Association Between Genetically Proxied SLC12A2 Inhibition and Inflammatory Bowel Disease: A Mendelian Randomization Study

The global rise in hypertension prompts the use of medications to manage blood pressure. However, selecting first-line drugs remains challenging as their efficacy often stems from blood pressure reduction rather than specific pharmacological actions. Evaluating interactions between antihypertensive drugs and common diseases can aid tailored treatment. Here, we assess the potential link between antihypertensives and inflammatory bowel disease (IBD). Summary-level coronary heart disease (CHD) data (184,305 individuals), systolic BP (SBP) data (757,601 individuals), ulcerative ileocolitis data (361,188 individuals), ulcerative colitis data (364,454 individuals), other ulcerative colitis data (361,619 individuals), and ulcerative proctitis data (361,700 individuals) were all from genome-wide association studies (GWASs), FinnGen or eQTL studies publicly accessible. The DrugBank10 and ChEMBL11 databases function to identify genes encoding protein products targeted by active constituents of BP-lowering drugs. Summary-data-based MR (SMR) estimated the associations between expressions of drug target genes and symptoms of IBD. A multivariable MR study was further conducted to examine if the observed association was direct association. Subsequently, we collected blood samples from IBD patients in the Gastroenterology Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University and blood from healthy individuals at the physical examination center. Real-time quantitative PCR was employed to detect the expression changes of drug target genes in the peripheral blood of patients with IBD. Furthermore, we used Caco2 cells to construct an in vitro model of IBD, examined the expression of the target molecules, and verified the potential of Bumetanide to improve IBD. SMR analysis revealed that enhanced SLC12A2 gene expression in blood (equivalent to a one standard deviation increase) was a risk factor for ulcerative ileocolitis (beta = 0.5861, se = 0.2972, p = 0.0486) and enhanced gene expression of ACE was a protective factor. Additionally, SCNN1D and SLC16A1 played protective roles of IBD, while NR3C1 was identified as a risk factor. However, among these genes, only SLC12A2 was considered to influence the progress of inflammatory bowel disease through systolic blood pressure based on Mendelian randomization analysis results. Other genes may be associated with IBD depending on the expression of their own proteins, independent of changes in blood pressure. In the peripheral blood of IBD patients and in vitro experiments, SCL12A2 has been shown to be highly expressed in IBD. In vitro experiments have confirmed that Bumetanide can inhibit SCL12A2 to improve tight junctions, reduce inflammation levels, and ameliorate IBD symptoms. Therapeutic inhibition of SCL12A2 may benefit patients with IBD. In the future, this study may contribute to the selection of more personalized antihypertensive medications for different subgroups of hypertensive patients.