/L), LDL (121±24.2 vs. 111±25.9 mg/dL; 3.13±0.62 vs. 2.88±0.67 mmol/L) and VLDL (28.8±12.1 vs. 25.1±16.1 mg/dL; 0.74±0.31 vs. 0.64±0.41 mmol/L) compared to the AA group (p<0.05). The AT/TT group had greatly increased cardiovascular risk, with an OR of 7.56 (95% CI, 1.82-36.24; p<0.001) compared to the AA group. Our results suggest that A54T polymorphism of the FABP2 gene is associated with cardiovascular disease risk in obese subjects.

Central Adiposity and Mortality after First-Ever Acute Ischemic Stroke

Background: The waist-to-height ratio (WHtR) may be a better adiposity measure than the body mass index (BMI). We evaluated the prognostic performance of WHtR in patients with acute ischemic stroke (AIS). Methods: First, we compared WHtR and BMI as adiposity measures in 712 healthy adults by tetrapolar bioimpedance analysis. Thereafter, baseline WHtR was analyzed as predictor of 12-month all-cause mortality in 821 Mexican mestizo adults with first-ever AIS by a Cox proportional hazards model adjusted for baseline predictors. Results: In healthy individuals, WHtR correlated higher than BMI with total fat mass and showed a higher accuracy in identifying a high percentage of body fat (p < 0.01). In AIS patients a U-shaped relationship was observed between baseline WHtR and mortality (fatality rate 29.1%). On multivariate analysis, baseline WHtR ≤0.300 or >0.800 independently predicted 12-month all-cause mortality (hazard ratio 1.91, 95% confidence interval 1.04-3.51). BMI was not associated with mortality, tested either as continuous, binomial or stratified variable. Conclusion: WHtR is a modifiable risk factor that accurately demonstrates body fat excess. Extreme WHtR values were associated with increased 12-month all-cause mortality in Mexican mestizo patients with AIS. No survival advantage was found with high WHtR as the pragmatic indicator of obesity in this population.

Effect of the ADIPOQ Gene -11391G/A Polymorphism Is Modulated by Lifestyle Factors in Mexican Subjects.

Background/Aims: Single nucleotide polymorphisms (SNPs) in the ADIPOQ gene could explain the adiponectin level. However, the knowledge about the influence of genetic and lifestyle factors is not sufficient. The aim was to analyze whether the effect of the -11391G/A SNP in the ADIPOQ gene is modulated by lifestyle factors in Mexican subjects. Methods: A cross-sectional study was performed in which 394 participants were analyzed. Genetic, anthropometric, biochemical, dietary, clinical and physical activity parameters were measured. Statistical analysis was performed with SPSSv19 software. Results: The distribution of the -11391G/A SNP genotypes was 55.6 and 44.4% for GG and AG, respectively. The adiponectin level was modulated by the -11391G/A SNP in response to the body mass index (BMI); A allele carriers showed a higher adiponectin level compared to G homozygous carriers but only in the minor BMI tertile group (p = 0.032). Adiponectin level variability was explained by gender [(r) = 1.5, 95% CI 1.1-1.9, p = 0.000], insulin resistance [(r) = -1.2, 95% CI -0.8 to -1.6, p = 0.000], physical activity [(r) = 0.6, 95% CI 0.2-0.9, p = 0.002] and monounsaturated fat intake [(r) = 0.5, 95% CI 0.38-1.0, p = 0.047]. Conclusions: The adiponectin level was modulated by the interaction between BMI and -11391G/A SNP; this suggests that the lifestyle rather than genetic factors modulates serum adiponectin.

Apolipoprotein AI and apolipoprotein E mRNA expression in peripheral white blood cells from patients with orthotopic liver transplantation

Background: Apolipoprotein AI/apolipoprotein E (apo‐AI/apo‐E) ratio change and its induction in non‐hepatic tissues have been reported during liver development, regeneration, and several pathophysiologic states. The clinical implication of such changes is unclear, but these could reflect recovery and/or severity of liver damage.

The Quételet index revisited in children and adults

BACKGROUND The body mass index (BMI) is based on the original concept that body weight increases as a function of height squared. As an indicator of obesity the modern BMI assumption postulates that adiposity also increases as a function of height in states of positive energy balance. OBJECTIVE To evaluate the BMI concept across different adiposity magnitudes, in both children and adults. METHODS We studied 975 individuals who underwent anthropometric evaluation: 474 children and 501 adults. Tetrapolar bioimpedance analysis was used to assess body fat and lean mass. RESULTS BMI significantly correlated with percentage of body fat (%BF; children: r=0.893; adults: r=0.878) and with total fat mass (children: r=0.967; adults: r=0.953). In children, body weight, fat mass, %BF and waist circumference progressively increased as a function of height squared. In adults body weight increased as a function of height squared, but %BF actually decreased with increasing height both in men (r=-0.406; p<0.001) and women (r=-0.413; p<0.001). Most of the BMI variance in adults was explained by a positive correlation of total lean mass with height squared (r(2)=0.709), and by a negative correlation of BMI with total fat mass (r=-0.193). CONCLUSIONS Body weight increases as a function of height squared. However, adiposity progressively increases as a function of height only in children. BMI is not an ideal indicator of obesity in adults since it is significantly influenced by the lean mass, even in obese individuals.

Asociación de los polimorfismos −319 C /T y 49 A/G del gen CTLA-4 en pacientes con infección por el virus de la hepatitis C

INTRODUCTION AND OBJECTIVE Molecular changes in the CTLA-4 gene can modify the ability to control T lymphocyte proliferation, and promote the persistence or elimination of the hepatitis C virus (HCV). We aimed to investigate the frequency and association of -319 C/T and +49 A/G polymorphism in the CTLA-4 gene in patients infected with HCV. METHODS The CTLA-4 gene polymorphisms (-319 C/T in the promoter region, and +49 A/G in exon 1) were analysed by T-ARMS-PCR in 420 individuals, including 205 chronic HCV infected patients and 215 healthy subjects. RESULTS We found a positive association of +49G allele with HCV infection (OR 1.48; 95% CI 1.09-2.02; p=.02), and with males (OR 1.80; 95% CI 1.16-2.79; p=.02), both in chronic disease (without cirrhosis). Also, significant differences in +49 A/G genotypes distribution between HCV infected patients and healthy subjects were shown in a dominant genetic model (GG+GA versus AA; OR 1.57; 95% CI 1.05-2.33; p=.04). No significant differences were observed in the -319 C/T polymorphism between HCV infected patients and healthy subjects. Moreover, -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection (OR 10.68; 95% CI 1.17-96.97; p=.04). CONCLUSIONS The +49G allele confers susceptibility to HCV infection and with male gender, both in chronic disease. In addition, the -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection. Our results support an important role of the -319 C/T and +49 A/G polymorphisms in HCV infection.