Abstract: PO1331
Rare Variants and Risk of ESKD: The Geisinger MyCode-DiscovEHR Study
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Chang, Alex R., Geisinger Health, Danville, Pennsylvania, United States
- Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States
- Singh, Gurmukteshwar, Geisinger Health, Danville, Pennsylvania, United States
- Anand, Prince Mohan, Geisinger Health, Danville, Pennsylvania, United States
- Strande, Natasha T., Geisinger Health, Danville, Pennsylvania, United States
- Mirshahi, Tooraj, Geisinger Health, Danville, Pennsylvania, United States
Background
Prior studies have reported that up to 1 in 10 patients with end-stage kidney disease (ESKD) have a diagnostic rare genetic variant but have lacked control groups.
Methods
Whole exome sequencing and electronic health records data from 147,750 participants in the Geisinger MyCode-DiscovEHR study, a health system-based cohort, were linked to the US Renal Data System to ascertain ESKD status and attributed cause. We compiled a list of variants in 80 autosomal or X-linked dominant (AD/XLD) genes used in commercial kidney genetics panels previously reported in Clinvar as pathogenic or likely pathogenic (P/LP) (minor allele frequency <0.01, any number of stars). We evaluated the association of these rare P/LP variants with risks of all-cause and cause-specific ESKD in logistic regression models adjusted for age and sex. Additional analyses were performed by subsets of kidney disease genes and by age of ESKD onset.
Results
Prevalence of previously reported rare P/LP variants in AD kidney disease genes was higher in participants with ESKD than those without ESKD (3.0% vs. 1.2%). Rare P/LP variants were most prevalent in congenital/cystic ESKD (12.6%), followed by ESKD attributed to genitourinary/nephrolithiasis disorders (4.9%), hypertension (4.3%), glomerular/vasculitis disorders (3.4%), and early onset diabetic ESKD (<60 years; 3.3%). By contrast, only 0.7% with later onset diabetic ESKD (60+ years) had rare P/LP variants. Individuals with rare variants were at increased risk of all-cause ESKD (OR 2.71, 95% CI: 1.99-3.70) (Table). When genes were grouped by specific categories, rare variants in cystic disease, Alport Syndrome, CAKUT, and FSGS gene panels were all associated with increased risk of ESKD.
Conclusion
Individuals in an unselected health system cohort with rare variants had substantially increased risk of ESKD, which was often attributed to hypertension or diabetes.
Associations between rare variants and ESKD phenotypes
| ESKD (n=1415) | ESKD (onset <60 y) due to diabetes, (n=301) | ESKD (onset ≥60 y) due to diabetes (n=302) | ESKD due to GN or vasculitis (N=205) | ESKD due to HTN (n=186) | ESKD due to congenital/ cystic cause (n=95) | |
| Category | OR (95% CI) P value | OR (95% CI) P value | OR (95% CI) P value | OR (95% CI) P value | OR (95% CI) P value | OR (95% CI) P value |
| P/LP variants in any AD kidney disease gene (n=1741) | 2.71 (1.99-3.70) P<0.001 | 2.85 (1.52-5.37) P=0.001 | 0.57 (0.14-2.29) P=0.4 | 2.97 (1.40-6.33) P=0.005 | 3.75 (1.84-7.62) P<0.001 | 12.08 (6.58-22.17) P<0.001 |
| P/LP variants in AD cystic disease genes (n=417) | 4.16 (2.37-7.29) P<0.001 | 2.83 (0.70-11.43) P=0.1 | - | 2.09 (0.29-14.94) P=0.5 | - | 39.92 (19.2-83.1) P<0.001 |
| P/LP variants in AD Alport genes (n=600) | 2.90 (1.70-4.97) P<0.001 | 0.97 (0.14-6.96) P=1.0 | - | 4.29 (1.37-13.47) P=0.01 | 7.78 (3.17-19.08) P<0.001 | 12.93 (4.73-35.36) P<0.001 |
| P/LP variants in AD CAKUT genes (n=209) | 2.68 (1.10-6.57) P=0.03 | 2.38 (0.33-17.05) P=0.4 | - | 3.64 (0.51-26.13) P=0.2 | 4.03 (0.56-29.10) P=0.2 | - |
| P/LP variants in FSGS (excluding Alports) genes (n=43) | 8.91 (2.67-29.74) P<0.001 | - | 11.56 (1.50-89.08) P=0.02 | 19.93 (2.70-147.09) P<0.001 | - | 12.02 (4.40-32.86) P<0.001 |
Funding
- NIDDK Support