Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study

Abstract

Background

Metabolic disorders are a hallmark feature of cancer. However, the evidence for the causality of circulating metabolites to promote or prevent colorectal cancer (CRC) is still lacking. We performed a two‐sample Mendelian randomization (MR) analysis to assess the causality from genetically proxied 486 blood metabolites to CRC.

Methods

Genome‐wide association study (GWAS) data for exposures were extracted from 7824 Europeans GWAS on metabolite levels. GWAS data for CRC from the GWAS catalog database GCST012879 were used for the preliminary analysis. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR‐Egger and weighted median as complementary analyses. Cochran Q test, MR‐Egger intercept test, MR‐PRESSO, Radial MR, and leave‐one‐out analysis were used for sensitivity analyses. For significant associations, additional independent CRC GWAS data GCST012880 were used for replication analysis and meta‐analysis. For the final identification of metabolites, Steiger test, linkage disequilibrium score regression, and colocalization analysis were performed for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on CRC.

Results

The results of this study indicated significant associations between six metabolites pyruvate (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.32–0.77, p = 0.002), 1,6‐anhydroglucose (OR: 1.33, 95% CI: 1.11–1.59, p = 0.002), nonadecanoate (19:0) (OR: 0.40, 95% C I:0.4–0.68, p = 0.0008), 1‐linoleoylglycerophosphoethanolamine (OR: 0.47, 95% CI: 0.30–0.75, p = 0.001), 2‐hydroxystearate (OR: 0.39, 95% CI: 0.23–0.67, p = 0.0007), gamma‐glutamylthreonine (OR: 2.14, 95% CI: 1.02–4.50, p = 0.040) and CRC. MVMR analysis revealed that genetically predicted pyruvate, 1‐linoleoylglycerophosphoethanolamine and gamma‐glutamylthreonine can directly influence CRC independently of other metabolites.

Conclusion

The current work provides evidence to support the causality of the six circulating metabolites on CRC and a new perspective on the exploration of the biological mechanisms of CRC by combining genomics and metabolomics. These findings contribute to the screening, prevention and treatment of CRC.

Abstract

Due to unavoidable study design weaknesses, previous studies have made it difficult to assess the causality from circulating metabolites to colorectal cancer. In this work, the authors used the most comprehensive blood metabolite genome‐wide association study data to assess the causality between metabolites and colorectal cancer based on a Mendelian randomization study. They found that genetic liability for higher levels of pyruvate, nonadecanoate (19:0), 1‐linoleoylglycerophosphoethanolamine, and 2‐hydroxystearate associated with lower colorectal cancer risk while higher levels of 1,6‐anhydroglucose and gamma‐glutamylthreonine increased risk of colorectal cancer.