Abstract 3228: Tobacco smoking and circulating immune-related biomarkers in monozygotic twins
Authors: Wang Jun , Conti David , Epeldegui Marta , Ollikainen Miina , Hwang Amie E. , Hamilton Ann S. , Magpantay Larry , Tyndale Rachel , Mack Thomas M. , Martinez-Maza Otoniel , Kaprio Jaakko , Cozen Wendy 
Published: August 2018

Abstract
Background: Tobacco smoking is a cause of a variety of cancers by various mechanisms. Paradoxically, smoking also increases the risk of atopy and asthma, which are inversely associated with some cancers such as glioma, colorectal cancer and non-Hodgkin lymphoma, but positively associated with others such as lung cancer. Tobacco smoking may affect the immune system, which may explain some of these associations. We assessed the association between smoking and levels of 27 serum immune/inflammatory markers and DNA methylation in healthy monozygotic (MZ) twins.
Methods: 67 MZ twin pairs were identified from the Finnish Twin Cohort Study. Cotinine and immune related biomarkers were measured from fasting serum samples using LC-MS/MS and Luminex multiples assays. Current smoking status was defined by cotinine &gt;3.08 ng/mL. Current smokers were further categorized into low vs high smoking level by the median cotinine (78.17 ng/mL) among smokers. Questionnaire reports of current and former smoking included duration, amount (cigarettes per day [CPD]) and years since quitting. Linear mixed models were used to assess the association between smoking variables and each individual biomarker. For each smoking variable P values were adjusted for multiple comparisons using Pact, taking into account correlations among biomarkers. For biomarkers significantly associated with smoking, we assessed whether blood DNA methylation of biomarker-related genes mediated the smoking-biomarker association.
Results: The median age of the study population was 24.8 years (range 21.0-68.9 years) and 56.7% were female twins. 32.1% of the twins were current smokers according to cotinine levels. Current smoking, defined by either cotinine or self-reports, was significantly associated with CCL17, B-cell activating factor (BAFF) and haptoglobin (Hp) levels respectively, after adjusting for multiple comparisons. For instance, serum cotinine was associated with increasing CCL17 levels (Pact for trend test = 0.002): the geometric mean CCL17, adjusted for age and sex among current high-level smokers was approximately 8.2% higher than noncurrent smokers. Similar positive dose-response relationships were observed for self-reported smoking variables with the 3 biomarkers. However, we found no associations between former smoking and any of the 27 biomarkers. We also found that smoking-associated DNA methylation alterations in 3 CpG sites of BAFF affected circulating CCL17 (CpG site: cg11726530) and Hp (cg09158314 and cg21784254) levels, respectively.
Conclusion: Current but not former smoking may be associated with alterations in circulating levels of CCL17, BAFF and Hp, suggesting that smoking may promote B-cell activation and affect Th2 immune response, which may play a role in carcinogenesis. Further, preliminary mediation analysis suggests that smoking-induced alterations in these biomarkers may partially mediate through DNA methylation.
Citation Format: Jun Wang, David Conti, Marta Epeldegui, Miina Ollikainen, Amie E. Hwang, Ann S. Hamilton, Larry Magpantay, Rachel Tyndale, Thomas M. Mack, Otoniel Martinez-Maza, Jaakko Kaprio, Wendy Cozen. Tobacco smoking and circulating immune-related biomarkers in monozygotic twins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3228.