Mendelian randomization analysis for intestinal disease: Achievement and future

Traditional epidemiological studies have identified numerous potential risk factors, but observational studies have struggled to establish causal links due to confounding factors and reverse causation. Theoretically avoiding confounding and reverse causation, Mendelian randomization (MR) infers causality, offering novel research perspectives and methods for investigating risk factors of intestinal diseases (Figure 1).

MR research on intestinal disease

Based on MR methodology, researchers have identified lifestyle factors, circulating nutrients, and obesity as being associated with the risk of various intestinal diseases (Figure 2). Unhealthy lifestyle habits such as alcohol consumption, smoking, insomnia, and sedentary behavior can increase the risk of bowel diseases like colorectal cancer and inflammatory bowel disease. Conversely, a healthy lifestyle, including regular exercise, can reduce the risks of these diseases. Some studies have found that vitamins A, C, D, E, and Omega-3 and 6 fatty acids may protect play a protective role in inflammatory bowel disease and colorectal cancer development. MR studies have also examined the effects of obesity and dyslipidemia on bowel disease. High body mass index, excess body fat, and a large waist-to-hip ratio have been associated with an increased risk of colorectal cancer, Crohn's disease, diverticular disease, and irritable bowel syndrome. These findings suggest that modifying lifestyle habits and optimizing diet can potentially reduce the risk of bowel disease.

MR studies have also identified causal associations between various inflammatory protein biomarkers and the risk of intestinal disease. For example, genetically predicted higher levels of IL-16, IL-18, and CXCL10 were associated with increased inflammatory bowel disease risk, while genetically predicted IL12p70 and CCL23 levels was associated with decreased risks of inflammatory bowel desease. Proteome-wide MR studies have revealed potential therapeutic targets, such as MST1, HGFAC, STAT3, ITPKA, and CXCL5, which play significant roles in inflammatory bowel disease. Genetically predicted higher GREM1 and CHRDL2 levels, along with lower CLSTN3 and POLR2F levels, are associated with an increased risk of colorectal cancer. These findings provide important insights for developing new drugs for intestinal diseases.

Drug target investigations using MR in intestinal diseases can be broadly categorised into two approaches. Proteome-wide analyses related numerous circulating proteins to disease outcomes, typically validating established while uncovering novel pharmacological targets that could inform drug development efforts. Repurposing studies focused on interrogating whether existing drugs developed for other indications might harbour additional therapeutic utility in intestinal diseases and evaluated the safety in intestinal, exemplified by evaluating antihyperlipidaemic and antihypertensive agents.

MR has also been used to investigate the association between intestinal flora and its metabolites with intestinal diseases. Additionally, MR has been employed to elucidate the associations between intestinal diseases and other diseases, such as psychiatric disorders, hepatobiliary and pancreatic diseases and autoimmune diseases (Figure 3).

Future perspectives of MR study in intestinal diseases

Integrating multiomics data through MR represents a promising future direction to uncover more complex mechanistic pathways. Leveraging research designs with different strengths and sources of bias allowed the triangulation of findings. When composing an MR paper, researchers should refer to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-MR guidelines to ensure the quality of their manuscript, which contributes to enhancing the quality of MR studies and ensuring their credibility and reproducibility. Larger sample sizes are needed to achieve the power required to detect variants especially of smaller effect for exposure, and larger sample sizes will be also needed for intestinal disease particularly for less heritable disorders. Most MR studies have focused on European populations, which may not be generalizable to other ancestries. It is encouraged to explore MR associations in populations with different ancestries.

See the article:

Xixian Ruan, Tianyi Che, Xuejie Chen, Yuhao Sun, Tian Fu, Shuai Yuan, Xue Li, Jie Chen, Xiaoyan Wang - Mendelian randomisation analysis for intestinal disease: achievement and future: eGastroenterology 2024;2:e100058.

https://doi.org/10.1136/egastro-2023-100058

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