Genetic Associations Found Between CRC, IBD, Obesity, and Inflammation

Novel genetic associations between obesity, colorectal cancer (CRC), irritable bowel disease (IBD), and inflammation were identified in a study published in the Journal of Diabetes & Metabolic Disorders.¹

CRC is the third most common cancer diagnosis in the world³ and is seeing a trend of increasing diagnoses in patients aged between 20 and 49 years. It is associated with obesity among other risk factors, and IBD is similarly associated with obesity.

The study aimed to evaluate the role of common genetic factors associated with obesity, CRC, and IBD based on genome-wide association studies (GWAS) that were previously published.¹

A genetic association can help in identifying those at higher susceptibility to any of the diseases | Image credit: immimagery - stock.adobe.com

The GWAS Catalog-EMBL-EBI was used to extract GWAS variants that were associated with CRC, IBD, or obesity. The common haplotypic structure of the disease was also identified, with gene-gene expression, protein-protein interactions, and gene survival analysis performed with the results.

Significant variants for GWAS associated with CRC and IBD, CRC and obesity, and IBD and obesity were identified using mapped variants. A total of 2054 subjects were used to find proxy variants. Expression quantitative trait locus (eQTL) variants were identified using the Genotype-Tissue Expression portal, and RegulomeDB was used to rank regulatory variants as well as the probability of functional variants.

A total of 8 common variants between CRC and IBD and 1 variant between advanced colorectal adenoma and IBD were found after analysis. The variants were all eQTL, and the scores for RegulomeDB were good.

There were 10 variants that were associated with both IBD and body mass index (BMI), with 3 variants associated with IBD and obesity traits. The variants were eQTL and had good RegulomeDB scores, except for rs921720 on the LINC02964 gene. BMI and CRC had 6 common variants, and CRC and waist-to-hip ratio had 3 related variants, with 1 variant related to obesity.

The only variant that was common between obesity, IBD, and CRC was rs3184504 on the SH2B3 gene.

A haplotype analysis found that 6 variants on the SH2B3 gene showed 2 haplotype blocks that identified rs3184504 as a common proxy variant for obesity, IBD, and CRC. Colon and rectal cancers had a significantly lower expression analysis of SH2B3 compared with normal tissues. Survival of patients in colon or rectal cancer was not associated with the role of the gene. SH2B3 was also found to be in the highest confidence protein-protein interaction with genes in associated with inflammatory and cancer-associated pathways.

The researchers concluded that there were novel genetic associations between obesity, IBD, and CRC, with the rs3184504 and AGCAGT haplotype variants on the SH2B3 gene being the primary genetic associations. The potential genetic link between these 3 diseases could help in identifying susceptibility to CRC and IBD among patients with overweight or obesity.

"These results indicate that there are complex shared genetic associations between these three diseases and inflammation," the authors concluded. "Future studies on these findings are needed to confirm them."

References

1. Gholami M. Novel genetic association between obesity, colorectal cancer, and inflammatory bowel disease. J Diabetes Metab Disord. 2024;23:739-744. doi:10.1007/s40200-023-01343-w
2. Colorectal cancer statistics. World Cancer Research Fund International. Accessed June 27, 2024. https://www.wcrf.org/cancer-trends/colorectal-cancer-statistics/