Abstract C047: Internal smoking dose is associated with specific blood DNA methylation patterns across race/ethnicity: The Multiethnic Cohort Study

Abstract

Abstract Background: Lung cancer is the most common cancer in the U.S. and leading cause of cancer-related death. We demonstrated in the Multiethnic Cohort Study that for the same number of cigarettes smoked, Native Hawaiians and African Americans have the highest risk compared to whites, while Japanese Americans and Latinos are at lower risk of disease. We showed that internal smoking dose (as measured by total nicotine equivalents (TNE)) per cigarette differs across race/ethnicity; in part explaining why African Americans have a higher risk of disease and Japanese Americans have a lower risk. DNA methylation of CpG sites from cigarette smoking is one of the most common epigenetic modifications linked to lifestyle. Although many smoking-related DNA methylated CpG sites have been identified, these studies have been primarily conducted in populations of European ancestry. Moreover, the influence of internal smoking dose on the epigenome across populations has not been investigated. Here, we report on an epigenome-wide association study for urinary TNE, an optimal marker of internal smoking dose that is not biased by self-report and reflects the interindividual variation in nicotine metabolism. Methods: This study includes 1,996 current smokers at time of specimen collection, from five racial/ethnic groups: African American (n=364), European American (n=398), Japanese American (n=523), Native Hawaiian (n=311) and Latino (n=400). Genome-wide DNA methylation in blood leukocytes was measured using the Illumina MethEPIC BeadChip. Models were adjusted for age at biospecimen collection, genetic ancestry, sex, and cell-type. Results: TNE was associated with the differential methylation levels of 1,178 probes (Bonferoni corrected p<5 × 10-8). The top 5 overall significant associations were in AHRR (cg05575921; p=1.58 × 10^-131 and cg23576855; p=7.64 × 10^-72), 2q37.1 near ALPPL2 (cg21566642; p=6.29 × 10^-81), RARA (cg17739917; p=1.41 × 10^-74) and PRSS23 (cg14391737; p=1.42 × 10^-71). These had previously been associated with smoking status. By race/ethnicity, level of significance and the number of significantly differentially methylated probes differed. For instance, in African Americans the second most significantly associated probe was cg25845814, in ELMSAN1, (p=1.19 × 10^-10). This probe was also statistically significant in Japanese Americans (p=1.69 × 10^-13) and Latinos (p=2.93 × 10^-16), but not in European Americans (p=1.33 × 10^-6) and Native Hawaiians (p=1.48 × 10^-6). Cg25845814 has been found to regulate miRNA MIR1268A, which may modify hepatocellular carcinoma risk. European Americans had the greatest number of differentially methylated probes (n=68), followed by Latinos (n=63), Japanese Americans (n=63), African Americans (n=10) and Native Hawaiians (n=9). Conclusions: Smoking dose, as measured by TNE, may differentially impact DNA methylation of leukocytes by race/ethnicity. These differences may help to explain the population differences in smoking-related lung cancer risk. Citation Format: Sungshim L Park, Yesha Patel, Lenora W.M. Loo, Annette Lum-Jones, Maarit Tiirikainen, Sharon Murphy, Kimberly Siegmund, Daniel O. Stram, Loic Le Marchand. Internal smoking dose is associated with specific blood DNA methylation patterns across race/ethnicity: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C047.