Article

Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC.

International Agency for Research on Cancer, Lyon, France.
Cancer Epidemiology Biomarkers &amp Prevention (impact factor: 4.12). 08/2011; 20(10):2250-61. DOI:10.1158/1055-9965.EPI-11-0496 pp.2250-61
Source: PubMed

ABSTRACT Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels.
We conducted an analysis in a lung cancer case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13.
Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.
15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation.
This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior.

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Keywords

10 polymorphisms
 
Circulating levels
 
cotinine
 
cotinine levels
 
cotinine measures
 
European Prospective Investigation
 
genetic variants influencing smoking behavior
 
genome-wide association studies
 
genotyped
 
largest
 
lung cancer
 
lung cancer case-control study nested
 
lung cancer risk
 
Multiple polymorphisms
 
nicotine metabolite cotinine
 
nicotinic acetylcholine receptor subunit genes CHRNA5
 
Nutrition
 
recent smoking behavior
 
recent smoking exposure
 
smoking behavior