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
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...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2016/9570424 |
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| author | Caroline A. Brorsson Lotte B. Nielsen Marie Louise Andersen Simranjeet Kaur Regine Bergholdt Lars Hansen Henrik B. Mortensen Flemming Pociot Joachim Størling Hvidoere Study Group on Childhood Diabetes |
| author_facet | Caroline A. Brorsson Lotte B. Nielsen Marie Louise Andersen Simranjeet Kaur Regine Bergholdt Lars Hansen Henrik B. Mortensen Flemming Pociot Joachim Størling Hvidoere Study Group on Childhood Diabetes |
| author_sort | Caroline A. Brorsson |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1f2fcf2e4c0340eeac4ce763ef934d19 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-1f2fcf2e4c0340eeac4ce763ef934d192025-08-20T03:54:36ZengWileyJournal of Diabetes Research2314-67452314-67532016-01-01201610.1155/2016/95704249570424Genetic 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 ControlCaroline A. Brorsson0Lotte B. Nielsen1Marie Louise Andersen2Simranjeet Kaur3Regine Bergholdt4Lars Hansen5Henrik B. Mortensen6Flemming Pociot7Joachim Størling8Hvidoere Study Group on Childhood Diabetes9Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkNovo Nordisk A/S, 2760 Måløv, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkCopenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics E, University Hospital Herlev, 2730 Herlev, DenmarkDECCP, Clinique Pédiatrique, CH de Luxembourg, 4 rue Barblé, 1210 Luxembourg, LuxembourgGenome-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.http://dx.doi.org/10.1155/2016/9570424 |
| spellingShingle | Caroline A. Brorsson Lotte B. Nielsen Marie Louise Andersen Simranjeet Kaur Regine Bergholdt Lars Hansen Henrik B. Mortensen Flemming Pociot Joachim Størling Hvidoere Study Group on Childhood Diabetes 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 |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://dx.doi.org/10.1155/2016/9570424 |
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