The causal role of plasma protein ratios in ulcerative colitis: insights from mendelian randomization and single-cell sequencing.

This Mendelian randomization study aimed to systematically investigate the causal associations of 2,821 plasma protein ratios with UC susceptibility and validate potential biomarkers through multi-omics approaches. This study employed a two-sample Mendelian randomization (MR) approach using publicly available genetic data from genome-wide association studies (GWAS), with single nucleotide polymorphisms (SNPs) serving as instruments for exposures and outcome variables. Using the two-sample MR approach, we assessed the associations between 2,821 plasma protein ratios and UC and performed a series of sensitivity analyses to enhance the robustness of our findings. Additionally, single-cell sequencing was used to validate and explore the MR results. And ELISA assays were carried to validate the expression of certain protein ratios. The inverse-variance weighted method identified significant relationships between 165 plasma protein ratios and UC (FDR<0.05). UC susceptibility, per one standard deviation increase in genetically predicted protein ratios, ranged from 0.539 (DCTN1/IKBKG, 95 % CI: 0.408-0.712) to 2.078 (CCT5/DCTN1, 95 % CI: 1.607-2.686). Various sensitivity analyses further confirmed the robustness of these causal relationships. Single-cell sequencing further revealed significant differences in DLL1/TGFBR2 ratios between UC and healthy controls (p<0.0001), with a moderate yet significant elevation in CCT5/DCTN1 ratios (p<0.01) and no notable difference in BCR/DCTN1 ratios. Validation using ELISA in 26 pairs of UC patients and healthy controls showed a significantly elevated DLL1/TGFBR2 ratio in the UC group (p<0.001), while CCT5/DCTN1 and BCR/DCTN1 ratios showed no differences. The findings reveal a robust causal relationship between the DLL1/TGFBR2 plasma protein ratio and UC, offering novel insights into the diagnosis and treatment of the disease.