Kidney Week

Abstract: SA-OR33

Diabetes-Specific Kidney Function Loci Identified in Genome-Wide Association Study of eGFR in 52,000 Individuals with Diabetes

Session Information

• Diabetic Kidney Disease - Basic: Discovery to Translational Science
  October 26, 2024 | Location: Room 7, Convention Center
  Abstract Time: 05:20 PM - 05:30 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Cole, Joanne B., University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States

Joanne B. Cole, PhD

• Fermin, Damian, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Damian Fermin, PhD

• Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Hongbo Liu, PhD

• Bjornstad, Petter, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States

Petter Bjornstad, MD

• Paterson, Andrew, Sick Kids Foundation, Toronto, Ontario, Canada

Andrew Paterson

• Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States

Andrzej S. Krolewski, MD, PhD

• Sandholm, Niina, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland

Niina Sandholm, MS, PhD

• Florez, Jose C., Mass General Brigham Inc, Boston, Massachusetts, United States

Jose C. Florez, MD, PhD

Background

Diabetic kidney disease (DKD) is a distinct life-altering pathological condition that is caused by both environmental and genetic factors. Previous genome-wide association studies (GWAS) have identified several loci associated with kidney disease and function both in the general population and in diabetes. While type 2 diabetes (T2D) is more common than type 1 diabetes (T1D), individuals with T2D have higher rates of kidney-damaging co-morbidities, and thus many develop non-specific kidney disease. Therefore, a comprehensive approach which incorporates T1D and T2D to maximize sample size and also integrates diabetes subtype, duration, and co-morbidities is key to improving the success of large-scale genomic discovery for DKD.

Methods

As part of the GENIE consortium, we leveraged widely available eGFR as a powerful quantitative trait to conduct the largest GWAS of eGFR in diabetes, including 17 T1D cohorts, UK Biobank, and SUMMIT Consortium T2D data with a total of 17K individuals with T1D and 36K individuals with T2D. To identify genetic loci most likely impacting kidney function via hyperglycemic pathways, we analyzed eGFR in a variety of settings that considered DKD disease status, diabetes subtype and duration, BMI, HbA1c, and the relationship between eGFR and albuminuria. We integrated multi-omics data to nominate candidate genes and elucidate mechanism.

Results

GWAS identified 13 loci associated with eGFR (P<5x10^-8); five were not associated or were in opposite directions with eGFR in the general population. rs11032245 near HIPK3 had opposite effects on eGFR in DKD cases versus diabetes controls, and single-cell RNA sequencing revealed a large difference in HIPK3 expression in podocytes between youth-onset T2D and healthy controls. rs76300256 near LPP had opposite effects in diabetes versus no diabetes and is a methylation QTL in kidney tissue for 3 CpGs in a kidney enhancer.

Conclusion

Together, our multi-faceted approach enabled us to identify candidate genes with diabetes-specific impact on kidney function, a critical step towards elucidating DKD pathophysiology and the development of novel more personalized therapies.

Funding

• NIDDK Support