TY  - JOUR
AU  - Drew, David A
AU  - Kim, Andre E
AU  - Lin, Yi
AU  - Qu, Conghui
AU  - Morrison, John
AU  - Lewinger, Juan Pablo
AU  - Kawaguchi, Eric
AU  - Wang, Jun
AU  - Fu, Yubo
AU  - Zemlianskaia, Natalia
AU  - Díez-Obrero, Virginia
AU  - Bien, Stephanie A
AU  - Dimou, Niki
AU  - Albanes, Demetrius
AU  - Baurley, James W
AU  - Wu, Anna H
AU  - Buchanan, Daniel D
AU  - Potter, John D
AU  - Prentice, Ross L
AU  - Harlid, Sophia
AU  - Arndt, Volker
AU  - Barry, Elizabeth L
AU  - Berndt, Sonja I
AU  - Bouras, Emmanouil
AU  - Brenner, Hermann
AU  - Budiarto, Arif
AU  - Burnett-Hartman, Andrea
AU  - Campbell, Peter T
AU  - Carreras-Torres, Robert
AU  - Casey, Graham
AU  - Chang-Claude, Jenny
AU  - Conti, David V
AU  - Devall, Matthew A M
AU  - Figueiredo, Jane C
AU  - Gruber, Stephen B
AU  - Gsur, Andrea
AU  - Gunter, Marc J
AU  - Harrison, Tabitha A
AU  - Hidaka, Akihisa
AU  - Hoffmeister, Michael
AU  - Huyghe, Jeroen R
AU  - Jenkins, Mark A
AU  - Jordahl, Kristina M
AU  - Kundaje, Anshul
AU  - Le Marchand, Loic
AU  - Li, Li
AU  - Lynch, Brigid M
AU  - Murphy, Neil
AU  - Nassir, Rami
AU  - Newcomb, Polly A
AU  - Newton, Christina C
AU  - Obón-Santacana, Mireia
AU  - Ogino, Shuji
AU  - Ose, Jennifer
AU  - Pai, Rish K
AU  - Palmer, Julie R
AU  - Papadimitriou, Nikos
AU  - Pardamean, Bens
AU  - Pellatt, Andrew J
AU  - Peoples, Anita R
AU  - Platz, Elizabeth A
AU  - Rennert, Gad
AU  - Ruiz-Narvaez, Edward
AU  - Sakoda, Lori C
AU  - Scacheri, Peter C
AU  - Schmit, Stephanie L
AU  - Schoen, Robert E
AU  - Stern, Mariana C
AU  - Su, Yu-Ru
AU  - Thomas, Duncan C
AU  - Tian, Yu
AU  - Tsilidis, Konstantinos K
AU  - Ulrich, Cornelia M
AU  - Um, Caroline Y
AU  - van Duijnhoven, Fränzel J B
AU  - Van Guelpen, Bethany
AU  - White, Emily
AU  - Hsu, Li
AU  - Moreno, Victor
AU  - Peters, Ulrike
AU  - Chan, Andrew T
AU  - Gauderman, W James
TI  - Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
JO  - Science advances
VL  - 10
IS  - 22
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2024-01155
SP  - eadk3121
PY  - 2024
AB  - Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
KW  - Humans
KW  - Colorectal Neoplasms: genetics
KW  - Colorectal Neoplasms: drug therapy
KW  - Anti-Inflammatory Agents, Non-Steroidal: pharmacology
KW  - Genome-Wide Association Study
KW  - Polymorphism, Single Nucleotide
KW  - Aspirin: pharmacology
KW  - Receptors, Prostaglandin E, EP4 Subtype: genetics
KW  - Receptors, Prostaglandin E, EP4 Subtype: metabolism
KW  - Male
KW  - Genetic Predisposition to Disease
KW  - Female
KW  - Case-Control Studies
KW  - Middle Aged
KW  - Genetic Loci
KW  - Aged
KW  - Anti-Inflammatory Agents, Non-Steroidal (NLM Chemicals)
KW  - Aspirin (NLM Chemicals)
KW  - Receptors, Prostaglandin E, EP4 Subtype (NLM Chemicals)
KW  - PTGER4 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38809988
C2  - pmc:PMC11135391
DO  - DOI:10.1126/sciadv.adk3121
UR  - https://inrepo02.dkfz.de/record/290551
ER  -