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.
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Acknowledgements
We thank the local research team from Fangchenggang First People’s Hospital for their contribution to the recruitment of study subjects. We thank XZ, HZ, and OL at the Genergy Biotechnology (Shanghai) Co., Ltd., for their assistance in the genotyping. Finally, we thank all study subjects for participating in this study.
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LL and YX designed the study. MZ, ZH, and YX coordinated the study and oversaw participant recruitment, collection, and analysis of biological samples. LL and HL conducted the statistical analyses. LL drafted the paper, which was reviewed by all authors. All authors approved the final version of the article, including the authorship list.
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This work was supported by the Guangxi Natural Science Fund for Innovation Research Team [2017GXNSFGA198003], Key projects of strategic international scientific and technological innovation cooperation of the Chinese Ministry of Science and Technology [2020YFE0201600], and Guangxi key Laboratory for Genomic and Personalized Medicine [19-185-33, 20-065-33].
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Li, L., Huang, L., Yang, A. et al. Causal Relationship Between Complement C3, C4, and Nonalcoholic Fatty Liver Disease: Bidirectional Mendelian Randomization Analysis. Phenomics 1, 211–221 (2021). https://doi.org/10.1007/s43657-021-00023-0
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DOI: https://doi.org/10.1007/s43657-021-00023-0