The Association between Non-Alcohol Liver Fatty Disease and Coronary Artery Calcification: A Two-Sample Mendelian Randomization Study

Liaoming He; Xieraili Tiemuerniyazi; Ziang Yang; Shengkang Huang; Lianxin Chen; Yifeng Nan; Yangwu Song; Wei Feng

doi:10.1093/eurjpc/zwae336

The Association between Non-Alcohol Liver Fatty Disease and Coronary Artery Calcification: A Two-Sample Mendelian Randomization Study

Eur J Prev Cardiol. 2024 Oct 14:zwae336. doi: 10.1093/eurjpc/zwae336. Online ahead of print.

Authors

Liaoming He¹, Xieraili Tiemuerniyazi¹, Ziang Yang¹, Shengkang Huang¹, Lianxin Chen¹, Yifeng Nan¹, Yangwu Song¹, Wei Feng¹

Affiliation

¹ Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

PMID: 39400052
DOI: 10.1093/eurjpc/zwae336

Abstract

Background: Although prior observational studies have suggested that patients with non-alcohol fatty liver disease (NAFLD) may have a higher risk of coronary artery calcification (CAC), these findings remain controversial. This study aimed to explore the causal association between NAFLD and CAC at genetic level by two-sample Mendelian randomization (MR) analysis.

Method: Utilizing summary-level data from multiple large-scale genome-wide association studies (GWAS) in European populations, a two-sample MR analysis was initially conducted to explore the potential causal association between NAFLD and CAC. The results of the MR analysis were pooled through random-effect meta-analysis. The inverse variance weighting (IVW) method served as the primary approach for MR analysis. Additionally, the weighted median, MR-Egger and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods was applied for sensitivity analysis. Summary-level data on liver fatty content was utilized for validation analysis, while summary-level data on cirrhosis served as positive control, further ensuring the validity and robustness of our findings. Reverse MR analysis was performed to assess the association between CAC and NAFLD, employing instrument variables derived from CAC.

Results: The MR analysis indicated that genetically predicted NAFLD had no effects on the risk of CAC (Beta: 0.01, 95% CI: -0.02 to 0.03, P = 0.74). Likewise, the reverse MR analysis found no significant genetic association between CAC and NAFLD (OR: 1.00, 95% CI: 0.96 to 1.06, P = 0.88). Validation analysis yielded consistent results, showing no significant association between fatty liver content and CAC.

Conclusion: Our two-sample MR analysis did not support that there is a causal association between NAFLD and CAC at genetic level. The association between NAFLD and CAC reported in some previous observational studies may rely on NAFLD complicated with metabolic disorders, rather than being directly linked to the hepatic steatosis.

Keywords: Mendelian randomization analysis; coronary artery calcification; non-alcohol fatty liver disease.

Plain language summary

This study used a genetic approach to investigate whether non-alcoholic fatty liver disease (NAFLD) directly causes coronary artery calcification (CAC), finding no evidence of a causal relationship at genetic level. The Mendelian randomization (MR) analysis revealed no genetic association between NAFLD and the risk of developing CAC, as well as no reverse association from CAC to NAFLD. The findings suggest that previous reports association between NAFLD and CAC may be influenced by metabolic disorders rather than a direct connection between the two conditions.