The online version of this article (https://doi.org/10.1007/s00125-018-4555-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
A complete list of participants in the DCCT/EDIC Research Group is presented in the Supplementary Material published online for the article in N Engl J Med 2015;372:1722–1733.
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).
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.
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.
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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- 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
Shelley B. Bull
Angelo J. Canty
Marcus G. Pezzolesi
George L. King
Hillary A. Keenan
Janet K. Snell-Bergeon
David M. Maahs
Barbara E. K. Klein
Trevor J. Orchard
Michael N. Weedon
Richard A. Oram
Andrew D. Paterson
DCCT/EDIC Research Group
- Springer Berlin Heidelberg
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