The -514C>T polymorphism in the LIPC gene modifies type 2 diabetes risk through modulation of HDL-cholesterol levels in Mexicans.

PURPOSE: Both type 2 diabetes (T2D) and low levels of high-density lipoprotein cholesterol (HDL-C) are very prevalent conditions among Mexicans. Genetic variants in the LIPC gene have been associated with both conditions. This study aimed to evaluate the association of the -514C < T (rs1800588) LIPC gene polymorphism with different metabolic traits, particularly the effects of this polymorphism on HDL-C plasma levels and T2D risk. METHODS: Mediation analysis was used to assess the direct and indirect effects of the -514C>T LIPC gene variant on HDL-C levels, T2D risk, and body mass index (BMI), in 2105 Mexican mestizo participants. We also assessed the functional effect of the -514C>T LIPC variant on the promoter activity of a reporter gene in the HepG2 cell line. RESULTS: Direct effects show that the -514C>T LIPC polymorphism is significantly associated with increased HDL-C plasma levels (ß = 0.03; p < 0.001). The -514C>T variant resulted in an indirect protective effect on T2D risk through increasing HDL-C levels (ß = - 0.03; p < 0.001). Marginal direct association between -514C>T and T2D was found (ß = 0.08; p = 0.06). Variables directly influencing T2D status were European ethnicity (ß = - 7.20; p < 0.001), age (ß = 0.04; p < 0.001), gender (ß = - 0.15; p = 0.017) and HDL-C (ß = - 1.07; p < 0.001). In addition, we found that the -514C>T variant decreases the activity of LIPC promoter by 90% (p < 0.001). CONCLUSIONS: The -514C>T polymorphism was not directly associated with T2D risk. HDL-C acts as a mediator between -514C>T LIPC gene variant and T2D risk in the Mexican population.

R230C but not - 565C/T variant of the ABCA1 gene is associated with type 2 diabetes in Mexicans through an effect on lowering HDL-cholesterol levels.

PURPOSE: Type 2 diabetes (T2D) and low serum concentration of high-density lipoprotein cholesterol (HDL-c) are common coexisting metabolic disorders. ABCA1 variants have been shown to be associated to these conditions. We sought to test the combined effect of two ABCA1 gene common variants, rs2422493 (- 565C > T) and rs9282541 (R230C) on HDL-c levels and T2D risk. METHODS: Path analysis was conducted in 3,303 Mexican-mestizos to assess the specific contributions of rs2422493 and rs9282541 ABCA1 variants, insulin resistance, waist-to-height ratio (WHtR), and age on HDL-c levels and T2D risk. Participants were classified into four groups according to their ABCA1 variants carrier status: (i) the reference group carried wild type alleles for both ABCA1 variants (-/-), (ii) +/- were carriers of rs2422493 but non-carriers of rs9282541, (iii) -/+ for carriers of rs9282541 but not carriers of rs2422493 and (iv) carriers of minor alleles for both SNPs (+/+). Principal components from two previous genome-wide association studies were used to control for ethnicity. RESULTS: We identified significant indirect effects on T2D risk mediated by HDL-c in groups -/+ and +/+ (ß = 0.04; p = 0.03 and ß = 0.06; p < 0.01, respectively) in comparison to the -/- reference group. Low concentrations of HDL-c were directly and significantly associated with increased T2D risk (ß = -0.70; p < 0.01). WHtR, male gender, age, and insulin resistance were also associated with T2D risk (p < 0.05). There was no significant direct effect for any of the ABCA1 groups on T2D risk: p = 0.99, p = 0.58, and p = 0.91 for groups +/-, -/+, and +/+ respectively. CONCLUSIONS: The ABCA1 rs9282541 (R230C) allele is associated with T2D in Mexicans through its effect on lowering HDL-c levels. This is the first report demonstrating that HDL-c levels act as an intermediate factor between an ABCA1 variant and T2D.

Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children.

