Investigating the causal associations between five anthropometric indicators and nonalcoholic fatty liver disease: Mendelian randomization study

ARTICLE HIGHLIGHTS

Research background

This study offers the first comprehensive assessment of causal associations between five anthropometric measures and nonalcoholic fatty liver disease (NAFLD) by using both Univariate Mendelian randomization (MR) and Multivariable MR methods. Considering the possibility of potential chance in the results, we additionally selected another exposure and outcome Genome-wide association study data from European population for replication, including a cross-analysis of two different sources of data.

Research motivation

Although the etiology of NAFLD has not been thoroughly understood, the emerging roles of anthropometric indicators in assessing and predicting the risk of NAFLD have been highlighted by accumulating evidence. Numerous previous observational studies have reported relationships between the risk of NAFLD and noninvasive quantitative measurements of the body, such as anthropometric indicators, which comprise height, weight, hip circumference, waist circumference (WC), waist-to-hip ratio, body mass index (BMI), and body fat percentage. Contradictory findings have been obtained in some other studies, indicating no relationship between anthropometric indicators and the risk of NAFLD. The causal relationships between anthropometric indicators and NAFLD risk remain undetermined, considering these inconsistent findings and the absence of randomized controlled studies.

Research objectives

This study demonstrates that genetically determined increased WC maintains a positive and causal association with NAFLD, even in the presence of confounders, including BMI and smoking. This underscores the potential of WC as a reliable indicator for the early identification and diagnosis of NAFLD.

Research methods

MR is a novel epidemiological tool that employs genetic data to investigate the causal relationship between exposure and outcome. Generally, genetic variants are independent of disease state and are randomly assigned to offspring through the maternal generation. Consequently, the limitations of conventional observational design can be overcome, and biases such as potential confounders and reverse causality can be minimized. Previous studies have demonstrated the use of MR to investigate causal relationships between NAFLD and numerous diseases, including cardiovascular disease and psoriasis.

Research results

Genetically determined increased WC maintains a positive and causal association with NAFLD, even in the presence of confounders, including BMI and smoking. Several limitations require attention. First, the exposure and outcome datasets were obtained from European ancestry; therefore, these findings may not be generalizable to other populations with different genetic backgrounds. Further studies are required to validate these results in other ethnic populations. Second, although the F-statistic can be used to evaluate the first hypothesis, verifying the second and third hypotheses is generally challenging and may lead to potential bias. Third, the causal relationship between anthropometric indicators and NAFLD in different sex/age groups cannot be investigated due to the lack of personal demographic information on anthropometric indicators.

Research conclusions

This study demonstrates that genetically determined increased WC maintains a positive and causal association with NAFLD, even in the presence of confounders, including BMI and smoking. This underscores the potential of WC as a reliable indicator for the early identification and diagnosis of NAFLD.

Research perspectives

Future studies should consider using WC as an auxiliary measurement for identifying NAFLD.