Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes

Christina M. Eckhardt; Pallavi Balte; Jack E. Morris; Surya P. Bhatt; David Couper; Jessica Fetterman; Neal Freedman; David R. Jacobs; Lifang Hou; Ravi Kalhan; Yongmei Liu; Laura Loehr; Pamela L. Lutsey; Joseph E. Schwartz; Wendy White; Sachin Yende; Stephanie J. London; Tiffany R. Sanchez; Elizabeth C. Oelsner

doi:10.1136/thorax-2023-220731

Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes

Christina M. Eckhardt, Pallavi Balte, Jack E. Morris, Surya P. Bhatt, David Couper, Jessica Fetterman, Neal Freedman, David R. Jacobs, Lifang Hou, Ravi Kalhan, Yongmei Liu, Laura Loehr, Pamela L. Lutsey, Joseph E. Schwartz, Wendy White, Sachin Yende, Stephanie J. London, Tiffany R. Sanchez, Elizabeth C. Oelsner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (−2.44 units, 95% CI −4.42 to −0.45), though to a lesser extent than exclusive use of cigarettes (−6.01 units, 95% CI −6.01 to −4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

Original language	English (US)
Pages (from-to)	1060-1068
Number of pages	9
Journal	Thorax
Volume	79
Issue number	11
DOIs	https://doi.org/10.1136/thorax-2023-220731
State	Published - Oct 16 2024

Funding

This study has been funded with federal funds from the National Heart, Lung and Blood Institute and National Institutes of Health (R21-HL121457, R21-HL-129924 and K23-HL-130627). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The authors thank the staff and participants of the ARIC study for their important contributions. Funding was also supported in whole or in part by 5RC2HL102419, 5R01NS087541, R01HL131136, 7R01AR073178, 5R00HL130580 and 5P01CA138338. PLL was partially supported by K24 HL159246. The authors thank the staff and participants of the ARIC study for their important contributions. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I) and Kaiser Foundation Research Institute (HHSN268201800004I). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). The laboratory work and analytical component were funded by the American Heart Association (17SFRN33700278 and 14SFRN20790000, Northwestern University, PI: LH). Study analysis was also supported by grants from the NHLBI (1R01HL15569-01A1, PI: YL) and NIA (R21AG068955, PI: YL and R01AG081244, PI: LH/YL). MESA (Multi-Ethnic Study of Atherosclerosis): MESA has been funded in whole or in part by The National Heart, Lung and Blood Institute and the National Institutes of Health (R01-HL-077612, R01-HL-093081, RC1-HL-100543, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169). The laboratory work were funded by (PI: YL). The Strong Heart Study has been funded in whole or in part with federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services (75N92019D00027, 75N92019D00028, 75N92019D00029, 75N92019D00030). The study was previously supported by research grants (R01HL109315, R01HL109301, R01HL109284, R01HL109282, R01HL109319) and by cooperative agreements (U01HL41642, U01HL41652, U01HL41654, U01HL65520, U01HL65521). This work was supported by a clinical and translational science awards grant (TL1TR001875 to CME).

Keywords

Clinical Epidemiology
Smoking

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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10.1136/thorax-2023-220731

Cite this

Eckhardt, C. M., Balte, P., Morris, J. E., Bhatt, S. P., Couper, D., Fetterman, J., Freedman, N., Jacobs, D. R., Hou, L., Kalhan, R., Liu, Y., Loehr, L., Lutsey, P. L., Schwartz, J. E., White, W., Yende, S., London, S. J., Sanchez, T. R., & Oelsner, E. C. (2024). Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes. Thorax, 79(11), 1060-1068. https://doi.org/10.1136/thorax-2023-220731

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abstract = "Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (−2.44 units, 95% CI −4.42 to −0.45), though to a lesser extent than exclusive use of cigarettes (−6.01 units, 95% CI −6.01 to −4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.",

keywords = "Clinical Epidemiology, Smoking",

author = "Eckhardt, {Christina M.} and Pallavi Balte and Morris, {Jack E.} and Bhatt, {Surya P.} and David Couper and Jessica Fetterman and Neal Freedman and Jacobs, {David R.} and Lifang Hou and Ravi Kalhan and Yongmei Liu and Laura Loehr and Lutsey, {Pamela L.} and Schwartz, {Joseph E.} and Wendy White and Sachin Yende and London, {Stephanie J.} and Sanchez, {Tiffany R.} and Oelsner, {Elizabeth C.}",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2024.",

year = "2024",

month = oct,

day = "16",

doi = "10.1136/thorax-2023-220731",

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volume = "79",

pages = "1060--1068",

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Eckhardt, CM, Balte, P, Morris, JE, Bhatt, SP, Couper, D, Fetterman, J, Freedman, N, Jacobs, DR, Hou, L , Kalhan, R, Liu, Y, Loehr, L, Lutsey, PL, Schwartz, JE, White, W, Yende, S, London, SJ, Sanchez, TR & Oelsner, EC 2024, 'Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes', Thorax, vol. 79, no. 11, pp. 1060-1068. https://doi.org/10.1136/thorax-2023-220731

TY - JOUR

T1 - Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes

AU - Eckhardt, Christina M.

AU - Balte, Pallavi

AU - Morris, Jack E.

AU - Bhatt, Surya P.

AU - Couper, David

AU - Fetterman, Jessica

AU - Freedman, Neal

AU - Jacobs, David R.

AU - Hou, Lifang

AU - Kalhan, Ravi

AU - Liu, Yongmei

AU - Loehr, Laura

AU - Lutsey, Pamela L.

AU - Schwartz, Joseph E.

AU - White, Wendy

AU - Yende, Sachin

AU - London, Stephanie J.

AU - Sanchez, Tiffany R.

AU - Oelsner, Elizabeth C.

PY - 2024/10/16

Y1 - 2024/10/16

N2 - Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (−2.44 units, 95% CI −4.42 to −0.45), though to a lesser extent than exclusive use of cigarettes (−6.01 units, 95% CI −6.01 to −4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

AB - Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (−2.44 units, 95% CI −4.42 to −0.45), though to a lesser extent than exclusive use of cigarettes (−6.01 units, 95% CI −6.01 to −4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

KW - Clinical Epidemiology

KW - Smoking

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ER -

Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes

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