Concerning the genetic factors of obesity, no consistent association between populations has been reported, which may be due to the frequency of polymorphisms, the lifestyle of studied populations and its interaction with other factors. We studied a possible association of polymorphisms FTO rs9939609, PPARG rs1801282, and ADIPOQ rs4632532 and rs182052 with obesity phenotypes in 215 Mexican children. Glucose, triglycerides, cholesterol, HDL and LDL were measured. In addition, weight, height, waist circumference and triceps skin thickness were recorded. High-energy diets and sedentary behavior were evaluated with a validated questionnaire. In contrast with other reports, only FTO rs9939609 was associated with obesity related-traits, including BMI (p = 0.03), waist circumference (p = 0.02), triceps skinfold (p = 0.03) and waist/height ratio (p = 0.01), and also with cholesterol levels (p = 0.02) and LDL (p = 0.009). Lower levels of triglycerides (p=0.04) were related with presence of PPARG rs1801282, while ADIPOQ rs4632532 showed an effect on HDL (p = 0.03) levels. On the other hand, diet, physical activity and screen time were not related with obesity. In summary, only FTO rs9939609 was associated with obesity related-traits, while PPARG2 rs1801282 and ADIPOQ rs4632532 were involved in lipid metabolism.

Genetic susceptibility to lung cancer based on candidate genes in a sample from the Mexican Mestizo population: a case-control study.

BACKGROUND: Lung cancer (LC) is the leading cause of mortality caused by neoplasias worldwide. Although cigarette smoking is the primary cause, not all smokers develop LC. Polymorphic variations in genes associated with carcinogen metabolism, DNA repair, and cell-cycle dysregulation may alter an individual risk of developing LC. A polygenic cancer model was proposed, which considers genetic susceptibility to cancer is a global mechanism and suggests that it might be defined by the contributions of low-risk alleles in several candidate genes. This study focused on the analysis of 15 polymorphisms in 12 low-penetrance genes in a case-control study of a sample of Mexican Mestizo population. METHODS: A case-control study was performed with a total of 572 unrelated individuals, including 190 cases with a primary LC diagnosis and 382 healthy controls. The polymorphic status of the individuals was determined by TaqMan probe and RFLP techniques. The association between LC and genotype score (GS) was assessed by logistic regression. RESULTS: The results suggests a protective effect of the genotypes Arg/Lys of AhR rs2066853 (odds ratio [OR] 0.55, p = 0.03), Ile/Val of CYP1A1 rs1048943 (OR 0.49, p = 0.009), Tyr/His of EPHX1 rs1051740 (OR 0.53, p = 0.03), and A/A of CCND1 rs603965 (OR 0.44, p = 0.02). Analyses using the GS suggest that average cases have a larger number of risk alleles than controls (Student's t test -4.85, p = 0.001; OR 1.25, p < 0.001). CONCLUSIONS: Our results suggest significant differences between the GS for the cases and controls, which support the hypothesis underlying the additive and polygenic models for lung cancer risk depending on the polymorphisms in low-penetrance genes.

Neurocognitive function in adult residents of a mining district in Mexico after reducing manganese exposure: Follow-up after 11 years.

BACKGROUND: Little is known about the neurotoxic effects of chronic exposure to airborne Mn once exposure has been reduced. The environmentally exposed and the reference adult populations evaluated in 2002 were followed, after an environmental management program (EMP) was implemented to reduce the exposure in a mining district in Mexico. OBJECTIVE: The aim of this study was to compare the association between exposure to Mn and neurocognitive performance in environmentally exposed and reference groups of adults before and after EMP implementation. METHODS: In 2013, the same battery of neurocognitive tests used in the initial study (2002) was applied to 58 adults exposed to airborne Mn and 30 adults from the reference community. A cumulative exposure index (CEI) was estimated for the study population before and after the EMP. Categorical outcomes were analyzed using logistic regression, and the resulting ORs were compared between studies. Continuous outcomes were analyzed using linear regression. All models were adjusted for age, years of education, socioeconomic status and blood lead levels. RESULTS: Exposed adults from the post-EMP study showed an improvement in fine motor and verbal regulation of motor skills (OR < 1) compared to the exposed adults from the pre-EMP study (OR > 1). In both pre- and post-studies, the exposed adults showed a deterioration in their dynamic organization of motor activity compared to the reference group (p < 0.05); however, they showed no significant change in attention and working-memory performance. DISCUSSION: After four years of a significant reduction in airborne Mn levels resulting from EMP implementation, chronically exposed adults showed an improvement in fine motor and verbal regulation of motor skills; however, the remaining areas of their motor and cognitive functions remained impaired.

Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.

BACKGROUND: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone.

Acute exposure to ozone has been related to a wide spectrum of health effects in susceptible individuals. Genetic factors may influence interindividual variation in ozone response. The current authors investigated the relationships between common polymorphisms in two genes involved in response to oxidative stress, i.e. glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), and both respiratory symptoms and lung function in response to ozone among childhood asthmatics. A total of 151 asthmatic children, who were participants in a randomised controlled trial of antioxidant vitamin supplementation in Mexico City, were studied. Children were genotyped using PCR methods and followed from October 1998-April 2000. Increases in reported breathing difficulty were associated with ozone exposure in children with GSTM1 null (8%, 95% confidence interval (CI) 1-15%, per 20-ppb increase in 1-h maximum daily average over 7 days) or GSTP1 Valine/Valine (Val/Val) genotypes (14%, 95% CI 5-25%). In children with both GSTM1 null and GSTP1 Val/Val genotypes, the increase in breathing difficulty associated with a 20-ppb increase in ozone exposure was even greater (21%, 95% CI 5-39%). GSTP1 genotypes were not significantly associated with ozone-related lung function changes. In conclusion, asthmatic children with glutathione S-transferase M1 null and glutathione S-transferase P1 Valine/Valine genotypes appear more susceptible to developing respiratory symptoms related to ozone exposure.

Antioxidant supplementation and nasal inflammatory responses among young asthmatics exposed to high levels of ozone.

The inflammatory response to ozone in atopic asthma suggests that soluble mediators of inflammation are released in response to oxidant stress. Antioxidants may alleviate additional oxidative stress associated with photochemical oxidant pollution. This study investigates the impact of antioxidant supplementation on the nasal inflammatory response to ozone exposure in atopic asthmatic children. We conducted a randomized trial using a double-blinded design. Children with asthma (n = 117), residents of Mexico City, were given randomly a daily supplement of vitamins (50 mg/day of vitamin E and 250 mg/day of vitamin C) or placebo. Nasal lavages were performed three times during the 4-month follow-up and analysed for content of interleukin-6 (IL-6), IL-8, uric acid and glutathione (GSx). IL-6 levels in the nasal lavage were increased significantly in the placebo group after ozone exposure while no increase was observed in the supplement group. The difference in response to ozone exposure between the two groups was significant (P = 0.02). Results were similar for IL-8, but with no significant difference between the groups (P = 0.12). GSx decreased significantly in both groups. Uric acid decreased slightly in the placebo group. Our data suggest that vitamin C and E supplementation above the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide some protection against the nasal acute inflammatory response to ozone.

Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City.

BACKGROUND: We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow (FEF(25-75)) in 158 asthmatic children in an area with high ozone exposure in Mexico City. METHODS: A study was undertaken to determine whether deletion of glutathione S-transferase M1 (GSTM1 null genotype), a gene involved in response to oxidative stress, influences ozone related decline in FEF(25-75) and the benefit of antioxidant supplementation. RESULTS: GSTM1 null children receiving placebo had significant ozone related decrements in FEF(25-75) (percentage change per 50 ppb of ozone 2.9 (95% CI -5.2 to -0.6), p=0.01); GSTM1 positive children did not. Conversely, the effect of antioxidants was stronger in children with the GSTM1 null genotype. CONCLUSIONS: Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation.