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IFN-γ, SCF, MIP1b and IL-16 Were Associated with Risk of Diabetic Nephropathy: A Mendelian Randomization Study
Li An1,2, Xiaomei Ren1, Ye Pan2
1Department of Geriatrics, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People's Republic of China.
Background:
The impact of inflammatory factors on the risk of diabetic nephropathy (DN) is inconsistent. Two-sample Mendelian randomization (MR) analyses were used to detect the causal role of inflammatory factors in DN risk.
Methods:
Inflammatory factor GWAS summary data were collected from a meta-analysis including 8,293 Finnish participants, and DN information was extracted from a GWAS of 213,746 individuals from FinnGen. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) outlier test was used for the removal of horizontal pleiotropic outliers. Multivariable MR analysis was also used to adjust for pleiotropy.
Results:
IFN-γ [ORIVW: 1.33; 95% CI: 1.09-1.63; p=0.005] and SCF [ORIVW: 1.25, 1.02-1.52; p = 0.027] were associated with an increased risk of DN. MIP1b [ORIVW: 0.92; 95% CI: 0.85-0.98; p = 0.022] and IL-16 [ORIVW: 0.89, 0.81-0.99; p = 0.043] showed negative associations with the risk of DN. We validated our MR results with MR-PRESSO analyses. Significant horizontal pleiotropy was not found. Moreover, in the multivariable MR analysis, the associations between cytokines and DN risk remained.
Conclusion:
Our MR results based on genetic data contribute to a better understanding of the pathogenesis of DN and provide evidence for a causal effect of inflammatory factors on DN. These findings support targeting specific inflammatory factors to alleviate DN risk.
Insights
Certain inflammatory factors causally impact diabetic nephropathy (DN) risk. Interferon-gamma and SCF increase DN risk, while MIP1b and IL-16 decrease it, offering therapeutic targets.
Area of Science:
- Genetics
- Immunology
- Nephrology
Background:
- The relationship between inflammatory factors and diabetic nephropathy (DN) risk is not fully understood.
- Existing research presents inconsistent findings regarding the impact of inflammation on DN development.
Purpose of the Study:
- To investigate the causal role of various inflammatory factors in the risk of developing diabetic nephropathy (DN).
- To leverage Mendelian randomization (MR) to analyze genetic data and infer causality.
Main Methods:
- Two-sample Mendelian randomization (MR) analyses were employed using large-scale genome-wide association study (GWAS) data.
- Data included inflammatory factor GWAS summary statistics from 8,293 Finnish participants and DN GWAS data from 213,746 FinnGen individuals.
- MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) and multivariable MR analyses were used to address potential pleiotropy and validate findings.
Main Results:
- Interferon-gamma (IFN-γ) and Stem Cell Factor (SCF) were significantly associated with an increased risk of DN.
- Macrophage Inflammatory Protein-1 beta (MIP1b) and Interleukin-16 (IL-16) showed a significant negative association with DN risk.
- MR-PRESSO and multivariable MR analyses confirmed these associations and found no significant horizontal pleiotropy.
Conclusions:
- Genetic evidence supports a causal role for specific inflammatory factors in the pathogenesis of diabetic nephropathy (DN).
- Targeting identified inflammatory factors may offer a novel therapeutic strategy to mitigate DN risk.
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