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DNA Methylation Is Associated with Airflow Obstruction in Patients Living

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DNA Methylation Is Associated with Airflow Obstruction in Patients Living Chronic obstructive pulmonary disease Original research Thorax: first published as 10.1136/thoraxjnl-2020-215866 on 18 December 2020. Downloaded from DNA methylation is associated with airflow obstruction in patients living with HIV Ana I Hernandez Cordero,1 Chen Xi Yang,1 Maen Obeidat,1 Julia Yang,1 Julie MacIsaac,2 Lisa McEwen,2 David Lin,2 Michael Kobor,2 Richard Novak,3 Fleur Hudson,4 Hartwig Klinker,5 Nila Dharan,6 SF Paul Man,1 Don D Sin,1 Ken Kunisaki ,7 Janice Leung,1 on behalf of the INSIGHT START Pulmonary and Genomic Substudy Groups For numbered affiliations see ABSTRACT end of article. Introduction People living with HIV (PLWH) suffer from Key messages age-related comorbidities such as COPD. The processes Correspondence to responsible for reduced lung function in PLWH are largely What is the key question? Dr Janice Leung, Centre for ► What explains the increased risk of COPD in Heart Lung Innovation, The unknown. We performed an epigenome-wide association University of British Columbia, study to investigate whether blood DNA methylation is patients living with HIV? Vancouver, BC V6T 1Z4, associated with impaired lung function in PLWH. What is the bottom line? Canada; Methods Using blood DNA methylation profiles from Janice. Leung@ hli. ubc.ca ► Peripheral blood methylation disruptions 161 PLWH, we tested the effect of methylation on FEV , 1 are numerous in patients with both airflow FEV /FVC ratio and FEV decline over a median of 5 Received 27 July 2020 1 1 obstruction and HIV infection. Revised 20 November 2020 years. We evaluated the global methylation of PLWH with Accepted 23 November 2020 airflow obstruction by testing the differential methylation Why read on? of transposable elements Alu and LINE-1, a well- ► Epigenetic disturbance related to chronic viral described marker of epigenetic ageing. infections may hold clues to early disease- Results Airflow obstruction as defined by a FEV1/ causing mechanisms in COPD. FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/ FVC<lower limit of normal. These DMPs were enriched Lung function decline in PLWH was recently for biological pathways associated with chronic viral reported in a large, multinational cohort demon- infections. The airflow obstruction group was globally strating that the timing of antiretroviral therapy hypomethylated compared with those without airflow initiation alone has no influence on the rate of http://thorax.bmj.com/ 5 obstruction. 103 and 7112 DMPs were associated with decline. As in any population, the variability of lung function is likely the consequence of complex FEV1 and FEV1/FVC, respectively. No positions were associated with FEV decline. environmental and genetic factors, as well as their 1 6 Conclusion A large number of DMPs were associated interaction ; however, the underlying molecular with airflow obstruction and lung function in a unique processes that explain these relationships in PLWH cohort of PLWH. Airflow obstruction in even relatively remain elusive. In this study, we explore the possi- young PLWH is associated with global hypomethylation, bility that epigenetic alterations such as DNA meth- on October 4, 2021 by guest. Protected copyright. suggesting advanced epigenetic ageing compared with ylation may influence lung function variability in those with normal lung function. The disturbance of PLWH. DNA methylation involves the addition of the epigenetic regulation of key genes not previously a methyl group to a cytosine base located next to identified in non- HIV COPD cohorts could explain the guanine base (CpG site). The methylation of CpG unique risk of COPD in PLWH. sites in regulatory elements (ie, promoter regions) often results in decreased gene expression7 and can potentially affect other traits. Environmental factors such as tobacco use and chronic diseases or infec- © Author(s) (or their INTRODUCTION tions as well as the natural ageing process can all employer(s)) 2020. Re- use The progress in the treatment of HIV has led to influence DNA methylation. Age-related diseases, permitted under CC BY- NC. No an increase in life expectancy and a decrease for instance, are characterised by genome- wide commercial re- use. See rights in immunodeficiency syndrome-related condi- hypomethylation.8 The methylation of ubiquitous and permissions. Published 1 by BMJ. tions among people living with HIV (PLWH). transposable elements like Alu and LINE-1 is used Age- related comorbidities, though, have become as markers for global methylation and is thought To cite: Hernandez common, including COPD,2 which is associated to play key roles in age- related genomic