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Targeting RAC1 might be a potential therapeutic strategy for diabetic kidney disease: a Mendelian randomization study
Shisheng Han1, Meng Jia1, Tianwen Yao1
1Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
Purpose:
This study aimed to ascertain the causal association between Ras-related C3 botulinum toxin substrate 1 (RAC1) and the incidence and progression of diabetic kidney disease (DKD) through Mendelian randomization analysis.
Methods:
RAC1 expression, evaluated using expression quantitative trait loci data from the eQTLGen Consortium, was served as the exposure variable. Outcomes encompassed the risk of DKD, end-stage renal disease (ESRD), albuminuria assessed by the urinary albumin-to-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) among individuals with diabetes. Causal associations were computed using the inverse variance weighted (IVW), weighted median, and MR-PRESSO models. Additionally, we conducted analyses for heterogeneity, horizontal pleiotropy, and sensitivity.
Results:
This study revealed a causal association between the genetic activation of RAC1 and an elevated risk of DKD among individuals with diabetes [IVW, odds ratio (OR) = 1.28, 95% confidence intervals (CI) 1.08-1.51, P = 0.004]. Furthermore, increased expression of RAC1 was linked to a higher risk of ESRD (IVW, OR = 1.20, 95% CI 1.02-1.43, P = 0.032). Excessive RAC1 expression was causally associated with elevated ACR (IVW, β = 0.052, 95% CI 0.003-0.100, P = 0.036). However, the analysis regarding RAC1 and eGFR showed significant heterogeneity and pleiotropy, with no discernible causal relationship.
Conclusions:
These findings suggested a positive correlation between the genetic activation of RAC1 and the incidence of DKD, the risk of ESRD, and exacerbated albuminuria among individuals with diabetes. Targeting RAC1 might potentially serve as a therapeutic strategy for DKD.
Insights
Genetic activation of Ras-related C3 botulinum toxin substrate 1 (RAC1) is causally linked to increased risk of diabetic kidney disease (DKD) and its progression. Targeting RAC1 may offer a new therapeutic approach for diabetic kidney disease.
Area of Science:
- Nephrology
- Genetics
- Pharmacology
Background:
- Diabetic kidney disease (DKD) is a major complication of diabetes.
- Identifying genetic factors influencing DKD is crucial for developing targeted therapies.
- Ras-related C3 botulinum toxin substrate 1 (RAC1) is implicated in cellular processes relevant to kidney function.
Purpose of the Study:
- To investigate the causal association between RAC1 genetic variants and the risk and progression of DKD.
- To explore the role of RAC1 in the development of end-stage renal disease (ESRD), albuminuria, and estimated glomerular filtration rate (eGFR) decline in diabetic individuals.
Main Methods:
- Utilized Mendelian randomization analysis with expression quantitative trait loci (eQTL) data for RAC1 expression.
- Assessed outcomes including DKD incidence, ESRD risk, urinary albumin-to-creatinine ratio (ACR), and eGFR in individuals with diabetes.
- Employed inverse variance weighted (IVW), weighted median, and MR-PRESSO methods, alongside sensitivity analyses for heterogeneity and pleiotropy.
Main Results:
- Found a significant causal association between genetically predicted RAC1 activation and increased risk of DKD (OR=1.28, P=0.004).
- Demonstrated a causal link between elevated RAC1 expression and higher risk of ESRD (OR=1.20, P=0.032) and increased albuminuria (β=0.052, P=0.036).
- No significant causal relationship was observed for RAC1 and eGFR, with notable heterogeneity and pleiotropy.
Conclusions:
- Genetic activation of RAC1 is causally associated with higher incidence of DKD, increased risk of ESRD, and exacerbated albuminuria in diabetic patients.
- Targeting RAC1 presents a potential therapeutic strategy for managing and treating diabetic kidney disease.
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