Abstract
This study investigates the causal relationship between genetically proxied iron-supplement drugs and inflammatory bowel disease (IBD) risk. After identifying 8 commonly used iron supplementation drugs based on the guidelines, a search for each of these drugs yielded 18 key regulatory targets and the locus information of each drug-targeted gene was obtained. Hemoglobin was selected as a biomarker downstream of drug regulation and its single nucleotide polymorphism (SNP) data were extracted and screened from genome-wide association studies (GWAS). Strict screening conditions were set to obtain valid SNPs information for each drug-target gene from hemoglobin downstream marker information. We successively included European and Asian populations in our analyses. The SNP information of IBD, ulcerative colitis (UC) and Crohn disease (CD) were extracted from the GWAS database as the outcome variables. The bidirectional and multivariate Mendelian randomization was performed between each target gene and each outcome variable, and the robustness of these results was validated using heterogeneity tests, horizontal pleiotropy tests, and leave-one-out methods. Data from 34,652 patients with IBD, 417,932 patients with UC, 20,883 patients with CD, and 408,112 individuals with hemoglobin measurement were analyzed. Genetically proxied Egl nine homolog 1 (EGLN1) was associated with increased IBD, UC and CD risk. Genetically proxied Flap Endonuclease 1 (FEN1) was associated with an increased risk of IBD and CD. Genetically proxied Ferritin heavy chain 1 (FTH1) and Transferrin receptor 2 (TFR2) were associated with an increased risk of CD. Genetically proxied DNA polymerase beta (POLB) was associated with a reduced risk of CD. Sensitivity analyses of them did not provide statistical evidence of serious bias. The reverse Mendelian results showed a positive result between IBD and EGLN1, meaning that there is a bidirectional causal relationship between the 2. Upon inclusion of the Asian ethnic cohort, potential causal associations were found between EGLN1, FEN1, Integrin, beta 3 (ITGB3), Transferrin receptor gene (TFRC) and UC, inverse Mendelian analyses showed a causal relationship between POLB and CD. This study suggests that target genes such as EGLN1, FEN1, ITGB3, TFRC, FTH1, and POLB are potentially associated with the pathogenesis of inflammatory bowel disease.