Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3. / Mocci, Evelina; Kundu, Prosenjit; Wheeler, William; Arslan, Alan A.; Beane-Freeman, Laura E.; Bracci, Paige M.; Brennan, Paul; Canzian, Federico; Du, Mengmeng; Gallinger, Steven; Giles, Graham G.; Goodman, Phyllis J.; Kooperberg, Charles; Le Marchand, Loic; Neale, Rachel E.; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Zheng, Wei; Albanes, Demetrius; Andreotti, Gabriella; Babic, Ana; Bamlet, William R.; Berndt, Sonja; Blackford, Amanda L.; Bueno-de-Mesquita, Bas; Buring, Julie E.; Campa, Daniele; Chanock, Stephen J.; Childs, Erica J.; Duell, Eric J.; Fuchs, Charles S.; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael G.; Hartge, Patricia; Hassan, Manal M.; Holly, Elizabeth A.; Hoover, Robert N.; Hung, Rayjean J.; Kurtz, Robert C.; Lee, I-Min; Malats, Nuria; Milne, Roger L.; Ng, Kimmie; Oberg, Ann L.; Panico, Salvatore; Peters, Ulrike; Porta, Miquel; Rabe, Kari G.; Riboli, Elio; Rothman, Nathaniel; Scelo, Ghislaine; Sesso, Howard D.; Silverman, Debra T.; Stevens, Victoria L.; Strobel, Oliver; Thompson, Ian M.; Tjonneland, Anne; Trichopoulou, Antonia; Van den Eeden, Stephen K.; Wactawski-Wende, Jean; Wentzensen, Nicolas; Wilkens, Lynne R.; Yu, Herbert; Yuan, Fangcheng; Zeleniuch-Jacquotte, Anne; Amundadottir, Laufey T.; Li, Donghui; Jacobs, Eric J.; Petersen, Gloria M.; Wolpin, Brian M.; Risch, Harvey A.; Kraft, Peter; Chatterjee, Nilanjan; Klein, Alison P.; Stolzenberg-Solomon, Rachael.
I: Cancer Research, Bind 81, Nr. 11, 2021, s. 3134-3143.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
AU - Mocci, Evelina
AU - Kundu, Prosenjit
AU - Wheeler, William
AU - Arslan, Alan A.
AU - Beane-Freeman, Laura E.
AU - Bracci, Paige M.
AU - Brennan, Paul
AU - Canzian, Federico
AU - Du, Mengmeng
AU - Gallinger, Steven
AU - Giles, Graham G.
AU - Goodman, Phyllis J.
AU - Kooperberg, Charles
AU - Le Marchand, Loic
AU - Neale, Rachel E.
AU - Shu, Xiao-Ou
AU - Visvanathan, Kala
AU - White, Emily
AU - Zheng, Wei
AU - Albanes, Demetrius
AU - Andreotti, Gabriella
AU - Babic, Ana
AU - Bamlet, William R.
AU - Berndt, Sonja
AU - Blackford, Amanda L.
AU - Bueno-de-Mesquita, Bas
AU - Buring, Julie E.
AU - Campa, Daniele
AU - Chanock, Stephen J.
AU - Childs, Erica J.
AU - Duell, Eric J.
AU - Fuchs, Charles S.
AU - Gaziano, J. Michael
AU - Giovannucci, Edward L.
AU - Goggins, Michael G.
AU - Hartge, Patricia
AU - Hassan, Manal M.
AU - Holly, Elizabeth A.
AU - Hoover, Robert N.
AU - Hung, Rayjean J.
AU - Kurtz, Robert C.
AU - Lee, I-Min
AU - Malats, Nuria
AU - Milne, Roger L.
AU - Ng, Kimmie
AU - Oberg, Ann L.
AU - Panico, Salvatore
AU - Peters, Ulrike
AU - Porta, Miquel
AU - Rabe, Kari G.
AU - Riboli, Elio
AU - Rothman, Nathaniel
AU - Scelo, Ghislaine
AU - Sesso, Howard D.
AU - Silverman, Debra T.
AU - Stevens, Victoria L.
AU - Strobel, Oliver
AU - Thompson, Ian M.
AU - Tjonneland, Anne
AU - Trichopoulou, Antonia
AU - Van den Eeden, Stephen K.
AU - Wactawski-Wende, Jean
AU - Wentzensen, Nicolas
AU - Wilkens, Lynne R.
AU - Yu, Herbert
AU - Yuan, Fangcheng
AU - Zeleniuch-Jacquotte, Anne
AU - Amundadottir, Laufey T.
AU - Li, Donghui
AU - Jacobs, Eric J.
AU - Petersen, Gloria M.
AU - Wolpin, Brian M.
AU - Risch, Harvey A.
AU - Kraft, Peter
AU - Chatterjee, Nilanjan
AU - Klein, Alison P.
AU - Stolzenberg-Solomon, Rachael
PY - 2021
Y1 - 2021
N2 - Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 similar to 10(-8) was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P-interaction = 3.08 x 10(-9)). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r(2) = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
AB - Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 similar to 10(-8) was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P-interaction = 3.08 x 10(-9)). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r(2) = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
KW - GENOME-WIDE ASSOCIATION
KW - GENE-ENVIRONMENT INDEPENDENCE
KW - ANTERIOR CINGULATE CORTEX
KW - SUSCEPTIBILITY LOCI
KW - CIGARETTE-SMOKING
KW - METAANALYSIS
KW - LINKAGE
KW - PROTEIN
KW - TRENDS
KW - GWAS
U2 - 10.1158/0008-5472.CAN-20-3267
DO - 10.1158/0008-5472.CAN-20-3267
M3 - Journal article
C2 - 33574088
VL - 81
SP - 3134
EP - 3143
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -
ID: 272399825