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Causal Relationship Between Complement C3, C4, and Nonalcoholic Fatty Liver Disease: Bidirectional Mendelian
Longman Li1,2,3, Lulu Huang1, Aimin Yang4
1Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021 Guangxi China.
Insights
Nonalcoholic fatty liver disease (NAFLD) is linked to complement system activation. This study found that while higher serum C3 levels correlate with NAFLD risk, NAFLD may actually cause changes in C3 levels, not the other way around.
Area of Science:
- Biochemistry
- Immunology
- Hepatology
Background:
- The complement system plays a role in nonalcoholic fatty liver disease (NAFLD) pathogenesis.
- Understanding the causal relationship between complement factors and NAFLD is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the causal relationship between serum C3 and C4 levels and the risk of developing NAFLD.
- To explore the bidirectional causal associations between complement factors and NAFLD using Mendelian randomization.
Main Methods:
- Cross-sectional and longitudinal analyses of 1600 and 572 Chinese Han men, respectively.
- Bidirectional Mendelian randomization analysis utilizing genetic variants associated with C3, C4, and NAFLD.
- Statistical analysis including odds ratios (OR) and hazard ratios (HR) to assess associations.
Main Results:
- Increased serum C3 levels were significantly associated with a higher risk of NAFLD in cross-sectional and longitudinal analyses (OR=1.65, HR=1.20).
- Serum C4 levels did not show a significant association with NAFLD risk.
- Mendelian randomization indicated no causal effect of genetically determined C3 on NAFLD risk, but suggested NAFLD influences C3 levels (β=0.020-0.021).
Conclusions:
- Serum C3 levels, but not C4 levels, are associated with NAFLD risk in Chinese Han men.
- The findings suggest that NAFLD may be a cause of altered C3 levels, rather than C3 directly causing NAFLD.
- Further research is needed to elucidate the complex interplay between the complement system and NAFLD.
Abstract:
The complement system is activated during the development of nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the causal relationship between serum C3 and C4 levels and NAFLD. After exclusion criteria, a total of 1600 Chinese Han men from the Fangchenggang Area Male Health and Examination Survey cohort were enrolled in cross-sectional analysis, while 572 participants were included in the longitudinal analysis (average follow-up of 4 years). We performed a bidirectional Mendelian randomization (MR) analysis using two C3-related, eight C4-related and three NAFLD-related gene loci as instrumental variables to evaluate the causal associations between C3, C4, and NAFLD risk in cross-sectional analysis. Per SD increase in C3 levels was significantly associated with higher risk of NAFLD (OR = 1.65, 95% CI 1.40, 1.94) in cross-sectional analysis while C4 was not (OR = 1.04, 95% CI 0.89, 1.21). Longitudinal analysis produced similar results (HRC3 = 1.20, 95% CI 1.02, 1.42; HRC4 = 1.10, 95% CI 0.94, 1.28). In MR analysis, there were no causal relationships for genetically determined C3 levels and NAFLD risk using unweighted or weighted GRS_C3 (βE_unweighted = -0.019, 95% CI -0.019, -0.019, p = 0.202; βE_weighted = -0.019, 95% CI -0.019, -0.019, p = 0.322). Conversely, serum C3 levels were significantly effected by the genetically determined NAFLD (βE_unweighted = 0.020, 95% CI 0.020, 0.020, p = 0.004; βE_weighted = 0.021, 95% CI 0.020, 0.021, p = 0.004). Neither the direction from C4 to NAFLD nor the one from NAFLD to C4 showed significant association. Our results support that the change in serum C3 levels but not C4 levels might be caused by NAFLD in Chinese Han men.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s43657-021-00023-0.
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