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. 2016 Jan 11:4:153-61.
doi: 10.1016/j.ebiom.2016.01.002. eCollection 2016 Feb.

Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans

Sean P David  1 , Ange Wang  2 , Kristopher Kapphahn  3 , Haley Hedlin  3 , Manisha Desai  3 , Michael Henderson  2 , Lingyao Yang  3 , Kyle M Walsh  4 , Ann G Schwartz  5 , John K Wiencke  6 , Margaret R Spitz  7 , Angela S Wenzlaff  5 , Margaret R Wrensch  6 , Charles B Eaton  8 , Helena Furberg  9 , W Mark Brown  10 , Benjamin A Goldstein  11 , Themistocles Assimes  12 , Hua Tang  13 , Charles L Kooperberg  14 , Charles P Quesenberry  15 , Hilary Tindle  16 , Manali I Patel  17 , Christopher I Amos  18 , Andrew W Bergen  19 , Gary E Swan  3 , Marcia L Stefanick  2
Affiliations

Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans

Sean P David et al. EBioMedicine. .

Abstract

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.

Keywords: African-Americans; Environment; Genetics; Lung Cancer; Single Nucleotide Polymorphisms; Smoking; rs2036527.

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Figures

Fig. 1
Fig. 1
Sample size flow chart. Legend: Description of analytic sample with available genetic, smoking and lung cancer data for (A) Women's Health Initiative (WHI) Single Nucleotide Polymorphism Health Association Resource (SHARe) and (B) Multicenter Lung Cancer Case–Control Study. There were 8421 women in the downloaded dbGaP data for WHI SHARe (dbGaP accession #4723: Gene by environment interactions for lung cancer in cohort of African-American women in Women's Health Initiative), and 1265 were excluded for missing salient variables. The final WHI SHARe cohort included 7156 women with 59 cases of lung cancer and 29 cases of lung cancer mortality. There were 1,358 lung cancer cases and 1,289 controls in the multicenter case–control study of lung cancer. We excluded 50 lung cancer cases and 419 controls because of missing data, leaving 1,308 lung cancer cases and 1,241 controls as the final study population. When modeling interactions, never-smokers were excluded, leaving 1078 cases and 822 controls.
Fig. 2
Fig. 2
Patterns of linkage disequilibrium in the chromosome 15q24–25.1 region. Legend: Panel a represents D’ and panel b represents r2 values. Darker shading indicates higher r2 values and greater correlation between the SNPs.
Fig. 3
Fig. 3
Interaction between SNPs and cigarettes per day and risk of lung cancer. Legend: Odds ratio for incident lung cancer (y-axis) in multicenter case–control study and in participants with one or more risk alleles for each SNP by cigarettes per day (x-axis).
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