Genetic polymorphisms associated with pediatric-onset type 2 diabetes: A family-based transmission disequilibrium test and case-control study.

BACKGROUND AND OBJECTIVE: Genetics play a very strong role in the development of pediatric-onset type 2 diabetes (T2D); however, little information exists about specific common single nucleotide polymorphisms (SNPs) associated with T2D in this age group. The aim of the study was to analyze the association and parental transmission of 64 obesity-related SNPs with pediatric-onset T2D in Mexican families. METHODS: A total of 57 pedigrees containing 171 probands with pediatric-onset T2D and 119 unrelated controls older than 18 years were included. The participants were genotyped for 64 polymorphisms. Association of each variant with pediatric-onset T2D was analyzed through a parent-offspring transmission disequilibrium test (TDT) and in a case-control comparison by χ2 analysis. RESULTS: Five SNPs exhibited associations with pediatric-onset T2D in the combined case-parent trio and case-control analysis: LINGO/rs10968576 (odds ratio [OR] 1.82, P = 0.003), POC5/rs2112347 (OR 1.96, P = 2.4E-5), RPS10-NUDT3/rs206936 (OR 1.40, P = 0.023), GLIS3/rs7034200 (OR 2.34, P = 1.2E-6), and VEGFA/rs6905288 (OR 1.58, P = 0.015). The first three were also associated with obesity status. The SNPs POC5/rs2112347 and RPS10-NUDT3/rs206936 were significantly associated through the maternal allele and GLIS3/rs7034200 through the paternal allele (P < 0.05). CONCLUSIONS: These findings suggest that certain SNPs associated with obesity and other metabolic traits may also be involved in risk of pediatric-onset T2D in Mexican families. We also identified preferential transmission of parental alleles in some variants.

Associations of common variants in the SLC16A11, TCF7L2, and ABCA1 genes with pediatric-onset type 2 diabetes and related glycemic traits in families: A case-control and case-parent trio study.

BACKGROUND: There is evidence of associations of single-nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D) and related glycemic traits in adults, but there is a little information about such associations in youths. OBJECTIVE: The aim of this study was to evaluate the associations of SNPs in the TCF7L2, SLC16A11, and ABCA1 genes with T2D and related glycemic traits in Mexican children and adolescents. SUBJECTS: A total of 99 families with children with T2D (n = 327) and 83 families with children without the disease (n = 212). METHODS: The associations between SNPs of TCF7L2 (rs7903146 and rs12255372), SLC16A11 (rs13342232), and ABCA1 (rs9282541) with T2D were analyzed. We also evaluated the effects of SNPs on quantitatively related glycemic traits after adjusting for age, sex, and the presence of overweight or obesity. RESULTS: The G allele of SLC16A1 /rs13342232 was associated with T2D in adults (adjusted odds ratio [ORadj] = 1.89; 95% confidence interval [CI]: 1.18; 3.06) and children (ORadj = 1.94; 95% CI: 1.25; 3.00). In addition, the combined analysis of case-control and case-parent trio was also significant (OR = 1.43; 95% CI: 1.12; 1.74). After adjusting for known confounding factors, we found a significant association between TCF7L2/rs122555372 and C-peptide (ß = -0.76, P = .005) in patients with diabetes and between fasting glucose (ß = 2.05, P = .039) and homeostatic model assessment of ß-cell function (ß = -32.14, P = .025) levels in individuals without diabetes. CONCLUSIONS: The results suggest that SLC16A1 /rs13342232 might be involved in the risk of pediatric-onset T2D in Mexican families. Moreover, TCF7L2/rs122555372 was associated with pancreatic reserve in patients with T2D and with fasting glucose and ß-cell function in individuals without diabetes.

Heritability, parental transmission and environment correlation of pediatric-onset type 2 diabetes mellitus and metabolic syndrome-related traits.

AIM: To estimate the heritability, parental transmission and environmental contributions to the phenotypic variation in type 2 diabetes mellitus and metabolic syndrome-related traits in families of Mexican children and adolescents. METHODS: We performed a cross-sectional study of 184 tri-generational pedigrees with a total of 1160 individuals (99 families with a type 2 diabetes mellitus proband before age 19). The family history of type 2 diabetes mellitus in three generations was obtained by interview. Demographic, anthropometric, biochemical and lifestyle information was corroborated in parents and offspring. We obtained correlations for metabolic traits between relative pairs, and variance component methods were used to determine the heritability and environmental components. RESULTS: The heritability of early-onset of type 2 diabetes mellitus was 0.50 (p<1.0e-7). The heritability was greater than 0.5 for hypertension, hypoalphalipoproteinemia, hypercholesterolemia, body mass index, waist circumference, blood pressure, 2-h insulin, and cholesterol (p<0.001). In contrast, we observed a high environmental correlation (>0.50) for blood pressure, HbA1c and HDL-cholesterol after multivariate adjustment (p<0.05). Several traits, such as type 2 diabetes mellitus and insulin resistance, were significantly correlated only through the mother and others, such as hypertriglyceridemia, were significantly correlated only through the father. CONCLUSION: This study demonstrates that type 2 diabetes mellitus and metabolic syndrome-related traits are highly heritable among Mexican children and adolescents. Furthermore, several cardiometabolic factors have strong heritability and/or high environmental contributions that highlight the complex architecture of these alterations.

Exploring single nucleotide polymorphisms previously related to obesity and metabolic traits in pediatric-onset type 2 diabetes.

AIMS: To evaluate the association of 64 obesity-related polymorphisms with pediatric-onset type 2 diabetes and other glucose- and insulin-related traits in Mexican children. METHODS: Case-control and case-sibling designs were followed. We studied 99 patients with pediatric-onset type 2 diabetes, their siblings (n = 101) without diabetes, 83 unrelated pediatric controls and 137 adult controls. Genotypes were determined for 64 single nucleotide polymorphisms, and a possible association was examined between those genotypes and type 2 diabetes and other quantitative traits, after adjusting for age, sex and body mass index. RESULTS: In the case-pediatric control and case-adult control analyses, five polymorphisms were associated with increased likelihood of pediatric-onset type 2 diabetes; only one of these polymorphisms (CADM2/rs1307880) also showed a consistent effect in the case-sibling analysis. The associations in the combined analysis were as follows: ADORA1/rs903361 (OR 1.9, 95% CI 1.2; 3.0); CADM2/rs13078807 (OR 2.2, 95% CI 1.2; 4.0); GNPDA2/rs10938397 (OR 2.2, 95% CI 1.4; 3.7); VEGFA/rs6905288 (OR 1.4, 95% CI 1.1; 2.1) and FTO/rs9939609 (OR 1.8, 95% CI 1.0; 3.2). We also identified 16 polymorphisms nominally associated with quantitative traits in participants without diabetes. CONCLUSIONS: ADORA/rs903361, CADM2/rs13078807, GNPDA2/rs10938397, VEGFA/rs6905288 and FTO/rs9939609 are associated with an increased risk of pediatric-onset type 2 diabetes in the Mexican population.