Unveiling CTRB2, RSPO3, KLOTB, and ROR1 as obesity-pancreatic disease association proteins: a comprehensive Mendelian randomization study.

Obesity is recognized as a prominent contributing factor for pancreatic diseases; however, the mechanisms remain elusive. We aimed to identify the mediating role of circulating proteins in these associations. A two-step Mendelian randomization (MR) was conducted to investigate associations between nine obesity indicators, thousands of circulating proteins, with three pancreatic diseases (acute pancreatitis, chronic pancreatitis, and pancreatic carcinoma). Colocalization analyses were performed to validate these associations. Protein mediating networks among obesity indicators and pancreatic diseases were investigated by mediation analysis. Genetically predicted circulating levels of 4, 2, and 2 proteins were associated with acute pancreatitis, chronic pancreatitis, and pancreatic carcinoma, respectively. In mediation analysis, decreased chymotrypsin B2 (CTRB2) levels mediated 1.03% (95% CI [confidence interval] 0.02%-2.03%) of the effects of body mass index on acute pancreatitis. Increased R-spondin 3 (RSPO3) levels mediated the effects of body mass index (2.95%, 95% CI 0.18%-5.73%), body fat percentage (4.53%, 95% CI 1.11%-7.96%), waist-hip ratio (8.48%, 95% CI 3.11%-13.86%), and visceral adipose tissue (3.93%, 95% CI 0.64%-7.22%) on acute pancreatitis. We also found increased klotho beta (KLOTB) levels mediated the effects of waist-hip ratio (7.01%, 95% CI 3.30%-10.71%) and visceral adipose tissue (8.98%, 95% CI 4.55%-13.41%) on chronic pancreatitis, and decreased receptor tyrosine kinase-like orphan receptor 1 (ROR1) levels mediated the effects of body mass index (10.39%, 95% CI 3.36%-17.42%) and visceral adipose tissue (6.29%, 95% CI 1.00%-11.58%) on pancreatic carcinoma. The MR suggests that circulating CTRB2, RSPO3, KLOTB, and ROR1 proteins may mediate associations between obesity and pancreatic diseases.