Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.
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Zhang Ting, Hua Xing, Mohindroo Chirayu, Wang Xiaoyu, Dutta Diptavo, Liu Jia, Katta Shilpa, Li Shengchao A, Wang Jiahui, Antwi Samuel O, Arslan Alan A, Beane Freeman Laura E, Bracci Paige M, Canzian Federico, Du Mengmeng, Gallinger Steven, Goodman Phyllis J, Katzke Verena, Kooperberg Charles, Le Marchand Loic, Neale Rachel E, Patel Alpa V, Perdomo Sandra, Shu Xiao-Ou, Visvanathan Kala, Van Den Eeden Stephen K, White Emily, Zheng Wei, Albanes Demetrius, Andreotti Gabriella, Bamlet William R, Brennan Paul, Buring Julie E, Chanock Stephen J, Chen Yu, Darst Burcu, Ferrari Pietro, Giovannucci Edward L, Goggins Michael, Haiman Christopher, Hassan Manal, Holly Elizabeth A, Hung Rayjean J, Jones Miranda R, Kraft Peter, Kurtz Robert C, Malats Núria, Moore Steven C, Ng Kimmie, Oberg Ann L, Orlow Irene, Peters Ulrike, Porta Miquel, Rabe Kari G, Rothman Nathaniel, Sánchez Maria-José, Sesso Howard D, Silverman Debra T, Southey Melissa C, Um Caroline Y, Yarmolinsky James, Yu Herbert, Yuan Chen, Zhong Jun, Wolpin Brian M, Risch Harvey A, Amundadottir Laufey T, Klein Alison P, Yu Kai, Zhang Haoyu, Stolzenberg-Solomon Rachael Z
Аннотация
METHODS: We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry.
RESULTS: Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions.
CONCLUSIONS: Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.