Chunhua Zhou, Xixian Ruan, Tianyi Che, Yao Zhang, Shuai Yuan, Xue Li, Jie Zheng, Xiaocang Cao, Jie Chen, Xiaoyan Wang, Duowu Zou
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Protein mediating networks among obesity indicators and pancreatic diseases were investigated by mediation analysis.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>The MR suggests that circulating CTRB2, RSPO3, KLOTB, and ROR1 proteins may mediate associations between obesity and pancreatic diseases.</p>","PeriodicalId":54275,"journal":{"name":"Gastroenterology Report","volume":"13 ","pages":"goaf057"},"PeriodicalIF":4.2000,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371523/pdf/","citationCount":"0","resultStr":"{\"title\":\"Unveiling CTRB2, RSPO3, KLOTB, and ROR1 as obesity-pancreatic disease association proteins: a comprehensive Mendelian randomization study.\",\"authors\":\"Chunhua Zhou, Xixian Ruan, Tianyi Che, Yao Zhang, Shuai Yuan, Xue Li, Jie Zheng, Xiaocang Cao, Jie Chen, Xiaoyan Wang, Duowu Zou\",\"doi\":\"10.1093/gastro/goaf057\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>The MR suggests that circulating CTRB2, RSPO3, KLOTB, and ROR1 proteins may mediate associations between obesity and pancreatic diseases.</p>\",\"PeriodicalId\":54275,\"journal\":{\"name\":\"Gastroenterology Report\",\"volume\":\"13 \",\"pages\":\"goaf057\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2025-07-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371523/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gastroenterology Report\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/gastro/goaf057\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gastroenterology Report","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/gastro/goaf057","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：肥胖被认为是胰腺疾病的一个重要因素；然而，其机制仍然难以捉摸。我们的目的是确定循环蛋白在这些关联中的介导作用。方法：采用两步孟德尔随机化（MR）研究9项肥胖指标、数千种循环蛋白与3种胰腺疾病（急性胰腺炎、慢性胰腺炎和胰腺癌）之间的关系。进行共定位分析以验证这些关联。通过中介分析研究了肥胖指标与胰腺疾病之间的蛋白质中介网络。结果：基因预测的4、2和2蛋白循环水平分别与急性胰腺炎、慢性胰腺炎和胰腺癌相关。在中介分析中，凝乳胰蛋白酶B2 （CTRB2）水平降低介导了1.03% （95% CI[置信区间]0.02%-2.03%）的体重指数对急性胰腺炎的影响。R-spondin 3 （RSPO3）水平升高介导了体重指数（2.95%,95% CI 0.18%-5.73%）、体脂率（4.53%,95% CI 1.11%-7.96%）、腰臀比（8.48%,95% CI 3.11%-13.86%）和内脏脂肪组织（3.93%,95% CI 0.64%-7.22%）对急性胰腺炎的影响。我们还发现klotho β (KLOTB)水平升高介导腰臀比（7.01%,95% CI 3.30%-10.71%）和内脏脂肪组织（8.98%,95% CI 4.55%-13.41%）对慢性胰腺炎的影响，受体酪氨酸激酶样孤儿受体1 （ROR1）水平降低介导体重指数（10.39%,95% CI 3.36%-17.42%）和内脏脂肪组织（6.29%,95% CI 1.00%-11.58%）对胰腺癌的影响。结论：磁共振提示循环CTRB2、RSPO3、KLOTB和ROR1蛋白可能介导肥胖和胰腺疾病之间的关联。
Unveiling CTRB2, RSPO3, KLOTB, and ROR1 as obesity-pancreatic disease association proteins: a comprehensive Mendelian randomization study.
Background: 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.
Methods: 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.
Results: 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.
Conclusions: The MR suggests that circulating CTRB2, RSPO3, KLOTB, and ROR1 proteins may mediate associations between obesity and pancreatic diseases.
期刊介绍：
Gastroenterology Report is an international fully open access (OA) online only journal, covering all areas related to gastrointestinal sciences, including studies of the alimentary tract, liver, biliary, pancreas, enteral nutrition and related fields. The journal aims to publish high quality research articles on both basic and clinical gastroenterology, authoritative reviews that bring together new advances in the field, as well as commentaries and highlight pieces that provide expert analysis of topical issues.
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