Association of total and pancreatic serum amylase enzymatic activity with insulin resistance and the glucose and insulin responses to oral starch test in Mexican children.

BACKGROUND/OBJECTIVES: Little is known about the effect of serum amylase enzymatic activity on glucose metabolism. We investigated the association of serum amylase enzymatic activity with fasting plasma glucose, insulin resistance (IR), and the plasma glucose and insulin response to an oral starch test (OST) in Mexican children. METHODS: Anthropometric data, glucose and insulin levels, and the serum enzymatic activity of total (AMYt), salivary (AMY1), and pancreatic (AMY2) amylase were analysed in 764 children (Nnormal weight  = 427/Nobesity  = 337). After categorization into low (LA) and high (HA) AMYt, an OST with commercial white bread was performed in 39 children (Nnormal weight  = 17/Nobesity  = 22). RESULTS: A positive association between serum enzymatic activity of AMY2 and IR was observed in children with obesity (p = 0.018). Children with normal weight had lower plasma glucose and insulin response to OST than children with obesity (Pglucose  = 4.1 × 10-12 ; Pinsulin  = 2.1 × 10-15 ). Compared with the LA group, children with HA showed lower plasma glucose and insulin response to OST (Pglucose ≤ 0.040; Pinsulin ≤ 0.015). CONCLUSION: Our results suggest that AMY2 is positively associated with IR. A high level of AMYt is related to lower glucose and insulin responses to OST in Mexican children, regardless of their weight status.

Association of rs9939609-FTO with metabolic syndrome components among women from Mayan communities of Chiapas, Mexico.

BACKGROUND: Metabolic syndrome (MetS) is a complex cluster of risk factors, considered as a polygenic and multifactorial entity. The objective of this study was to determine the association of rs9939609-FTO polymorphism and MetS components in adult women of Mayan communities of Chiapas. METHODS: In a cross-sectional study, sociodemographic, anthropometric, clinical, and biochemical data were obtained from 291 adult women from three regions of Chiapas, Mexico. The prevalence of MetS and the allele and genotype frequencies of the rs9939609-FTO were estimated. Multivariate logistic regression models were used to assess the association of the single nucleotide polymorphism (SNP) with each of the MetS components. RESULTS: The MetS prevalence was 60%. We found a statistically significant association between rs9939609-FTO and hyperglycemia in the dominant model (OR 2.6; 95% CI 1.3-5.3; p = 0.007). CONCLUSIONS: Women from Mayan communities of Chiapas presented a high prevalence of MetS and a relevant association of the FTO variant with hyperglycemia. This is the first study carried out in these Mayan indigenous communities from Chiapas.

The MC4R p.Ile269Asn mutation confers a high risk for type 2 diabetes in the Mexican population via obesity dependent and independent effects.

We investigated the association between the loss-of-function mutation MC4R p.Ile269Asn and T2D risk in the Mexican population. We enrolled 6929 adults [3175 T2D cases and 3754 normal glucose tolerant (NGT) controls] and 994 NGT children in the study. Anthropometric data and T2D-related quantitative traits were studied in 994 NGT children and 3754 NGT adults. The MC4R p.Ile269Asn mutation was genotyped using TaqMan. The MC4R p.Ile269Asn mutation was associated with T2D [OR = 2.00, 95% confidence interval (CI) 1.35-2.97, p = 0.00057] in Mexican adults. Additional adjustment for body-mass index (BMI) attenuated but did not remove the association (OR = 1.70, 95% CI 1.13-2.56, p = 0.011). The MC4R p.Ile269Asn mutation was associated with T2D (OR = 1.88, 95% CI 1.14-3.08, p = 0.013) in a subset of 1269 T2D cases and 1269 NGT controls matched for sex, age, and BMI. A mediation analysis estimated that BMI accounts for 22.7% of the association between MC4R p.Ile269Asn mutation and T2D risk (p = 4.55 × 10-6). An association was observed between the MC4R p.Ile269Asn mutation and BMI in NGT children and adults (children: beta = 3.731 ± 0.958, p = 0.0001; adults: beta = 2.269 ± 0.536, p = 2.3 × 10-5). In contrast, the mutation was not associated with T2D-related quantitative traits. We demonstrate that the MC4R p.Ile269Asn mutation predisposes to T2D via obesity-dependent and independent effects in the Mexican population.

AGT rs4762 is associated with diastolic blood pressure in Mexicans with diabetic nephropathy.

