Key result
Genetically proxied interleukin-6 receptor blockade was associated with a significantly increased risk of nonalcoholic fatty liver disease (OR 1.80).
Why the study?
Interleukin-6 receptor blockade is approved for inflammation-associated diseases, but whether it is effective in treating non-alcoholic fatty liver disease was unknown.
Does inhibiting the IL-6 signaling pathway via IL-6R blockade increase the risk of nonalcoholic fatty liver disease?
Observational (n=238,056)
Does inhibiting the IL-6 signaling pathway via IL-6R blockade increase the risk of nonalcoholic fatty liver disease?
Odds Ratio: 1.8 (95% CI 1.26–2.57)
p-value: p=0.001
Mendelian randomization suggests that inhibiting the IL-6 signaling pathway via IL-6R blockade may increase the risk of nonalcoholic fatty liver disease.
Background: Interleukin-6 receptor (IL-6R) blockade has been approved for inflammation-associated diseases and whether it is effective in treating non-alcoholic fatty liver disease (NAFLD) is still unknown. Methods: A target-based Mendelian randomization was performed to appraise whether inhibiting the IL-6 signaling pathway via IL-6R blockade can reduce the risk of NAFLD. The previously established genetic proxy SNP rs2228145 was mainly used to appraise the therapeutic effects and the genetic-predicted circulating IL-6 level was treated as the exposure with ∼30,000 samples. The genetic association between SNP rs2228145 (A > C) and NAFLD was obtained from non-FinnGen GWAS (1,483 cases and 17,781controls) and FinnGen GWAS (894 cases and 217,898 controls). The causal effects were estimated using a Wald ratio method and were combined using a fixed-effects meta-analysis. Furthermore, the SNP rs12048091 was employed as another proxy in the sensitivity analysis. Results: The positive control analysis suggested the SNP rs2228145 can mimic the effects of IL-6R blockade where inhibiting IL-6 signaling can reduce the risk of rheumatoid arthritis [OR = 0.68 (0.58, 0.80)] and coronary heart disease [OR = 0.75 (0.68, 0.84)]. This Mendelian randomization analysis suggested that IL-6R blockade can adversely increase the risk of NAFLD in the non-FinnGen GWAS [OR = 1.99 (1.27, 3.13)] while not significant in the FinnGen consortium. The fixed-effects meta-analysis indicated inhibiting the IL-6 signaling pathway can reduce the risk of NAFLD [OR = 1.80 (1.26, 2.57)]. When including SNP rs12048091 as the genetic instrument, the meta-analysis using two genetic variants also indicated a similar effect on NAFLD [OR = 1.83 (1.32, 2.53)]. There was no heterogeneity in the whole analysis. Conclusion: Our Mendelian randomization suggested inhibiting the IL-6 signaling pathway via IL-6R blockade might increase the risk of NAFLD, suggesting IL-6R should play a protective role in NAFLD.
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Li et al. (2022) conducted an observational in Nonalcoholic Fatty Liver Disease (NAFLD) (n=238,056). Genetic proxy for Interleukin-6 Receptor (IL-6R) blockade vs. Reference alleles (no IL-6R blockade proxy) was evaluated on Risk of Nonalcoholic Fatty Liver Disease (NAFLD) (OR 1.80, 95% CI 1.26, 2.57, p=0.001). Genetically proxied interleukin-6 receptor blockade was associated with a significantly increased risk of nonalcoholic fatty liver disease (OR 1.80).
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