Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases
Graphical abstract
Introduction
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health concern worldwide and has reached the pandemic level with a recent prevalence estimate of 29.8 % [1], [2]. NAFLD was deemed a multisystem disease that increases the risks of intrahepatic diseases, and also affects the risks of extrahepatic diseases including cardiovascular diseases, type 2 diabetes (T2D), chronic kidney disease, and extrahepatic malignancies [3], [4]. A large body of observational studies have assessed the correlations between NAFLD and extrahepatic diseases, but conflicting results remain. For instance, prior studies reported that NAFLD was associated with an increased risk of stroke and cardiovascular events [5], [6], [7], [8]. The association was maintained after adjustment for metabolic components. However, a matched cohort study of 18 million European adults reported null associations between NAFLD and acute myocardial infarction and stroke [9].
The inconsistency between observational studies might be ascribed to potential limitations including different measurements for NAFLD (e.g., ultrasound vs. biomarkers), insufficient adjustment for confounders (e.g., metabolic traits), population heterogeneity, and short follow-up times. Moreover, estimates from observational studies are vulnerable to reverse causality. Mendelian randomization (MR) analysis using genetic information is less susceptible to unmeasured confounders and reverse causality because alleles are randomly assigned during meiosis and are independent of environmental exposures [10]. More importantly, MR analysis interprets association as evidence that the exposure has a causal effect on the outcome [11].
Several MR studies have been conducted to examine the association between NAFLD and extrahepatic diseases. For example, Liu et al. reported that genetically determined NAFLD causally promotes T2D [12]. Wu et al. found that NAFLD confers a causal effect on two subtypes of stroke [13]. However, the prior MR analyses mostly used a small number of genetic instrumental variables (IVs) for NAFLD and gave inconsistent findings. For instance, Lauridsen et al. used PNPLA3 rs738409 as an IV and found that genetic NAFLD was not causally associated with risk of ischemic heart disease [14]. Another MR study using eight IVs reported a significantly positive association between NAFLD and coronary artery disease (CAD) [15]. Given the inconsistency between MR studies, an orchestrated MR analysis procedure and more valid IVs are needed to yield robust conclusions. Additionally, the associations between NAFLD and most extrahepatic diseases have not yet been assessed using MR methods. Whether NAFLD is an active contributor or just an innocent bystander for the disease of interest is still unclear and warrants further investigation.
Section snippets
Literature search
We conducted a literature search in PubMed to identify NAFLD-related extrahepatic diseases on March 1, 2022. The search strategy is shown in Supplementary Table S1 and yielded a total of 1176 publications for screening. The inclusion criteria were as follows: (1) cohort, prospective, or longitudinal study design, or meta-analysis on these types of studies; (2) reporting a statistically significant risk ratio or hazard ratio; (3) the exposure was NAFLD; and (4) the primary outcome was
Statistics for instrumental variables
For MR analysis of the association between NAFLD and 34 extrahepatic diseases, the number of included SNPs ranged from 30 to 54, explaining 9.2 % to 15.7 % of the total variance in NAFLD (Supplementary Tables S2–3). All of the mean-F statistics were >400, and the values of IGX2 were >95%, suggesting low probabilities for weak IV and measurement error biases. In the current scenario, the MR analysis has sufficient statistical power (>80 %) to detect a minor association (OR in 0.95–1.05) between
Discussion
In the present study, we assessed the causal relationships between NAFLD and 34 extrahepatic diseases that showed a significantly positive association with NAFLD in observational studies. The MR analyses suggested that NAFLD was causally correlated with an increased risk of two endocrine diseases (i.e., T2D and DH), four circulatory diseases (i.e., CAD, MI, HF, and hypertension), and a digestive disease (i.e., cholelithiasis). In contrast, NAFLD was causally associated with a decreased risk of
Financial support statement
National Postdoctoral Program for Innovative Talents (grant number: BX2021077); China Postdoctoral Science Foundation (grant number: 2021M700841); National Natural Science Foundation of China (grant numbers: 820736378, 82122060); the National Key Research and Development Program of China (grant numbers: 2019YFC1315804, 2019FY101103).
Data availability statement
The sources of GWAS summary data used in the present study are shown in Table 1.
CRediT authorship contribution statement
ZL conceived the study design. ZL and HF performed the statistical analysis. ZL and CS wrote the manuscript and performed the data visualization. XC, LJ and TZ supervised the study. All authors provided critical revisions of the draft and approved the submitted draft. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. XC is the guarantor.
Declaration of competing interest
None to declare.
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