The genetic road to renal failure
Diabetic nephropathy (DN) is a major complication of Type 1 Diabetes (T1D) and occurs in over 40% of patients with Type 1 diabetes. It has been shown to cluster in families, consistent with a major role for genetic factors that may interact with other genes and environmental factors.
Development of DN is multi-stage disease process where DN manifests itself first as microalbuminuria, then progresses to proteinuria. This in turn may lead to renal failure, which requires dialysis or kidney transplantation, an outcome referred to as end-stage renal disease (ESRD).
During the last decade, research has revealed that microalbuminuria regresses to normoalbuminuria in a large proportion of patients. Only one third of patients with microalbuminuria progress to overt proteinuria.
By contrast, proteinuria is more stable and is accompanied by significant morphological kidney lesions. Half of patients with proteinuria progress to ESRD. In the general population of T1D, lifetime risks of these successive stages of DN are estimated to be 60% for microalbuminuria, 20-30% for proteinuria and 10-15% for ESRD.
For those who reach ESRD, the interval between their onsets of proteinuria and ESRD varies quite widely – from a couple of years to several decades. Stated differently, for patients with T1D and proteinuria who begin to lose renal function, progression to ESRD may be rapid, moderate, or slow. For patients with proteinuria who are not at risk of ESRD, renal function is stable for decades – despite poor glycaemic control and hypertension.
The overarching goal of this 3 phase-project is to provide an efficient and robust multi-pronged attack on risk of diabetic nephropathy in T1D. We aim to:
- Find genes responsible for such rapid progression in the largest, currently available, carefully phenotyped case-control study (Phase 1)
- Investigate the time to the onset of ESRD in T1D participants with proteinuria (Phase 2)
- Focus on a series of longitudinal change in renal function (eGFR), the primary phenotype of kidney disease (Phase 3)
Design and method
The project is a 3-year, multi-national, genetic project funded by the Juvenile Diabetes research Foundation (JDRF) International Prime Award, Number 17-2013-8.
The project forms the assembly of a well-functioning collaboration and is expected to create a combined cohort of 10,000 cases with DN and 10,000 controls.
Thus, this will be the largest and most complete collection of samples relevant to genetic discovery in nephropathy due to T1D.
The nephropathy phenotypes in this project are defined with a proteinuria-based definition, a renal function-based definition and an extreme definition based on time from diabetes diagnosis until ESRD. The follow-up data will be available on app. 4,000 patients, of which 1,079 are from Steno. They will be genotyped by common variant genotyping (GWAS) as well as for rare variants (ExomeChip).
The statistical power will be sufficient to identify not only a moderate effect of a common variant but also a strong effect of rare variants.
Patients with type 1 diabetes with and without diabetic nephropathy.
We expect to identify the genes that determine the risk of development of overt diabetic nephropathy, as well as time to onset of ESRD in T1D patients.
Funding and collaborators
The project is funded by Juvenile Diabetes Research Foundation (JDRF) International Prime Award Number 17-2013-8.
It is performed in collaboration with the following partners: Dr. Andrzej Krolewski (PI) (Joslin Diabetes Center), Jose Florez (Harvard Medical School/Broad Institute), Per Henrik Groop (University of Helsinki), Samy Hadjadj (Inserm), Andrew Paterson (SickKids) and Steve Rich (University of Virginia).