Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans
Sean P. David,
Ange Wang,
Kristopher Kapphahn,
Haley Hedlin,
Manisha Desai,
Michael Henderson,
Lingyao Yang,
Kyle M. Walsh,
Ann G. Schwartz,
John K. Wiencke,
Margaret R. Spitz,
Angela S. Wenzlaff,
Margaret R. Wrensch,
Charles B. Eaton,
Helena Furberg,
W. Mark Brown,
Benjamin A. Goldstein,
Themistocles Assimes,
Hua Tang,
Charles L. Kooperberg,
Charles P. Quesenberry,
Hilary Tindle,
Manali I. Patel,
Christopher I. Amos,
Andrew W. Bergen,
Gary E. Swan,
Marcia L. Stefanick
Affiliations
Sean P. David
Division of General Medical Disciplines, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Ange Wang
Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Kristopher Kapphahn
Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Haley Hedlin
Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Manisha Desai
Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Michael Henderson
Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Lingyao Yang
Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Kyle M. Walsh
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
Ann G. Schwartz
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
John K. Wiencke
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
Margaret R. Spitz
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
Angela S. Wenzlaff
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
Margaret R. Wrensch
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
Charles B. Eaton
Center for Primary Care and Prevention, Department of Family Medicine, Warren Alpert Medical School of Brown University, Pawtucket, RI, United States
Helena Furberg
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
W. Mark Brown
Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Benjamin A. Goldstein
Department of Biostatistics & Bioinformatics, Duke University School of Medicine, Durham, NC, United States
Themistocles Assimes
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Hua Tang
Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
Charles L. Kooperberg
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Charles P. Quesenberry
Kaiser Permanente, Division of Research, Oakland, CA 94612, United States
Hilary Tindle
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
Manali I. Patel
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Christopher I. Amos
Departments of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
Andrew W. Bergen
BioRealm, Culver City, CA, United States
Gary E. Swan
Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Marcia L. Stefanick
Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Background: Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene–environment interactions is not well understood. Methods: We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case–control study of African-American females and males (1078 lung cancer cases and 822 controls). Findings: Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10−5). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = −0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans. Interpretation: These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.
