Award: Fellows-in-Training Award (Functional Bowel Disease Category)
Award: Presidential Poster Award
Isabel A. Hujoel, MD1, Margaux Hujoel, PhD2; 1Mayo Clinic, Rochester, MN; 2Harvard T.H. Chan School of Public Health, Boston, MA
Introduction: Irritable bowel syndrome (IBS) is a prevalent condition that is associated with significant financial and personal cost. Treatment options can have limited efficacy and those with IBS often have poor quality of life. More effective treatment options are needed, and understanding the underlying pathophysiology of IBS may focus this search. A prior study has found that those with IBS are more likely to have an elevated copper-zinc ratio. It is unknown if serum levels of these two metals play a pathogenic role in IBS. Methods: We conducted a two-sample Mendelian randomization (MR) study. MR capitalizes on the random assignment of single-nucleotide polymorphisms (SNPs) at conception to mimic randomization and therefore associations identified with MR are seen as causal under certain assumptions. For our study, we used SNPs identified in a genome-wide association study performed on adult twins and their families in Australia. Specifically, we selected those SNPs that were both independent (r2< 0.05) and strongly associated (p< 5x10-8) with erythrocyte copper and zinc levels. To evaluate the SNP and IBS association, we used publicly available statistics from the UK Biobank on 5,548 individuals with IBS and 334,783 controls. To combine information from multiple genetic variants into one causal estimate we used an inverse variance weighting (IVW) method and a weighted median estimator (WM). A sensitivity analysis was performed with MR-Egger. Results: There were three independent and strongly associated SNPs for copper levels and three for zinc levels. Higher genetically instrumented copper was significantly associated with a lower risk of IBS using both IVW (p=0.016) and WM (p=0.006). The MR-Egger intercept did not differ from the null (p=0.875). Higher genetically instrumented zinc was not significantly associated with the risk of IBS (p=0.277 and 0.145 for IVW and WM respectively) (Figure 1). Discussion: We found that genetically determined elevated erythrocyte copper levels may be protective for IBS. Copper plays a role in several of the proposed etiologic pathways in IBS including the gut immune function, permeability, microbiome, and brain-gut axis. Our finding has significant potential implications. Copper levels are readily modifiable with alterations in diet or through the use of supplementation. If our findings are validated with further study, this may provide an avenue for safe and inexpensive prevention and treatment of this disease.
Single-nucleotide polymorphism-specific and overall inverse variance weighted fixed-effect associations (odds ratios) of log-transformed standardized residuals of copper and zinc with irritable bowel syndrome
Disclosures: Isabel Hujoel indicated no relevant financial relationships. Margaux Hujoel indicated no relevant financial relationships.