Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.

Authors

Zhang T, Hua X, Mohindroo C, Wang X, Dutta D, Liu J, Katta S, Li SA, Wang J, Antwi SO, Arslan AA, Beane Freeman LE, Bracci PM, Canzian F, Du M, Gallinger S, Goodman PJ, Katzke V, Kooperberg C, Le Marchand L, ...show more Neale RE, Patel AV, Perdomo S, Shu XO, Visvanathan K, Van Den Eeden SK, White E, Zheng W, Albanes D, Andreotti G, Bamlet WR, Brennan P, Buring JE, Chanock SJ, Chen Y, Darst B, Ferrari P, Giovannucci EL, Goggins M, Haiman C, Hassan M, Holly EA, Hung RJ, Jones MR, Kraft P, Kurtz RC, Malats N, Moore SC, Ng K, Oberg AL, Orlow I, Peters U, Porta M, Rabe KG, Rothman N, Sánchez MJ, Sesso HD, Silverman DT, Southey MC, Um CY, Yarmolinsky J, Yu H, Yuan C, Zhong J, Wolpin BM, Risch HA, Amundadottir LT, Klein AP, Yu K, Zhang H, Stolzenberg-Solomon RZ

Affiliations

• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, United States.
• Medical Oncology Service, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
• Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States.
• Department of Obstetrics and Gynecology, New York University Grossman School of Medicine, New York, NY, United States.
• Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States.
• Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
• Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
• Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, Ontario, Canada.
• SWOG Statistical Center, Fred Hutchinson Cancer Center, Seattle, WA, United States.
• Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

BACKGROUND: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.

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.