This proposal focuses on studies of epigenetic mechanisms of asthma during the period of adolescent transition, which encompasses hormonal and body mass index changes, growth effects, and the possible use of contraceptives, acetaminophen for relief of menstrual symptoms, and nicotine. Many studies have indicated a gender reversal of asthma prevalence during this transition due to a higher incidence and lower remission in girls. This provides a great opportunity to investigate the epigenetic mechanisms of asthma and associated risk factors during adolescence. Specifically, we will 1) assess genome-wide DNA methylation (DNA-M) at CpG sites using blood DNA samples taken before and after adolescent transition; identify CpGs associated with asthma transition and CpGs showing gender specificity in these associations; 2) test the association of asthma risk factors with DNA-M or its changes on these selected sites; 3) evaluate the agreement of methylation in peripheral blood leukocytes (PBL) and bronchial epithelial cells (BEC), and in PBL and in BEC, functionally assess the identified epigenetic marks in cis and trans via gene expressions and risk factors. Our overall hypothesis is: the reversal of asthma prevalence in adolescence can be explained by novel methylation difference between genders during the pre- to post-adolescent transition. We will test: (H1) DNA-M or its change across adolescence is associated with the change in asthma risk (TEMs), and the association is gender-specific (TGEMs). (H2) Adolescence-related, environmental, and socio-economic status (SES) risk factors are associated with DNA-M or its changes. (H3) DNA-M in PBL and BEC are correlated for CpG sites associated with asthma status. (H4) DNA-M of TEMs and TGEMs correlates with gene expression in PBL and in BEC and such correlation is gender specific, and (H5) gene expression is associated with TEMs and TGEMs- related risk factors. Expected findings will significant improve our understanding of gender-reversal of asthma prevalence in adolescence, thus provide a strong foundation for promoting asthma remission and predicting and preventing persistent and new onset asthma in adolescence. The results will help pediatricians and public health units to identify children at high risk of asthma in adolescence. Two comparable longitudinal birth cohorts will be investigated in this study. The Isle of Wight (IOW) birth cohort, established in 1989, is comprised of 1,456 children characterized for asthma and allergy at birth, 1, 2, 4, 10, and 18 years of age. The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in Bristol, established in 1991, includes 4,213 children characterized for asthma and allergy at ages 7-8 and 15-17 years. Both cohorts have extensive phenotype data, environmental exposure data, and DNA samples from pre- and post-adolescence. More importantly, PBL DNA-M have been measured for a large portion of subjects in each cohort. Our research team has a long track record of successful collaboration and two related projects [trans- generational epigenetic study 1R01AI091905, Karmaus (PI); asthma temporal phenotypic pattern study R21AI099367, Zhang (PI)] are recently funded by NIH.

Public Health Relevance

Early prevention of asthma is essential to reduce the burden of this high-impact and avoidable disease. The switch-over of asthma prevalence between boys and girls during adolescence, due to a higher incidence and lower remission in girls, provides a unique opportunity to investigate possible epigenetic mechanisms of asthma during this period and identify biomarkers contributing to asthma status change in adolescence. The findings from the projects have strong potential to critically impact our ability to prevent incidence and promote remission of asthma during adolescence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI121226-03
Application #
9405360
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Dong, Gang
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Memphis
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
055688857
City
Memphis
State
TN
Country
United States
Zip Code
38152
Kaushal, Akhilesh; Zhang, Hongmei; Karmaus, Wilfried J J et al. (2017) Comparison of different cell type correction methods for genome-scale epigenetics studies. BMC Bioinformatics 18:216
Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2017) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol :
Arshad, S Hasan; Karmaus, Wilfried; Zhang, Hongmei et al. (2017) Multigenerational cohorts in patients with asthma and allergy. J Allergy Clin Immunol 139:415-421
Chen, Su; Mukherjee, Nandini; Janjanam, Vimala Devi et al. (2017) Consistency and Variability of DNA Methylation in Women During Puberty, Young Adulthood, and Pregnancy. Genet Epigenet 9:1179237X17721540
Kaushal, Akhilesh; Zhang, Hongmei; Karmaus, Wilfried J J et al. (2017) Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life. Environ Health 16:50
Elliott, Hannah R; Shihab, Hashem A; Lockett, Gabrielle A et al. (2017) Role of DNA Methylation in Type 2 Diabetes Etiology: Using Genotype as a Causal Anchor. Diabetes 66:1713-1722
Han, Shengtong; Zhang, Hongmei; Karmaus, Wilfried et al. (2017) Adjusting background noise in cluster analyses of longitudinal data. Comput Stat Data Anal 109:93-104
Sharp, Gemma C; Salas, Lucas A; Monnereau, Claire et al. (2017) Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Hum Mol Genet 26:4067-4085
Janjanam, Vimala Devi; Mukherjee, Nandini; Lockett, Gabrielle A et al. (2016) Tetanus vaccination is associated with differential DNA-methylation: Reduces the risk of asthma in adolescence. Vaccine 34:6493-6501