DNA methylation is associated with airflow obstruction in patients living with HIV

Abstract

Introduction: People living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.

Methods: Using blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV₁, FEV₁/FVC ratio and FEV₁ decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.

Results: Airflow obstruction as defined by a FEV₁/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 for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV₁ and FEV₁/FVC, respectively. No positions were associated with FEV₁ decline.

Conclusion: A large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.

Keywords: COPD ÀÜ mechanisms; immunodeficiency; respiratory measurement; viral infection.

Figure 1

Differentially methylated points (DMPs) for airflow obstruction and top 10 biologic-enriched pathways for airflow obstruction (C). The x-axis on A and B represents the effect size difference of the DMPs between subjects with and without airflow obstruction (reference group: no airflow obstruction). The y-axis on figures A and B represents the level of statistical significance for each DMPs. Airflow obstruction was defined as (A) FEV₁/FVC ratio was <0.70 and (B) FEV₁/FVC <lower limit of normal. The red and blue colours represent hypomethylation and hypermethylation, respectively. The dashed horizontal line in A and B represents the −log10 p value that corresponds to the false discovery rate (FDR)<0.10. The axis in C represents the enrichment level of significance (×) for each biological pathway (y). The size of the circles inside the figure represents the number of overlapping genes in the pathways and the genes characterised by DMPs. The colour green represents significant enrichment based on the FDR<0.1. KEGG, Kyoto Encyclopedia of Genes and Genomes.

Figure 2

Alu and LINE-1 differentially methylated sites in people living with HIV with airflow obstruction. (A) and (B) Differentially methylated points (DMPs) in transposable element Alu between subjects with and without airflow obstruction (reference group: without airflow obstruction). (C) and (D) DMPs in transposable element LINE-1 between subjects with and without airflow obstruction (reference group: without airflow obstruction). The x-axis on the plots represents the effect size difference of the DMPs between subjects with and without airflow obstruction. The y-axis on the plots represents the level of significance for each DMPs. Airflow obstruction was defined as FEV₁/FVC ratio was <0.70 (A and C) and FEV₁/FVC <lower limit of normal (B and D). The dashed horizontal line inside the plots represents the −log10 p value that corresponds to the false discovery rate<0.10.