Epigenetics of skin intrinsic florescence

Introduction & Objective: Cumulated advanced glycation end products (AGEs) in the bloodstream and tissues contribute to the pathogenesis of diabetes complications. The skin intrinsic fluorescence (SIF) is a non-invasive measurement of dermal AGEs level using spectrometer, and it can be used as a biomarker in AGEs-related diseases. Previously, specific epigenomic factor has been found to be associated with haemoglobin A1c (HbA1c). HbA1c is a type of glycated haemoglobin – the HbA1c test measures the average glycemic control over the period of 3 months. However, the effect of epigenetic factors on the level of AGEs in the skin remains unknown. We hypothesize that some cytosine-guanine dinucleotides (CpGs) are associated with SIF. An epigenome-wide associations study (EWAS) was performed to identify CpG sites associated with SIF in people with type 1 diabetes. Methods: 499 people with type 1 diabetes that have both methylation and SIF from the Diabetes Control Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were included. We fit linear regression models for SIF with each CpG site one at a time. The epigenome-wide significance level (p=5e-8) was applied. Then the result is compared with the null hypothesis where CpGs are not associated with SIF to check the inflation. In order to check the assumptions of the multiple linear models at a single CpG, we use diagnostic plots. Results: We did not identify a specific CpG that is significantly associated with neither skin intrinsic fluorescence 1 (SIF1) nor skin intrinsic fluorescence 12 (SIF 12).The CpG site with strongest effect is cg06538183 ([SE] -2.73 [0.61], p = 8.72e-6) on SIF1 and cg12871967 ([SE] 2.52, 0.53, p = 2.71e-6) on SIF12. Conclusion: We did not find any specific CpG that was significantly associated with either SIF 1 or SIF12. In general, the result suggests that DNA methylation does not impact the accumulation of AGEs in skin cells. DNA methylation data has a unique pattern of distribution that drives the non-uniform distribution of the p-values. The group of 275,301 CpGs that have means above the median and standard deviations below the median has the expected uniform p-value distribution.

Predictors of Change in Skin Intrinsic Fluorescence in Type 1 Diabetes: The Epidemiology of Diabetes Complications study

Background Skin intrinsic fluorescent (SIF) scores are indirect measures of advanced glycation end-products (AGEs). SIF scores are cross-sectionally associated with type 1 diabetes (T1D) complications such as increased albumin excretion rate (AER), coronary artery calcification (CAC) and neuropathy. We assessed predictors of SIF score change in those with T1D. Methods Data from the 30-year longitudinal Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D were used to assess AGEs measured with a SIF score produced by the SCOUT DS® device. SIF scores were assessed twice in 83 participants: between 2007-08 and again between 2010-14. Regression analyses were used to assess independent predictors of SIF score change Results At baseline, mean age was 47.9 ± 6.9 years, diabetes duration was 36.7 ± 6.4 years, and median glycosylated hemoglobin (HbA1c) was 7.1 (interquartile range: 6.5, 8.5). During a mean follow-up of 5.2 ± 0.9 years, mean change in SIF score was 2.9 ± 2.8 arbitrary units. In multivariable linear regression models, log HbA1c ( P < 0.001), log estimated glomerular filtration rate (eGFR) ( P < 0.001), overt nephropathy (defined as AER ≥ 200 µg/min, P = 0.06), and multiple daily insulin shots/pump use (MDI) exposure years ( P = 0.02) were independent predictors of SIF score change. Conclusions Increases in SIF score over 5 years were related to increased glycemic levels and decreased kidney function (eGFR). MDI and glomerular damage were related to a decreased SIF score. This is one of the first studies with repeated SIF assessments in T1D and provides unique, albeit preliminary, insight about these associations.