The causal role of plasma protein ratios in ulcerative colitis: insights from mendelian randomization and single-cell sequencing
Kuo Kang, Linfeng Wei, Xuanxuan Li, Shalong Wang, Changhao Huang, Zhiwei WuAbstract
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.