AIMS: Since angiotensinogen has a pivotal role in the renin-angiotensin-aldosterone system, the analysis of polymorphisms of the angiotensinogen (AGT) gene could help explain its potential involvement in hypertension and diabetic nephropathy (DN) pathogenesis. For that reason, we investigated 1) the association of AGT rs4762 with blood pressure (BP) and kidney function-related traits and 2) the interaction effect of AGT rs4762 with DN on BP and kidney function-related traits in 546 Mexican adults with type 2 diabetes (T2D). METHODS: We enrolled 546 unrelated Mexican patients with T2D (350 cases with DN and 196 controls without DN). AGT rs4762 was genotyped in all participants using TaqMan technology (effect allele: A). BP and kidney function-related traits, including serum urea and creatinine, urinary albumin, urine albumin to urine creatinine ratio (ACR), and glomerular filtration rate, were studied. DN was defined as having a previous diagnosis of T2D and an ACR ≥ 30 mg/g. The association between these parameters was investigated using logistic regression with adjustment for covariates. RESULTS: AGT rs4762 A allele was significantly associated with diastolic blood pressure (N = 546, ß = 1.243 ± 0.918, p = 0.029). A significant interaction between DN and AGT rs4762 was also observed in relation to diastolic blood pressure (DBP) (N = 546, ß = 0.930 ± 0.433, p=0.032). A follow-up analysis of simple effects particularly revealed a positive association between AGT rs4762 A allele and DBP only in patients with diabetic nephropathy (N = 350, ß = 2.837 ±â€¯1.267, p = 0.026). CONCLUSION: Our results evidence that, although AGT rs4762 is not associated with DN, the AGT rs4762 A allele is positively associated with DBP in the Mexican population with DN.

Sex/Gender Modifies the Association Between the MC4R p.Ile269Asn Mutation and Type 2 Diabetes in the Mexican Population.

CONTEXT: Studies in mice and humans suggest that melanocortin-4 receptor (MC4R) deficiency affects body weight in a sex-/gender-dependent manner. However, similar evidence for type 2 diabetes (T2D) is scarce. OBJECTIVE AND DESIGN: We investigated whether sex/gender modifies the association between the loss-of-function MC4R p.Ile269Asn mutation and T2D in 6929 Mexican adults (3175 T2D cases and 3754 normal glucose tolerance [NGT] controls). The 2003 American Diabetes Association criteria were used to define NGT and T2D. The MC4R p.Ile269Asn mutation was genotyped in all participants using TaqMan technology. RESULTS: The MC4R p.Ile269Asn mutation was associated with T2D in 6929 Mexican adults (Ncontrols = 3754, Ncases = 3175, odds ratio [OR] = 2.00, 95% confidence interval [CI], 1.35-2.97; P = 5.7 × 10-4). The MC4R p.Ile269Asn mutation had a frequency of 0.86 and 1.05% in women with NGT and T2D, and 0.78 and 1.32% in men with NGT and T2D, respectively. We identified a significant interaction between the MC4R p.Ile269Asn mutation and sex/gender on T2D risk (P = 0.049). Although a strong association between the mutation and T2D was observed in men (Ncontrols = 2418, Ncases = 1807, OR = 2.63, 95% CI, 1.62-4.28, P = 9.3 × 10-5), results were not significant in women (Ncontrols = 1336, Ncases = 1368, OR = 1.16, 95% CI, 0.60-2.26, P = 0.65). Further adjustment for body mass index in the logistic regression model did not alter the sex-/gender-specific pattern of association (men: OR = 2.22, 95% CI, 1.34-3.67, P = 0.0019; women: OR = 1.02, 95% CI, 0.51-2.02, P = 0.95). CONCLUSION: This is the first report of a male-specific association between the MC4R p.Ile269Asn loss-of-function mutation and T2D in the Mexican population.

Association of gut microbiome with fasting triglycerides, fasting insulin and obesity status in Mexican children.

BACKGROUND: The association of gut microbiota with obesity and its cardio-metabolic complications in paediatric populations is still controversial. OBJECTIVE: We investigated the association of obesity and cardio-metabolic traits with gut microbiota on 167 and 163 children with normal weight and obesity from Mexico City and Oaxaca, Mexico. METHODS: Anthropometric and biochemical traits were measured. The microbial communities were determined by high-throughput sequencing of bacterial 16S rRNA gene v3-v4 region. RESULTS: The gut microbial community structure was associated with obesity and fasting plasma insulin (FPI) in Mexico City (PObesity = 0.012, PFPI = 0.0003) and Oaxaca (PObesity = 0.034, PFPI = 0.016), and with triglycerides (TG) in Oaxaca (P = .0002). The Firmicutes/Bacteroidetes ratio was positively associated with TG in Oaxaca (P = .003). Firmicutes and Bacteroidetes phyla were positively and negatively associated with obesity (Mexico City: PFirmicutes = 0.013, PBacteroidetes = 0.009) and TG (Oaxaca: PFirmicutes = 0.002, PBacteroidetes = 0.004). In Oaxaca, Verrucomicrobia was negatively associated with obesity (P = .004). In Mexico City, the bacterial genus Fusicatenibacter, Romboutsia, Ruminococcaceae, Ruminiclostridium, Blautia, Clostridium, Anaerostipes and Intestinibacter were associated with obesity and FPI, while in Oaxaca, Bacteroides, Alistipes and Clostridium were associated with TG. CONCLUSION: The gut microbial community structure in children is associated with obesity and FPI in Mexico City, and with obesity, FPI and TG in Oaxaca.

