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.
Highlights
Obesity in adults and children is one of the largest worldwide health-care problems
The underlying hypothesis was that the insulin resistance (IR)+ DNA pool would contain more susceptibility alleles for IR than the IR − DNA pool, which could be detected as a difference in allele frequencies or in relative allele signal intensities
Using pooled-DNA genome-wide association study (GWAS) analyses, we identified five single nucleotide polymorphisms (SNPs) and corresponding genes significantly associated with IR in a population of obese children and adolescents: rs212540 (ECE1), rs3218888 (IL1R2), rs252111 (GNPDA1), rs9261108 (HLA-J), and rs2258617 (PYGB)
Summary
Obesity in adults and children is one of the largest worldwide health-care problems. A recent comprehensive analysis of overweight and obesity in 195 countries between 1990 and 2015 has revealed sobering trends in that the rate of increase of obesity in children has been greater than the rate of increase in adults.[1]. Several genetic variants have been associated with IR in humans using candidate gene and genomewide association study (GWAS) approaches.[5,9] There is a higher incidence of IR with the simultaneous presence of obesity and Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, Domzale 1000, Slovenia. 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. RESULTS: We identified five top-ranking SNPs from the pooled-DNA GWAS analysis within the ECE1, IL1R2, GNPDA1, HLA-J and PYGB loci. 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
