Liver disease is a significant risk factor for cardiovascular outcomes – A UK Biobank study

Liver disease is a significant risk factor for cardiovascular outcomes – A UK Biobank studyJournal of HepatologyVol. 79Issue 5PreviewChronic liver disease (CLD) is associated with increased cardiovascular disease (CVD) risk. We investigated whether early signs of liver disease (measured by iron-corrected T1-mapping [cT1]) were associated with an increased risk of major CVD events. Full-Text PDF Open Access We read with great interest the study by Roca-Fernandez A et al. which revealed the associations of early liver disease on iron-corrected T1(cT1) mapping with the risk of cardiovascular disease using 33,616 participants from the UK Biobank (UKBB).[[1]Roca-Fernandez A. Banerjee R. Thomaides-Brears H. Telford A. Sanyal A. Neubauer S. et al.Liver disease is a significant risk factor for cardiovascular outcomes - A UK Biobank study.J Hepatol. 2023; 79: 1085-1095Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] However, conventional observational studies are susceptible to potential bias such as unmeasured confounders and reverse causality, the result can hardly be interpreted as causal associations. Mendelian randomization (MR) analysis is a genetic epidemiological method which used instrumental variables (IVs) such as single-nucleotide polymorphisms (SNPs) as proxies for a risk factor to estimate the causal association between a given exposure on an outcome. Herein, we aimed to answer whether the association of cT1 with cardiovascular disease were causal using the two-sample MR study design. SNPs associated with cT1 identified from a genome-wide association study (GWAS) including 14,440 Europeans from the UKBB were used as IVs.[[2]Parisinos C.A. Wilman H.R. Thomas E.L. Kelly M. Nicholls R.C. McGonigle J. et al.Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis.J Hepatol. 2020; 73: 241-251Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar] Four GWASs of the cardiovascular disease including coronary artery disease (CAD)[[3]Nikpay M. Goel A. Won H.H. Hall L.M. Willenborg C. Kanoni S. et al.A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.Nat Genet. 2015; 47: 1121-1130Crossref PubMed Scopus (1560) Google Scholar], atrial fibrillation (AF)[[4]Nielsen J.B. Thorolfsdottir R.B. Fritsche L.G. Zhou W. Skov M.W. Graham S.E. et al.Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018; 50: 1234-1239Crossref PubMed Scopus (392) Google Scholar], heart failure (HF)[[5]Shah S. Henry A. Roselli C. Lin H. Sveinbjornsson G. Fatemifar G. et al.Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.Nat Commun. 2020; 11: 163Crossref PubMed Scopus (359) Google Scholar] and stroke[[6]Malik R. Chauhan G. Traylor M. Sargurupremraj M. Okada Y. Mishra A. et al.Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018; 50: 524-537Crossref PubMed Scopus (849) Google Scholar] were available, including 60,801 cases and 123,504 controls (CAD), 60,620 cases and 970,216 controls (AF), 47,309 cases and 930,2014 controls (HF), and 67,162 cases and 454,450 controls (stroke), respectively. To assess the potential causal relationship of cT1 with risk of cardiovascular disease, we combined the ratio estimates using the inverse-variance weighted (IVW) method and weighted-median method. Besides, to assess the presence of pleiotropy, we performed MR-Egger regression and MR-PRESSO test. In line with the result of the observational study, our MR analysis indicated that genetically predicted elevated cT1 could increase the risk of HF using the IVW method based on a fixed-effects model [odd ratio (OR) 1.08, 95% CI 1.02 to 1.13, and P = 0.005]. MR-Egger regression analysis did not suggest evidence of potential directional pleiotropy (P value for intercept = 0.143). However, MR analysis indicated that genetically predicted cT1 were not associated with the risk of CAD (OR 0.96, 95% CI 0.89 to 1.03, and P = 0.272), AF (OR 1.02, 95% CI 0.97 to 1.06, and P = 0.468) or stroke (OR 0.99, 95% CI 0.92 to 1.05, and P = 0.623) (Figure 1). No evidence of potential directional pleiotropy was found using MR-Egger regression analysis (P value for intercept = 0.886, 0.867 and 0.436, respectively). In general, our MR analyses confirmed the causal associations between cT1 and HF, while indicated null causal associations between cT1 and CAD, AF or stroke. This result is inconsistent with that derived by Roca-Fernandez A et al. There are a few explanations for this: (1) Roca-Fernandez A et al. regarded 800ms as cT1 threshold and reported a non-linear association of cT1 with cardiovascular disease; however, we could not directly estimate the nonlinear causal effect using MR analysis; (2) a broader definition of cardiovascular disease was used in our study, while Roca-Fernandez A et al. were mainly focused on non-fatal cardiovascular disease events; (3) such causal associations could vary between different populations, which could explain, to some degree, why cT1 is not associated with some cardiovascular diseases. In addition, conventional observational studies are susceptible to unmeasured confounders and reverse causality. Our MR analyses showed that cT1 were causally associated with HF, and inconsistent finding awaits future longitudinal studies with larger sample sizes to give robust casual estimates. The authors received no financial support to produce this manuscript. All GWAS summary statistics can be downloaded from GWAS catalog (https://www.ebi.ac.uk/gwas/). He CY acquired the data and performed the main MR analyses. He CY and Lu D drafted the manuscript. Xu X and Zheng SS revised the manuscript. The authors declare that they have no competing interests. We would like to thank all investigators of GWAS catalog for making summary statistics openly available.