Association of tyrosine hydroxylase 01 (TH01) microsatellite and insulin gene (INS) variable number of tandem repeat (VNTR) with type 2 diabetes and fasting insulin secretion in Mexican population.

PURPOSE: A variable number of tandem repeats (VNTR) in the insulin gene (INS) control region may be involved in type 2 diabetes (T2D). The TH01 microsatellite is near INS and may regulate it. We investigated whether the TH01 microsatellite and INS VNTR, assessed via the surrogate marker single nucleotide polymorphism rs689, are associated with T2D and serum insulin levels in a Mexican population. METHODS: We analyzed a main case-control study (n = 1986) that used univariate and multivariate logistic regression models to calculate the risk conferred by TH01 and rs689 loci for T2D development; rs689 results were replicated in other case-control (n = 1188) and cross-sectional (n = 1914) studies. RESULTS: TH01 alleles 6, 8, 9, and 9.3 and allele A of rs689 were independently associated with T2D, with differences between sex and age at diagnosis. TH01 alleles with ≥ 8 repeats conferred an increased risk for T2D in males compared with ≤ 7 repeats (odds ratio, ≥ 1.46; 95% confidence interval, 1.1-1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed ≥ 46 years but conferred protection when diagnosed ≤ 45 years. Similarly, rs689 allele A was associated with T2D in these groups. In males, larger TH01 alleles and the rs689 A allele were associated with a significant decrease in median fasting plasma insulin concentration with age in T2D cases; the reverse occurred in controls. CONCLUSION: Larger TH01 alleles and rs689 A allele may potentiate insulin synthesis in males without T2D, a process disabled in those with T2D.

CYP2C9*3 gene variant contributes independently to glycaemic control in patients with type 2 diabetes treated with glibenclamide.

WHAT IS KNOWN AND OBJECTIVE: Glibenclamide is a prescribed glucose-lowering medication for diabetes, but there are interindividual variations in the therapeutic response. In this cross-sectional study, the aim was to explore the association of genetic variants in CYP2C9, ABCC8, KCNJ11 and TCF7L2 with good glycaemic control in Mexican type 2 diabetes (T2D) treated with glibenclamide. METHODS: Patients with T2D receiving treatment with glibenclamide or glibenclamide plus metformin were included. Patients with A1C ≤ 7% were considered to have good glycaemic control, whereas patients with A1C ≥ 8% were considered having poor glycaemic control. Genotyping was performed by real-time PCR using TaqMan probes for the genetic variants. Association was performed by calculating OR with 95% confidence intervals (95% CI). For the multivariate analysis, a multiple logistic regression was performed including the confounding variables age, exercised, BMI, glibenclamide dose, time with T2D and concomitant metformin. RESULTS AND DISCUSSION: Four hundred and four patients were included in the study, median age of the participants was 50 years (IQR 11.0), the median time with disease was 6 years (IQR 8.0), 118 (29.2%) were men, and 243 (60.1%) received glibenclamide in combination with metformin. CYP2C9*3 variant was associated with good glycaemic control (OR = 2.747 [95% CI, 1.194-6.324]), whereas the variants, CYP2C9*2, TCF7L2 rs7903146 and rs12255372, ABCC8 rs757110 and KCNJ11 rs5219, were not. In the multivariate analysis, the CYP2C9*3 variant maintained its association (OR = 2.779 [95% CI, 1.142-6.763]). WHAT IS NEW AND CONCLUSION: The findings suggest that CYP2C9*3 genetic variant independently contributes to good glycaemic control of patients with type 2 diabetes treated with glibenclamide.

Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City.

BACKGROUND: Type 2 diabetes (T2D) is influenced by diverse environmental and genetic risk factors. Metabolic syndrome (MS) increases the risk of cardiovascular disease and diabetes. We analysed 14 cases of polymorphisms located in 10 candidate loci, in a sample of patients with T2D and controls from Mexico City. METHODS: We analysed the association of 14 polymorphisms located within 10 genes (TCF7L2, ENPP1, ADRB3, KCNJ11, LEPR, PPARgamma, FTO, CDKAL1, SIRT1 and HHEX) with T2D and MS. The analysis included 519 subjects with T2D defined according to the ADA criteria, 389 with MS defined according to the AHA/NHLBI criteria and 547 controls. Association was tested with the program ADMIXMAP including individual ancestry, age, sex, education and in some cases body mass index (BMI), in a logistic regression model. RESULTS: The two markers located within the TCF7L2 gene showed strong associations with T2D (rs7903146, T allele, odd ratio (OR) = 1.76, p = 0.001 and rs12255372, T allele, OR = 1.78, p = 0.002), but did not show significant association with MS. The non-synonymous rs4994 polymorphism of the ADRB3 gene was associated with T2D (Trp allele, OR = 0.62, p = 0.001) and MS (Trp allele, OR = 0.74, p = 0.018). Nominally significant associations were also observed between T2D and the SIRT1 rs3758391 SNP and MS and the HHEX rs5015480 polymorphism. CONCLUSIONS: Variants located within the gene TCF7L2 are strongly associated with T2D but not with MS, providing support to previous evidence indicating that polymorphisms at the TCF7L2 gene increase T2D risk. In contrast, the non-synonymous ADRB3 rs4994 polymorphism is associated with T2D and MS.

