Epigenetics of Chronic Kidney Disease

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: KATALIN  SUSZTAK
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $465,499
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

The estimated heritability of kidney disease is around 50%. Common variants, that are almost always
non-coding, account for much of the predisposition to prevalent, later-onset kidney diseases such as diabetic
and hypertensive kidney disease (DKD, HKD). Genome wide association studies (GWAS) have provided a
comprehensive inventory of these variants, each variant with modest impact on disease risk, but in aggregate
they can explain most of disease heritability. Despite the remarkable success of GWAS, it has not translated
into improved disease diagnostics and therapeutics as we fail to understand how non-coding variants
cause kidney disease.
 The generally agreed model is that disease causing variants are on gene regulatory (open
chromatin) region, alter transcription factor binding strength and quantitatively change the expression
of a target gene in a cell type specific manner. Causal variant identification is impeded as DNA sequences
that are close to each other are inherited together making it difficult to pick from the many linked variants. Due
to secondary chromatin structure the nearest coding gene is not always the causal gene. The genotype effect
may be cell-type specific explaining organ specific disease development.
 During the last award cycle, we catalogued genotype-driven gene-expression variation (eQTL;
expression quantitative trait loci) in the glomerular and tubule compartments of human kidneys. Integration of
the kidney GWAS and eQTL catalogues has been successful in identifying putative disease-causing genes
and in a follow-up mouse gene knock-out study we showed that Dab2 is such new disease-causing gene.
Kidney single cell gene expression analysis pointed to enrichment of disease associated genes in proximal
tubules.

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