Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus.
The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10-6, FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10-3[odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10-5). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, China.|Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Jieyun
J
Yin
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Hongliang
H
Liu
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Zhensheng
Z
Liu
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
Kouros
K
Owzar
Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
Younghun
Y
Han
Massachusetts General Hospital, Boston, Massachusetts.|Department of Environmental Health, Harvard School of Public Health, Boston, MassachusettsMassachusetts.
Li
L
Su
Massachusetts General Hospital, Boston, Massachusetts.|Department of Environmental Health, Harvard School of Public Health, Boston, MassachusettsMassachusetts.
Yongyue
Y
Wei
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Rayjean J
RJ
Hung
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Yonathan
Y
Brhane
Public Health Ontario, Toronto, Ontario, Canada.
John
J
McLaughlin
Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
Paul
P
Brennan
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
Heike
H
Bickeboeller
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
Albert
A
Rosenberger
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Richard S
RS
Houlston
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Neil
N
Caporaso
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Maria Teresa
MT
Landi
Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Epidemiology I, Neuherberg, Germany.|Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany.
Joachim
J
Heinrich
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.|Department of Epigenomics and Cancer Risk Factors, DKFZ - German Cancer Research Center, Heidelberg, Germany.|Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
Angela
A
Risch
Massachusetts General Hospital, Boston, Massachusetts.|Department of Environmental Health, Harvard School of Public Health, Boston, MassachusettsMassachusetts.
David C
DC
Christiani
Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
Christopher I
CI
Amos
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Qingyi
Q
Wei
D000072470:Cytochrome P450 Family 4 / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
D005227:Fatty Acids; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human
fatty acid metabolism; genome wide association study; lung cancer; tumor markers