Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.

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Abstrakt

Tytuł:: Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.
Autorzy:: Roshandel D; Genetics and Genome Biology Program, Peter Gilgan Centre for Research and Learning (PGCRL), The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 1H3, Canada.
Gubitosi-Klug R; University Hospitals Case Western Medical Center, Cleveland, OH, USA.
Bull SB; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
Canty AJ; Department of Mathematics and Statistics, McMaster University, Hamilton, ON, Canada.
Pezzolesi MG; Division of Nephrology and Hypertension, Diabetes and Metabolism Center, University of Utah, Salt Lake City, UT, USA.
King GL; Research Division, Joslin Diabetes Center, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Keenan HA; Research Division, Joslin Diabetes Center, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Snell-Bergeon JK; Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Maahs DM; Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Department of Paediatrics, Stanford School of Medicine, Stanford, CA, USA.
Klein R; Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
Klein BEK; Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
Orchard TJ; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Costacou T; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Weedon MN; Institute for Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
Oram RA; Institute for Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.; National Institute for Health Research, Exeter Clinical Research Facility, Exeter, UK.
Paterson AD; Genetics and Genome Biology Program, Peter Gilgan Centre for Research and Learning (PGCRL), The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 1H3, Canada. .; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. .
Corporate Authors:: DCCT/EDIC Research Group
Źródło:: Diabetologia [Diabetologia] 2018 May; Vol. 61 (5), pp. 1098-1111. Date of Electronic Publication: 2018 Feb 05.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: Berlin Springer Verlag
MeSH Terms:: Genome-Wide Association Study*
C-Peptide/*blood
Chromosomes, Human, Pair 1/*genetics
Diabetes Mellitus, Type 1/*genetics
Histocompatibility Antigens Class I/*genetics
Adolescent ; Adult ; Alleles ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/blood ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Insulin-Secreting Cells/metabolism ; Male ; Polymorphism, Single Nucleotide ; Young Adult
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Grant Information:: U01 DK094176 United States DK NIDDK NIH HHS; R01 DK077510 United States DK NIDDK NIH HHS; R01 HL079611 United States HL NHLBI NIH HHS; 17-2013-9 United States JDRF Juvenile Diabetes Research Foundation; UL1 RR025758-03 United States DK NIDDK NIH HHS; R01EY03083 United States EY NEI NIH HHS; U01 DK094157 United States DK NIDDK NIH HHS; UL1 RR025758 United States RR NCRR NIH HHS; R01 HL061753 United States HL NHLBI NIH HHS; P30 DK017047 United States DK NIDDK NIH HHS; P30 DK57516 International DERC Clinical Investigation Core; R01 HL113029 United States HL NHLBI NIH HHS; P30 DK036836 United States DK NIDDK NIH HHS; U01 DK062418 United States DK NIDDK NIH HHS; UL1 TR001082 United States TR NCATS NIH HHS; R37 DK034818 United States DK NIDDK NIH HHS; R01 DK116731 United States DK NIDDK NIH HHS; R01 DK034818 United States DK NIDDK NIH HHS
Contributed Indexing:: Keywords: C-peptide; Genome-wide association study; Insulin-secreting cells; Single nucleotide polymorphism; Type 1 diabetes
Substance Nomenclature:: 0 (C-Peptide)
0 (Histocompatibility Antigens Class I)
Entry Date(s):: Date Created: 20180207 Date Completed: 20190128 Latest Revision: 20220917
Update Code:: 20240104
PubMed Central ID:: PMC5876265
DOI:: 10.1007/s00125-018-4555-9
PMID:: 29404672
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Aims/hypothesis: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS).
Methods: We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels.
Results: In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 × 10 -8 ), meeting the genome-wide significance threshold (p < 5 × 10 -8 ). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p = 8.43 × 10 -8 ). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (β [SE] = - 0.39 [0.07], p = 9.72 × 10 -8 ). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 × 10 -8 ). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes.
Conclusions/interpretation: We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.

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