title: Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer.
abstract: Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 × 10(-4)) and UGT1A6 (P = 8 × 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P(additive) = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Montse.GarciaClosas@icr.ac.uk
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.forename: Summer S
authors.initials: SS
authors.lastname: Han
authors.forename: Dalsu
authors.initials: D
authors.lastname: Baris
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jacobs
authors.forename: Nuria
authors.initials: N
authors.lastname: Malats
authors.forename: Immaculata
authors.initials: I
authors.lastname: De Vivo
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.forename: Sapna
authors.initials: S
authors.lastname: Sharma
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Fu
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Consol
authors.initials: C
authors.lastname: Serra
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Reina
authors.initials: R
authors.lastname: García-Closas
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Alison
authors.initials: A
authors.lastname: Johnson
authors.forename: Molly
authors.initials: M
authors.lastname: Schwenn
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Alan
authors.initials: A
authors.lastname: Schned
authors.forename: Gerald
authors.initials: G
authors.lastname: Andriole
authors.forename: Robert
authors.initials: R
authors.lastname: Grubb
authors.forename: Amanda
authors.initials: A
authors.lastname: Black
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gapstur
authors.forename: Michael
authors.initials: M
authors.lastname: Thun
authors.forename: William Ryan
authors.initials: WR
authors.lastname: Diver
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jacobs
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Fraumeni
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002278:Carcinoma in Situ / Q000209:etiology* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000473:pathology; D055815:Young Adult
references.citation: J Natl Cancer Inst. 2009 Nov 18;101(22):1553-61
references.pmid: 19917915
references.citation: Nat Genet. 2009 Sep;41(9):991-5
references.pmid: 19648920
references.citation: Biometrics. 2008 Sep;64(3):685-694
references.pmid: 18162111
references.citation: Curr Probl Cancer. 2001 Jul-Aug;25(4):219-78
references.pmid: 11514784
references.citation: Int J Epidemiol. 2007 Feb;36(1):236-41
references.pmid: 17510079
references.citation: J Clin Oncol. 2007 Nov 1;25(31):4974-81
references.pmid: 17971596
references.citation: Lancet. 2005 Aug 20-26;366(9486):649-59
references.pmid: 16112301
references.citation: Carcinogenesis. 2011 Feb;32(2):182-9
references.pmid: 21037224
references.citation: Hum Mol Genet. 2012 Apr 15;21(8):1918-30
references.pmid: 22228101
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1348-54
references.pmid: 16835335
references.citation: Am J Epidemiol. 1985 Nov;122(5):904-14
references.pmid: 4050778
references.citation: Clin Pharmacol Ther. 2008 Apr;83(4):635-9
references.pmid: 18323859
references.citation: IARC Sci Publ. 2011;(163):281-301
references.pmid: 22997868
references.citation: Nat Genet. 2010 Nov;42(11):978-84
references.pmid: 20972438
references.citation: Nat Rev Genet. 2005 Apr;6(4):287-98
references.pmid: 15803198
references.citation: J Am Stat Assoc. 2009 Mar 1;104(485):220-233
references.pmid: 19430598
references.citation: Hum Mol Genet. 2011 Nov 1;20(21):4282-9
references.pmid: 21824976
references.citation: JAMA. 2011 Aug 17;306(7):737-45
references.pmid: 21846855
references.citation: Nat Genet. 2010 May;42(5):415-9
references.pmid: 20348956
references.citation: Am J Epidemiol. 2012 Dec 1;176(11):1060-7
references.pmid: 23118105
references.citation: Nat Genet. 2008 Nov;40(11):1307-12
references.pmid: 18794855
references.citation: Hum Mol Genet. 2011 Nov 1;20(21):4268-81
references.pmid: 21750109
references.citation: Oncogene. 2006 Mar 13;25(11):1649-58
references.pmid: 16550165
references.citation: PLoS Genet. 2010 Aug 05;6(8):
references.pmid: 20700436
references.citation: Nat Genet. 2009 Feb;41(2):221-7
references.pmid: 19151717
references.citation: Pharmacogenet Genomics. 2011 Apr;21(4):231-6
references.pmid: 20739907
references.citation: Am J Epidemiol. 2002 Jul 15;156(2):95-109
references.pmid: 12117698
references.citation: Genetics. 2000 Jun;155(2):945-59
references.pmid: 10835412
references.citation: J Natl Cancer Inst. 2011 Jul 6;103(13):1037-48
references.pmid: 21705679
references.citation: Am J Epidemiol. 1980 Oct;112(4):467-70
references.pmid: 7424895