Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control

Journal of Diabetes Research
Caroline Anna BrorssonHvidoere Study Group on Childhood Diabetes

Abstract

Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological ...Continue Reading

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Citations

Oct 31, 2017·Current Diabetes Reports·Maria J RedondoAndrea K Steck
Mar 3, 2018·Journal of Diabetes Investigation·Fangying XieRonald Cw Ma
Nov 21, 2017·Biomedicine Hub·Richard InselJoseph Hedrick
Jun 22, 2018·Nature Immunology·Jamie R J InshawJohn A Todd

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Methods Mentioned

BETA
genotyping
PCR
CTSH

Software Mentioned

KASPar
PANTHER
STRING

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