Identification of novel alleles associated with insulin resistance in childhood obesity using pooled-DNA genome-wide association study approach

Abstract

Background:Recently, we witnessed great progress in the discovery of genetic variants associated with obesity and type 2 diabetes (T2D), especially in adults. Much less is known regarding genetic variants associated with insulin resistance (IR). We hypothesized that novel IR genes could be efficiently detected in a population of obese children and adolescents who may not exhibit comorbidities and other confounding factors.Objectives:This study aimed to determine whether a genome-wide association study (GWAS), using a DNA-pooling approach, could identify novel genes associated with IR.Subjects:The pooled-DNA GWAS analysis included Slovenian obese children and adolescents with and without IR matched for body mass index, gender and age. A replication study was conducted in another independent cohort with or without IR.Methods:For the pooled-DNA GWAS, we used HumanOmni5-Quad SNP array (Illumina). Allele frequency distributions were compared with modified t-tests and χ2-tests and ranked using PLINK. Top single nucleotide polymorphisms (SNPs) were validated using individual genotyping by high-resolution melting analysis and TaqMan assay.Results:We identified five top-ranking SNPs from the pooled-DNA GWAS analysis within the ECE1, IL1R2, GNPDA1, HLA-J and PYGB loci. All except SNP rs9261108 (HLA-J locus) were confirmed in the validation phase using individual genotyping. The SNP rs2258617 within PYGB remained statistically significant for both recessive and additive models in both cohorts and in a merged analysis of both cohorts and present the strongest novel candidate gene for IR.Conclusion:We report for the first time a pooled-DNA GWAS approach to identify five novel SNPs or genes for IR in a paediatric population. The four loci confirmed in the second validation phase study warrant further studies, especially the strongest SNP rs2258617 within PYGB, and provide targets for further basic research of IR mechanisms and for the development of potential new IR and T2D therapies.

Trajectories of changes in glucose tolerance in a multiethnic cohort of obese youths: an observational prospective analysis

“…(4, 27–29) However, demonstrating the pivotal role that ethnicity plays in the pathogenesis of youth onset impaired glucose tolerance, we support the concept that the genetic background, of which ethnicity is a reliable proxy, (30) is the major determinant of change in glucose tolerance in this age group, and, potentially, of the response to the therapeutic options. Indeed, genetic factors affecting both the individual insulin sensitivity (31, 32) and the beta cell response in the context of the whole body insulin sensitivity could explain the dysfunctional response to impaired glucose tolerance observed in the NHB group. (33)…”

Reduced serum calcium is associated with a higher risk of retinopathy in non-diabetic individuals: The Chinese Multi-provincial Cohort Study

“…By these findings, elevated glucose may alter calcium homeostasis in the retina ( 24 ) and enhance constriction of retinal venules through activation of the reverse-mode sodium-calcium exchanger ( 25 ). On the other hand, abnormalities in circulating calcium levels could have a crucial role in insulin release and glucose homeostasis ( 26 ). The impact of decreased calcium on the relation between high glucose and retinopathy risk warrants prospective assessment in the future.…”

DNA methylation signature in blood mirrors successful weight-loss during lifestyle interventions: the CENTRAL trial

“…Besides the clear differences in methylation between responders and non-responders of a lifestyle therapy, the DMR is further associated with parameters of glucose metabolism in our study. This is reasonable since RNF39 is located in close proximity to the HLA-J ( Major Histocompatibility Complex, Class I, J ) locus on chromosome 6p22, a pseudogene of HLA-A ( Major Histocompatibility Complex, Class I, A ), and genetic variants in this region have been shown to be associated with insulin resistance in childhood obesity [ 41 ] as well as non-obstructive coronary artery disease in women [ 42 ]. Furthermore, our results go in line with data from Meeks et al showing that a DMR of 13 CpG sites in close proximity to RNF39 is associated with obesity in human blood samples among 547 Ghanaians subjects [ 43 ].…”