The role of haplotype in 15q25.1 locus in lung cancer risk: results of scanning chromosome 15.
The role of haplotypes and the interaction of haplotypes and smoking in lung cancer risk have not been well characterized. We analyzed data from an Italian population-based, case-control study with 1815 lung cancer patients and 1959 healthy controls in discovery, and performed a validation using a case-control study with 2983 lung cancer patients and 3553 healthy controls of European ancestry for replication. Sliding window haplotype analysis within chromosome 15, evaluating 4722250 haplotypes and pair-wise haplotype analysis identified that CHRNA5 rs588765-rs16969968 was the most significant haplotype associated with lung cancer risk (omnibus P = 8.35×10(-15) in discovery and 7.26×10(-14) in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test P = 0.006 for rs16969968 and 3.83×10(-14) for rs588765 in discovery, 0.009 for rs16969968 and 4.62×10(-13) for rs588765 in replication, compared with rs588765-rs16969968). Compared with the wild-type homozygous diplotype, CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI 1.46-3.07 in discovery, and OR = 2.01; 95% CI 1.51-2.67 in replication). Even among never-smokers, CA/CA homozygote showed an increased risk of lung cancer with borderline significance in discovery (adjusted OR = 1.75, 95% CI 0.96-3.19) and statistical significance in replication (adjusted OR = 2.10, 95% CI 1.12-3.96), compared with combined genotypes (CG/CG + CG/TG). Accordingly, rs588765-rs16969968 may be a genetic marker to lung cancer risk, even among never-smokers.
Xuemei
X
Ji
Jiang
J
Gui
Younghun
Y
Han
International Agency for Research on Cancer, 69372 Lyon, France.
Paul
P
Brennan
Yafang
Y
Li
International Agency for Research on Cancer, 69372 Lyon, France.
James
J
McKay
Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Neil E
NE
Caporaso
Department of Clinical Sciences and Community Health, Department of Preventive Medicine, University of Milan, Fondazione IRCCS Ca' Granda Policlinico Hospital, 20122 Milan, Italy.
Pier Alberto
PA
Bertazzi
Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Maria Teresa
MT
Landi
Christopher I
CI
Amos
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects