New Locus for Skin Intrinsic Fluorescence in Type 1 Diabetes Also Associated With Blood and Skin Glycated Proteins

Delnaz Roshandel, Ronald Klein, Barbara E K Klein, Bruce H R Wolffenbuttel, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Gil Atzmon, Danny Ben-Avraham, Jill P Crandall, Nir Barzilai, Shelley B Bull, Angelo J Canty, S Mohsen Hosseini, Linda T Hiraki, John Maynard, David R Sell, Vincent M Monnier, Patricia A Cleary, Barbara H Braffett, DCCT/EDIC Research Group, Andrew D Paterson, Delnaz Roshandel, Ronald Klein, Barbara E K Klein, Bruce H R Wolffenbuttel, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Gil Atzmon, Danny Ben-Avraham, Jill P Crandall, Nir Barzilai, Shelley B Bull, Angelo J Canty, S Mohsen Hosseini, Linda T Hiraki, John Maynard, David R Sell, Vincent M Monnier, Patricia A Cleary, Barbara H Braffett, DCCT/EDIC Research Group, Andrew D Paterson

Abstract

Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). A locus on chromosome 1, rs7533564 (P = 1.9 × 10(-9)), was associated with skin intrinsic fluorescence measured by SCOUT DS (excitation 375 nm, emission 435-655 nm), which remained significant after adjustment for time-weighted HbA1c (P = 1.7 × 10(-8)). rs7533564 was associated with mean HbA1c in meta-analysis (P = 0.0225), mean glycated albumin (P = 0.0029), and glyoxal hydroimidazolones (P = 0.049), an AGE measured in skin biopsy collagen, in DCCT. rs7533564 was not associated with diabetes complications in DCCT/EDIC or with SF in subjects without diabetes (nondiabetic [ND]) (N = 8,721). In conclusion, we identified a new locus associated with SF in T1D subjects that did not show similar effect in ND subjects, suggesting a diabetes-specific effect. This association needs to be investigated in type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00360815 NCT00360893.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1
Figure 1
Regional plot of 200 kb surrounding rs7533564 with SNP P values from DCCT/EDIC and WESDR meta-GWAS (A) and LifeLines (B), with ND subjects on the left y-axis, their genomic position (GRCh37/hg19) on the x-axis, and estimated recombination rates on the right y-axis. The plot was made using LocusZoom (http://locuszoom.sph.umich.edu/locuszoom/) (36). The linkage disequilibrium measures and recombination rates are based on the HapMap CEU population (release 22).
Figure 2
Figure 2
Bee swarm plots showing level of SIF1 for each participant in the DCCT/EDIC and WESDR according to rs7533564 genotype. SIF1 is natural log transformed.

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