Association of AMY1A/AMY2A copy numbers and AMY1/AMY2 serum enzymatic activity with obesity in Mexican children.

BACKGROUND: Mexican children are characterized by a high-starch intake diet and high prevalence of obesity. OBJECTIVES: To investigate the association of AMY1A/AMY2A copy numbers (CNs) and AMY1/AMY2 serum enzymatic activity with childhood obesity in up to 427 and 337 Mexican cases and controls. METHODS: Anthropometric and dietary starch intake data were collected. CN of AMY1A/AMY2A and AMY1/AMY2 serum enzymatic activity were determined using droplet digital PCR (ddPCR) and enzymatic colorimetry, respectively. An individual participant level data meta-analysis of association between AMY1A CNVs and obesity was also performed. RESULTS: A positive association between AMY1A/AMY2A CNs and their corresponding AMY1/AMY2 serum enzyme activity was observed in children with normal weight and obesity. The serum enzyme activity of AMY1 and AMY2 was negatively associated with childhood obesity risk, and the association was restricted to kids eating medium/high amount of starch (Pinteraction = .004). While no association between AMY1A and AMY2A CNs and childhood obesity was observed in our sample, we confirmed a significant association between AMY1A CN and obesity in a meta-analysis of 3100 Mexican children. CONCLUSIONS: Our data suggest that genetically determined salivary and pancreatic amylase activity can increase/decrease the risk of obesity in Mexican children, this effect being blunted by a low-starch diet.

Causal Association of Haptoglobin With Obesity in Mexican Children: A Mendelian Randomization Study.

CONTEXT: Little is known about the association between haptoglobin level and cardiometabolic traits. A previous genome-wide association study identified rs2000999 in the HP gene as the stronger genetic contributor to serum haptoglobin level in European populations. OBJECTIVE AND DESIGN: We investigated the association of HP rs2000999 with serum haptoglobin and childhood and adult obesity in up to 540/697 and 592/691 Mexican cases and controls, respectively. Anthropometric and biochemical data were collected. Serum haptoglobin was measured by an immunoturbidimetry assay. HP rs2000999 was genotyped using the TaqMan technology. Mendelian randomization analysis was performed using the Wald and inverse variance weighting methods. RESULTS: Haptoglobin level was positively associated with childhood and adult obesity. HP rs2000999 G allele was positively associated with haptoglobin level in children and adults. HP rs2000999 G allele was positively associated with childhood but not adult obesity. The association between HP rs2000999 and childhood obesity was removed after adjusting for haptoglobin level. In a Mendelian randomization analysis, haptoglobin level genetically predicted by HP rs2000999 showed a significant causal effect on childhood obesity by the Wald and inverse variance weighting methods. CONCLUSION: Our data provide evidence for the first time for a causal positive association between serum haptoglobin level and childhood obesity in the Mexican population. Our study contributes to the genetic elucidation of childhood obesity and proposes haptoglobin as an important biomarker and treatment target for obesity.

The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans.

CONTEXT: Rare partial/complete loss-of-function mutations in the melanocortin-4 receptor (MC4R) gene are the most common cause of Mendelian obesity in European populations, but their contribution to obesity in the Mexican population is unclear. OBJECTIVE AND DESIGN: We investigated whether deleterious mutations in MC4R contribute to obesity in Mexican children and adults. RESULTS: We provide evidence that the MC4R p.Ile269Asn (rs79783591) mutation may have arisen in modern human populations from a founder event in native Mexicans. The MC4R Isoleucine 269 is perfectly conserved across 184 species, which suggests a critical role for the amino acid in MC4R activity. Four in silico tools (SIFT, PolyPhen-2, CADD, MutPred2) predicted a deleterious impact of the p.Ile269Asn substitution on MC4R function. The MC4R p.Ile269Asn mutation was associated with childhood (Ncontrols = 952, Ncases = 661, odds ratio (OR) = 3.06, 95% confidence interval (95%CI) [1.94-4.85]) and adult obesity (Ncontrols = 1445, Ncases = 2,487, OR = 2.58, 95%CI [1.52-4.39]). The frequency of the MC4R p.Ile269Asn mutation ranged from 0.52 to 0.59% and 1.53 to 1.59% in children and adults with normal weight and obesity, respectively. The MC4R p.Ile269Asn mutation co-segregated perfectly with obesity in 5 multigenerational Mexican pedigrees. While adults with obesity carrying the p.Ile269Asn mutation had higher BMI values than noncarriers, this trend was not observed in children. The MC4R p.Ile269Asn mutation accounted for a population attributable risk of 1.28% and 0.68% for childhood and adult obesity, respectively, in the Mexican population. CONCLUSION: The MC4R p.Ile269Asn mutation may have emerged as a founder mutation in native Mexicans and is associated with childhood and adult obesity in the modern Mexican population.