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. 2015 Mar 17;313(11):1133-42.
doi: 10.1001/jama.2015.1815.

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants

Hongmei Nan  1 , Carolyn M Hutter  2 , Yi Lin  3 , Eric J Jacobs  4 , Cornelia M Ulrich  5 , Emily White  6 , John A Baron  7 , Sonja I Berndt  8 , Hermann Brenner  9 , Katja Butterbach  10 , Bette J Caan  11 , Peter T Campbell  4 , Christopher S Carlson  3 , Graham Casey  12 , Jenny Chang-Claude  13 , Stephen J Chanock  8 , Michelle Cotterchio  14 , David Duggan  15 , Jane C Figueiredo  12 , Charles S Fuchs  16 , Edward L Giovannucci  17 , Jian Gong  3 , Robert W Haile  12 , Tabitha A Harrison  3 , Richard B Hayes  18 , Michael Hoffmeister  10 , John L Hopper  19 , Thomas J Hudson  20 , Mark A Jenkins  19 , Shuo Jiao  3 , Noralane M Lindor  21 , Mathieu Lemire  22 , Loic Le Marchand  23 , Polly A Newcomb  3 , Shuji Ogino  24 , Bethann M Pflugeisen  3 , John D Potter  25 , Conghui Qu  3 , Stephanie A Rosse  3 , Anja Rudolph  13 , Robert E Schoen  26 , Fredrick R Schumacher  12 , Daniela Seminara  2 , Martha L Slattery  27 , Stephen N Thibodeau  28 , Fridtjof Thomas  29 , Mark Thornquist  3 , Greg S Warnick  3 , Brent W Zanke  30 , W James Gauderman  12 , Ulrike Peters  6 , Li Hsu  31 , Andrew T Chan  32 ; CCFR; GECCO
Affiliations

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants

Hongmei Nan et al. JAMA. .

Abstract

Importance: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.

Objective: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.

Design, setting, and participants: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.

Exposures: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.

Main outcomes and measures: Colorectal cancer.

Results: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).

Conclusions and relevance: In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

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Figures

Figure 1
Figure 1. Main associations of regular use of aspirin and/or NSAIDs (a) and aspirin-only (b) with the risk of colorectal cancer
“Aspirin and/or NSAIDs” includes the regular use of aspirin-only, NSAIDs-only, or both aspirin and NSAIDs; and “Aspirin-only” includes the regular use of aspirin-only. The size of the data markers is proportional to the precision of the estimate, which is the inverse of the variance.
Figure 1
Figure 1. Main associations of regular use of aspirin and/or NSAIDs (a) and aspirin-only (b) with the risk of colorectal cancer
“Aspirin and/or NSAIDs” includes the regular use of aspirin-only, NSAIDs-only, or both aspirin and NSAIDs; and “Aspirin-only” includes the regular use of aspirin-only. The size of the data markers is proportional to the precision of the estimate, which is the inverse of the variance.
See this image and copyright information in PMC

Comment in

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