title: 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.
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 functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment.
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Brorsson
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Marie Louise
authors.initials: ML
authors.lastname: Andersen
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Simranjeet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Novo Nordisk A/S, 2760 Måløv, Denmark.
authors.forename: Regine
authors.initials: R
authors.lastname: Bergholdt
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, Denmark.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.affiliation: DECCP, Clinique Pédiatrique, CH de Luxembourg, 4 rue Barblé, 1210 Luxembourg, Luxembourg.
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D040741:Genetic Load; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006442:Glycated Hemoglobin / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D006442:Glycated Hemoglobin; D007371:Interferon-gamma; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C573415:IFNG protein, human; C508585:IL1B protein, human; C517652:hemoglobin A1c protein, human