APOA5 and APOA1 polymorphisms are associated with triglyceride levels in Mexican children.

BACKGROUND: Dyslipidemia is an important risk factor for the development of several diseases. The genetic component of hypertriglyceridemia has been studied in adults, but little is known in children. OBJECTIVE: The objective is to evaluate the association of two variants in APOA5 (rs662799) and APOA1 (rs5072) with triglyceride (TG) levels in Mexican children. METHODS: Anthropometric parameters were measured in 1559 Mexican children 5-14 years of age. DNA was isolated from blood samples. Lipid profiles and glucose concentrations were determined from serum and genotyping of rs662799, and rs5072 was performed using TaqMan® technology. Additive and dominant models adjusted for age, gender and body mass index were used to evaluate the association of these single nucleotide polymorphisms with TG levels. RESULTS: Children with high TG levels were found to have a higher body mass index and waist circumference as well as a worse lipids profile and glucose levels (p < 0.001). Additive and dominant models demonstrated a significant association between the rs662799 and rs5072 with TG. The dominant model showed the strongest significant association (OR = 1.81; 95% CI 1.46-2.24; p = 5.40 × 10-08 for rs662799 and OR = 1.54; 95% CI 1.05-2.25; p = 2.60 × 10-02 for rs5072). CONCLUSION: The minor alleles of rs662799 (APOA5) and rs5072 (APOA1) modulate TG levels in Mexican children.

KIR gene in ethnic and Mestizo populations from Mexico.

Killer cell immunoglobulin-like receptors are characterized by their great diversity of genes and alleles. Population studies have identified the presence of a broad variety of genotypes. In Mexico, there are diverse ethnic groups representing 9% of the total population and the rest is composed of Mestizos with a more varied biology. For the purpose of this study, genotyping was performed in Mestizos, in Mexico City inhabitants, and in three ethnic groups. The frequencies of genes KIR2DL2, 2DL5, 2DS1-3, 2DS5, and 3DS1 showed a greater variability in the groups studied. A total of 12 different genotypes were identified, the higher number for the Mestizos and the lower number for the Tarahumaras. Genotype 1 was found at a greater frequency in all the groups, except for the Tarahumaras, in which genotype 4 was more frequent. The frequency of genotypes 4 and 8 in Mexicans was higher than that for other populations analyzed. By subtyping of KIR3DL1, 3DL2, 2DL1, and 2DL3, two B haplotypes were identified in families; both were absent in Caucasian families. Our results indicated a greater diversity of genes in the Mestizos group than in the ethnic groups.

Dup-24 bp in the CHIT1 Gene in Six Mexican Amerindian Populations.

Chitotriosidase (CHIT, EC 3.2.1.14) is an enzyme secreted by activated macrophages with the ability to hydrolyze the chitin of pathogens. The high activity of this enzyme has been used as a secondary biomarker of response to treatment in patients with Gaucher disease (OMIM 230800). Within the world's population, approximately 6% is homozygous and 35% is heterozygous for the most common polymorphism in the CHIT1 gene, a 24-bp duplication (dup-24 bp), with homozygosity of this duplication causing inactivation of the enzyme but without major consequences for health. To determine the frequency of the dup-24 bp CHIT1 gene in indigenous populations from Mexico, 692 samples were analyzed: Purepecha (49), Tarahumara (97), Huichol (97), Mayan (139), Tenek (97), and Nahua (213). We found that the groups were in Hardy-Weinberg equilibrium. The dup-24 bp allele frequency was found to be (in order of highest to lowest) 37% (Mayan), 34% (Huichol and Nahua), 33% (Purepecha), 31% (Tenek), and 29% (Tarahumara).