Research

Gene Mapping Studies in Kidney Disease

We focus on the mapping and identification of genes underlying kidney disease-related traits in humans. These efforts include a range of study designs: from family-based studies (such as linkage and sequencing in pedigrees), to population-based studies (such as GWAS, CNV and rare variant association approaches). Most of our work has been focused on the genetics of IgA nephropathy (IgAN).

IgAN has a complex genetic architecture. Linkage studies demonstrate significant locus heterogeneity. Population-based studies support additive contributions of multiple common variants. Our recent GWAS involving >20,000 individuals implicated both adaptive and innate immunity in the disease pathogenesis, and defined the “Immune Network of Intestinal IgA Production” as one of the key pathogenic disease pathways.

Our ongoing studies concentrate on refining the genetic architecture of IgAN by fine-mapping of the known loci and discovery of additional genetic risk variants.

Systems Genetics and Gene Regulatory Networks

We use network-based approaches to study molecular consequences of inherited kidney disease risk variants. We integrate human genetic, epigenetic, transcriptomic and protein data to reconstruct causal gene regulatory networks. We then identify master regulators and key molecular drivers of such networks to better define novel targets for potential therapeutic interventions.

We use this approach to study immunologic endophenotypes related to glomerular diseases that are reflective of the complement activation, IgA1 production and IgA1 glycosylation. For example, defective O-glycosylation of IgA1 represents one of the key pathogenic features of IgA nephropathy and Henoch-Schönlein purpura nephritis; galactose-deficient IgA1 promotes the formation of pathogenic immune complexes and their glomerular deposition.

Using systems genetics approaches, we re-construct IgA1 interactomes (i.e. global maps of molecular interactions in human IgA1-secreting cells) to define the precise molecular events contributing to IgA1 glycosylation defects.

Translational Genetics and Personalized Nephrology

The ultimate goal of our lab is to improve the diagnosis and treatment of patients suffering from kidney disease. Our genetic investigations provide new insights into disease pathogenesis, but also require clinical translation through rigorous and well-designed clinical studies. Such studies range from simple genotype-phenotype correlation analyses to prospective biomarker studies and randomized trials. We are also interested in testing the utility of new molecular diagnostic tools (such as Next Generation sequencing) in the clinical nephrology practice setting.

We selected IgA nephropathy (IgAN) as a disease model for implementation of some of these studies. IgAN leads to progressive kidney failure in up to 50% of affected individuals. The prognosis, however, is quite variable and the outcome is difficult to predict in individual patients. It is estimated that 20%-40% of cases develop end stage renal disease (ESRD) within 20 years of diagnosis. Our translational studies aim to validate new genetic and molecular markers to enable precise diagnosis, improve prognostication, predict relapse and recurrence, and ultimately lead to improved personalized treatment strategies.