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Published on: April 20, 2021
A two-sample mendelian randomization analysis excludes causal relationships between non-alcoholic fatty liver disease
Xintao Li1,2,3, Yongpeng Xie4, Lu Tang2
1Department of Traditional Chinese Medicine, The Sixth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing, China.
Objectives:
Non-alcoholic fatty liver disease (NAFLD) has been linked to an increased risk of kidney stones in prior observational studies, However, the results are inconsistent, and the causality remains to be established. We aimed to investigate the potential causal relationship between NAFLD and kidney stones using two-sample Mendelian randomization (MR).
Methods:
Genetic instruments were used as proxies for NAFLD. Summary-level data for the associations of exposure-associated SNPs with kidney stones were obtained from the UK Biobank study (6536 cases and 388,508 controls) and the FinnGen consortium (9713 cases and 366,693 non-cases). MR methods were conducted, including inverse variance weighted method (IVW), MR-Egger, weighted median, and MR-PRESSO. MR-Egger Regression Intercept and Cochran's Q test were used to assess the directional pleiotropy and heterogeneity.
Results:
cALT-associated NAFLD did not exhibit an association with kidney stones in the Inverse variance weighted (IVW) methods, in both the FinnGen consortium (OR: 1.02, 95%CI: 0.94-1.11, p = 0.632) and the UKBB study (OR: 1.000, 95%CI: 0.998-1.002, p = 0.852). The results were consistent in European ancestry (FinnGen OR: 1.05, 95%CI: 0.98-1.14, p = 0.144, UKBB OR: 1.000, 95%CI: 0.998-1.002, p = 0.859). IVW MR analysis also did not reveal a significant causal relationship between NAFLD and the risk of kidney stone for the other three NAFLD-related traits, including imaging-based, biopsy-confirmed NAFLD, and more stringent biopsy-confirmed NAFLD. The results remained consistent and robust in the sensitivity analysis.
Conclusions:
The MR study did not provide sufficient evidence to support the causal associations of NAFLD with kidney stones.
Insights
This study found no causal link between non-alcoholic fatty liver disease (NAFLD) and kidney stones. Mendelian randomization analysis using large datasets did not support a genetic association, suggesting NAFLD does not increase kidney stone risk.
Area of Science:
- Hepatology
- Nephrology
- Genetic Epidemiology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent globally.
- Observational studies suggest a potential link between NAFLD and kidney stones, but causality remains unproven.
- Inconsistent findings necessitate robust methods to establish a causal relationship.
Purpose of the Study:
- To investigate the potential causal relationship between non-alcoholic fatty liver disease (NAFLD) and kidney stones.
- Utilize two-sample Mendelian randomization (MR) to assess causality, overcoming limitations of observational studies.
Main Methods:
- Employed genetic variants associated with NAFLD as instrumental variables.
- Analyzed summary-level data from large cohorts: FinnGen (9,713 cases, 366,693 non-cases) and UK Biobank (6,536 cases, 388,508 controls).
- Applied various MR methods (IVW, MR-Egger, weighted median) and sensitivity analyses (MR-PRESSO, heterogeneity tests) to ensure robustness.
Main Results:
- No significant causal association was detected between NAFLD (including cALT-associated NAFLD) and kidney stones in either the FinnGen or UK Biobank datasets.
- Results were consistent across different NAFLD definitions (imaging-based, biopsy-confirmed) and sensitivity analyses.
- No evidence of pleiotropy or significant heterogeneity was found, supporting the validity of the MR analysis.
Conclusions:
- The Mendelian randomization study provides no sufficient evidence to support a causal association between NAFLD and an increased risk of kidney stones.
- These findings suggest that the previously observed associations may be due to confounding factors or reverse causality.
- Further research may be needed to explore other potential risk factors or mechanisms linking liver health and kidney stone formation.
