Genetic Associations Between Gastrointestinal Diseases and Chronic Kidney Disease: An Integrated Mendelian...

Chronic  kidney  disease  (CKD)  is  a  progressive condition  with  complex  genetic  and  environmental  influences. This  study  aims  to  investigate  the  genetic  causal  relationships between  gastrointestinal  diseases  and  CKD  using  the  Mendelian Randomization (MR) approach and bioinformatics analysis.

We  analyzed  genetic  associations  between  nineteen gastrointestinal diseases including celiac disease (CeD), inflammatory bowel  disease  (IBD),  intestinal  malabsorption,  and  CKD.  A  two- sample  MR  analysis  was  performed  using  publicly  available Genome-Wide  Association  Studies  (GWAS)  data  with  SingleNucleotide Polymorphisms (SNPs) as instrumental variables (IVs). The primary analysis employed the inverse variance weighted (IVW) method, with MR-Egger and weighted median as supplements. To explore potential biological mechanisms, Functional Mapping and Annotation (FUMA) analysis was used to map genes corresponding to IVs, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.

Significant genetic causal effects were observed for CeD (OR = 1.021, 95% CI = 1.002-1.041, P = .032), IBD (OR = 1.051, 95% CI = 1.014-1.089, P = .006), and intestinal malabsorption (OR = 1.031, 95% CI = 1.006-1.056, P = .013) on the risk of developing CKD. Other gastrointestinal  diseases  did  not  demonstrate  significant  causal effects  on  CKD.  Reverse  MR  analyses  did  not  reveal  significant causal  effects  of  CKD  on  CeD,  IBD,  or  intestinal  malabsorption, respectively. FUMA analysis identified 93 genes associated with CeD, 143  genes  with  IBD,  and  26  genes  with  intestinal  malabsorption. GO  and  KEGG  enrichment  analyses  highlighted  key  pathways, including  T-cell  receptor  signaling,  cytokine-cytokine  receptor interaction, chromatin regulation, and immune-related pathways.

This  study  provides  genetic  and  bioinformatics evidence  linking  CeD,  IBD,  and  intestinal  malabsorption  to  an increased risk of CKD, highlighting the systemic impact of immune dysregulation and inflammation on kidney health.