instability,9 Cordero AI, Yang CX, with increased mortality3 and significant respira- which may lead to tumorigenesis and senescence. Obeidat M, et al. Thorax Epub 4 ahead of print: [please tory symptom burden. Whether tobacco expo- Previous efforts to understand the effect of include Day Month Year]. sure, illicit drug use, repeated infections, or chronic DNA methylation on lung function have focused doi:10.1136/ inflammation are the key causes of this increased mainly on non- HIV cohorts.10 11 Evidence from thoraxjnl-2020-215866 risk for COPD in PLWH is still unclear. these studies suggests, however, that methylation Hernandez Cordero AI, et al. Thorax 2020;0:1–8. doi:10.1136/thoraxjnl-2020-215866 1 Chronic obstructive pulmonary disease may play an important role in lung function and the aetiology as with worse lung function in non-PL WH study cohorts.21 Alu Thorax: first published as 10.1136/thoraxjnl-2020-215866 on 18 December 2020. Downloaded from of COPD.12 For this study, we conducted an epigenome- wide and LINE-1 sites were imputed using the machine learning tool association analysis to investigate the relationship of blood DNA repetitive element methylation prediction.22 methylation with lung function of PLWH. We hypothesised that PLWH with airflow obstruction have a distinct methylation Statistical analysis pattern when compared with those with normal lung function. The cell type proportion of each sample was estimated using We also hypothesised that differential DNA methylation is asso- the deconvolution method of Houseman et al23 which provides ciated with lung function decline in PLWH. the proportion of CD4 T cells, CD8 T cells, natural killer cells, monocytes, granulocytes (neutrophils+eosinophils) and B cells. METHODS The EPISTRUCTURE software24 was used to infer the ancestry. Study cohort This software calculates the principal components using CpGs The study cohort consisted of 161 PLWH over the age of 40 that are highly correlated with SNPs, capturing the genetic vari- years who were enroled in the genomic and the pulmonary ation within a population. Additional covariates were chosen substudies of the Strategic Timing of Antiretroviral Therapy based on the algorithm outlined by Lee et al.25 To identify (START, Clinicaltrials.gov NCT00867048) trial, which has been differentially methylated positions (DMPs) between PLWH previously described.13 14 Briefly, this was a multicentre, interna- with airflow obstruction and with normal lung function, we tional, randomised controlled trial designed to compare imme- performed an epigenome- wide association study using a robust diate versus deferred initiation of antiretroviral therapy. The linear model (rlm) implemented in the MASS R package (M- es- START cohort included adult PLWH with CD4 T cell counts timation),26 and adjusted as follows: >500 cells/mm3 and who had not yet been exposed to antiret- roviral therapy.5 Methylation M value Airflow obstruction status + Age + ∼ baseline Sex + CD8 T cells + CD4 T cells + NK cells + Lung function and filtering criteria ( ) All participants underwent spirometry testing yearly for up to B cells + Monocytes + Granulocytes + Epistructure PC1 to PC5 6 years, according to methods previously described.5 Participants with three or more spirometric tests were retained for the anal- The model presented above was also used to interrogate Alu ysis on FEV decline. In total, 152 participants were retained for 1 and LINE-1 methylation sites. FEV decline analysis, while all 161 subjects were included in 1 To investigate the effect of methylation over cross- sectional cross- sectional analyses (online supplemental figure S1). Partic- FEV , and FEV /FVC (at baseline visit) in PLWH we also used ipants were characterised as having airflow obstruction if the 1 1 rlm adjusted for the following covariates: FEV /FVC ratio was <0.70. In addition, airflow obstruction was 1 Lung function trait Methylation beta value + Sex + also assessed based on FEV1/FVC ratio <lower limit of normal ∼ 2 2 (LLN), according to the Global Lung Function Initiative 2012 Age + Age + Height + Height + Smoking( status) + 15 normative equations. Smoking Pack Years + CD8 T cells + − CD4 T cells + NK cells + B cells + Monocytes + DNA methylation profiling and quality control http://thorax.bmj.com/ Participants had a whole blood sample drawn at study entry. The Granulocytes + Epistructure PC1 to PC10 DNeasy Blood and Tissue Kit (Qiagen, Hilden, Germany) was The effect of methylation over FEV1 decline over the course used to extract DNA from this sample. Unmethylated cytosine of 6 years was studied using a random coefficient model (lme) residues present in the DNA extract were converted to uracil implemented in the nlme R package27; both a random intercept using the EZ DNA Methylation Kit (Zymo, Irvine, California, term and a
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