Moumita Barua | University Health Network
Does genetic analysis of combined kidney measures in the population prioritize and identify novel signals?
Co-Applicant(s): Andrew D Paterson
Lay Abstract
Does genetic analysis of combined kidney traits seen in the population reveal new insights?
Background: Blood in the urine, called hematuria, is a sign of kidney disease but is under studied despite its reported association with kidney failure. The reported prevalence of hematuria varies broadly between 0.8% to 31.4%, in part owing to methodologic differences for case definition. For instance, defining hematuria cases by clinical diagnostic codes submitted by physicians is likely less sensitive but more specific compared to using urinalysis data directly. In our previous analysis, we used in-patient clinical diagnostic codes to define hematuria cases and identified associated genetic factors in a large population-based cohort called the UK Biobank. Understanding these genetic associations helps us understand biological mechanisms underlying hematuria.
Purpose: To expand our genetic association analyses, we propose to incorporate traits correlated with both hematuria and urine protein excretion (called albuminuria). We propose to do this in a combined analysis of 6 cohorts totaling over 1 million participants, in which both clinical and genetic data are available. These cohorts include the UK Biobank (UK), Canadian Longitudinal Study on Aging (CLSA), Lifelines (Netherlands), deCODE (Iceland), Geisinger MyCode (Pennsylvania) and All of Us (USA).
Method: Although most genetic studies analyze one clinical characteristic at a time, clinical syndromes are typically defined by combinations of traits. Testing traits in combinations can improve power to detect regions in our DNA that influence multiple phenotypes through similar biological pathways. Thus, we have also evaluated DNA regions associated with the combined traits of hematuria and albuminuria in 2,429 cases and 343,509 controls from the UK Biobank (Scientific Reports 2023, ASN oral presentation 2022).
Four genetic regions met genome-wide significance with the nearest genes (regions of DNA that encode molecules for various biological functions): COL4A4 causal for Alport syndrome (a genetic condition characterized by kidney failure), TRIM27 which is part of the extended HLA region on chromosome 6 important for the immune system, CUBN previously reported to be associated with albuminuria but not in hematuria, and a novel region near a gene call ETV1.
We propose to extend our work by systematically evaluating different combinations of kidney traits to better understand shared biological mechanisms contributing to kidney health.
Our study aims are:
1. Test the combined traits of hematuria and albuminuria for association with all available clinical characteristics (called phenome) as well as circulating proteins and metabolites
2. Perform tests for association of genetic factors with the combinations of hematuria, albuminuria and kidney function known as eGFR
Anticipated Outcomes: Our work in the UK Biobank has already shed important insights into kidney traits in patients commonly seen by nephrologists. Our ongoing work will continue to expand the diagnostic spectrum underlying hematuria and associated kidney traits which can be translated immediately to the clinic through genetic testing. This project will also innovatively assess multi-level omics (proteins and metabolites) data to identify associated biomarkers influencing hematuria and associated phenotypes.
Patient Engagement: Our human genetics contributions have garnered international recognition. Our work has captured the attention of the patient organization, the Alport Syndrome Foundation (ASF), a registered U.S. based non-profit organization led by and dedicated to patients and families affected by the disease (letter attached). The ASF in turn also has close partnerships with the Kidney Foundation of Canada (KFoC) and the National Kidney Foundation (NKF). The research team regularly communicates with the ASF and their partners at KFoC and NKF due to the PI, M Barua’s membership (first Canadian) on the ASF Scientific Advisory Research Network.
Relevance to Patients: There is a large unmet clinical need for mechanism-based therapy for kidney disease. Our approach holds the promise of accelerating biomarker and fundamental discovery that can one day be translated to targeted therapy development by guiding clinicians as to possible causes for these traits. Thus, these results will have both diagnostic and therapeutic implications.