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Kidney Week

Abstract: FR-OR52

Phenome-Wide Association Study of Common Genetic Variants in SGLT2 and Health Disparities in Kidney Outcomes

Session Information

Category: CKD (Non-Dialysis)

  • 2102 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

  • Mashayekhi, Mona, Vanderbilt University, Nashville, Tennessee, United States
  • Robinson-Cohen, Cassianne, Vanderbilt University, Nashville, Tennessee, United States
  • Chen, Hua-Chang, Vanderbilt University, Nashville, Tennessee, United States
  • Akwo, Elvis A., Vanderbilt University, Nashville, Tennessee, United States
  • Tao, Ran, Vanderbilt University, Nashville, Tennessee, United States
  • Yu, Zhihong, Vanderbilt University, Nashville, Tennessee, United States
  • Wheless, Lee, Vanderbilt University, Nashville, Tennessee, United States
  • Chung, Cecilia P., Vanderbilt University, Nashville, Tennessee, United States
  • Hung, Adriana, Vanderbilt University, Nashville, Tennessee, United States
Background

SGLT2 inhibition represents one of the greatest therapeutic achievements of the last two decades, improving cardiovascular outcomes and slowing the progression of CKD to ESRD by 30% in patients with diabetes. Whether common genetic variants in SGLT2 gene contribute to kidney disease progression and to health disparities in kidney disease is unknown.

Methods

We tested the association of two SNPs in the SLC5A2 gene encoding SGLT2 with clinically diagnosed phenotypes in a phenome-wide association study in 428,438 whites and 114,536 non-Hispanic blacks (NHB)s from the Million Veteran Program. Using logistic regression adjusted for age, sex, and 10 principal components of ancestry, we regressed 250 phenotypes against the two SNPs (rs9934336; rs3116150), stratified by race and diabetes status. Minor allele frequencies for rs9934336 were 0.26 and 0.20 and for rs3116150 were 0.24 and 0.04 in White and non-Hispanic Black participants, respectively.

Results

The rs9934336 variant was associated with multiple kidney phenotypes in NHBs as shown in the table, while no associations of rs9934336 and kidney phenotypes were observed in whites. When stratified by diabetes, renal failure NOS remained significantly associated in diabetics, and anemia of CKD in non-diabetics. The rs3116150 variant was also associated with several kidney phenotypes in NHBs, while no associations were observed in whites. When stratified by diabetes, most of the associations of rs3116150 and kidney phenotypes remained.

Conclusion

Our study shows that SGLT2 variants are associated with CKD and ESRD in non-Hispanic blacks. This novel association with health disparities needs to be further evaluated. Mendelian randomization studies for SLC5A2 variants are underway

Table 1. SGLT2 Variants and Renal Disease ICD Codes in Non-Hispanic Blacks (odds ratio with unadjusted p-value)
 rs9934336rs3116150
Anemia in CKDAll: 0.89, p=6.25 x10-5
Non-DM: 0.83, p=1.17 x10-3
All: 1.18, p=2.67 x10-4
DM: 1.18, p=1.49 x10-3
Renal failure NOSAll: 0.88, p=2.44 x10-4
DM: 0.88, p=1.28 x10-3
All: 1.17, p=1.56 x10-3
HyperpotassemiaAll: 0.92, p=4.33 x10-3 
Renal dialysisAll: 0.91, p=5.76 x10-3 
ESRDAll: 0.92, p=7.57 x10-3All: 1.14, p=5.07 x10-3
DM: 1.16, p=5.09 x10-3
Disorders resulting from impaired renal functionAll: 0.92, p=9.69 x10=3All: 1.15, p=3.96 x10-3
DM: 1.17, p=6.08 x10-3
Renal osteodystrophy All: 1.36, p=1.46 x10-3
DM: 1.36, p=4.88 x10-3
Acute glomerulonephritis NOS All: 2.28, p=5.12 x10-3

Funding

  • Veterans Affairs Support