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Abstract: PO0920

Cytosine Methylation Changes in Early Diabetic Kidney Disease (DKD) in a Pima Indian Cohort

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sullivan, Katie, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Qiu, Chengxiang, University of Washington, Seattle, Washington, United States
  • Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Nelson, Robert G., National Institutes of Health, Bethesda, Maryland, United States
  • Hanson, Robert L., National Institutes of Health, Bethesda, Maryland, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Pima Indians of Arizona have an extremely high prevalence of type 2 diabetes and DKD. Genetically related Pima Indians living in Mexico, whose lifestyle remains traditional, have a much lower prevalence of these morbidities. The differences in lifestyle indicate that environmental factors play an important role in disease origins and suggest involvement of epigenetic programming. We analyzed cytosine methylation (5mC) changes in Pima Indians from Arizona.

Methods

327 Pima Indians (205 women, 122 men) were selected from a longitudinal cohort, all had an eGFR greater than 60ml/min and ACR <300mg/g at baseline. DNA methylation from peripheral blood leukocytes was analyzed on an Illumina Infinium HumanMethylation 450 Beadchip. Preprocessing and Quality Control were performed using Minfi Package, normalization was performed using BMIQ. Methylation changes were expressed transformed to M values. Covariates included age, sex, duration of diabetes, mean blood pressure, HbA1c, genotype, batch, cell count and conversion efficiency. P-values were corrected for multiple comparisons.

Results

Mean age was 42.4±11.9 years, diabetes duration 7.8±7.5 years, HbA1c 8.8±2.4%, GFR 107±16 ml/min and median albuminuria was 20.2[48.2]mg/g. Subjects were followed for a median of 10 years (range 3-17 years) and had a mean GFR decline of 2.0±2.8 ml/min/year. Ranked regression, adjusted for key variables, identified 20 probes that passed the corrected significance threshold for kidney function decline. Most significant probes were enriched on gene regulatory regions such as promoters and enhancers. The top identified probe was cg05711886 around the Maternally expressed gene 3 (MEG3)on chromosome 14, (p=2.66E-10). MEG3 is a non-coding RNA previously associated with diabetic microvascular complications. Other probes included cg11306628 (p=1.62E-5) in Platelet Derived Growth Factor Alpha (PDGFA) on chromosome 7, a known type 2 diabetes risk gene, as well as cg06392169 (p=3.14E-5) in Interferon Related Factor 4 (IRF4) on chromosome 6 and cg12577105 (p=4.11E-5) in Corticotrophin Releasing Hormone Receptor 1 (CRHR1) on chromosome 17 involved in the HPA axis.

Conclusion

We identified cytosine methylation changes that correlated with early kidney function decline in Pima Indians with type 2 diabetes.