Kidney IRon by HAptoglobin genotype (KIRHA)
Young adults with type 1 diabetes (T1D) exhibit dramatically higher cardiorenal disease rates despite only minor risk factor differences vs. the general population. Thus, there is a critical need to identify currently unrecognized sources of increased susceptibility to vascular T1D complications. In the absence of such knowledge, the development of effective prevention strategies to address the excess cardiorenal rates in T1D will likely remain challenging. In the past decade, the Haptoglobin (Hp) 2-2 genotype has risen as a major contributor to T1D/T2D complication risk. Our long term goal is to identify the mechanisms by which Hp 2-2 contributes to T1D/T2D cardiorenal risk, in order to develop optimal intervention strategies to reduce/eliminate the genetic susceptibility conferred by Hp 2-2. Our objective in this pilot study is to lay the foundations for the identification of the biologic mechanisms by which this established functional variant, Hp, affects predisposition to T1D kidney disease. Our central hypothesis is that Hp 2-2 is associated with increased kidney iron deposition and proximal tubular injury, leading to declining kidney function and progression to end-stage renal disease (ESRD) in T1D. With this project we will obtain preliminary data on kidney iron as well as on the concentration of biomarkers of proximal tubular injury and oxidation by Hp genotype 1-1 or 2-2 in individuals with T1D. Individuals with T1D and known Hp genotype will be recruited from participants of the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (PI: Orchard) attending the 30 year follow-up examination or from the HapE study (PI: Costacou). The preliminary data generated in this project will aid the subsequent submission of an R01 application to fully assess this hypothesis in a larger sample, including all Hp genotypes (1-1, 2-1 and 2-2) and also assessing the potential beneficial effects of treatment with the antioxidant vitamin E (given existing data of benefit against coronary heart disease among those with diabetes and Hp 2-2) and/or chelation therapy (in which the consortium has expressed interest) in the genetically susceptible group with T1D and the Hp 2-2 genotype (>40% of the T1D population).

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