# A multi-trait epigenome-wide association study identified DNA methylation signature of inflammation among people with HIV

## TL;DR

This study finds DNA methylation patterns linked to inflammation in people with HIV, using a multi-trait approach to uncover new molecular insights.

## Contribution

The study introduces a multi-trait EWAS approach to identify novel DNA methylation sites associated with inflammation in people with HIV.

## Key findings

- Multi-trait EWAS identified 112 overlapping DNA methylation sites associated with inflammation not detected in single-trait analyses.
- Top methylation sites were linked to genes like IFITM1, PARP9, and STAT1 involved in immune and viral response pathways.
- The findings suggest molecular mechanisms underlying persistent inflammation in people with HIV.

## Abstract

Inflammation underlies many conditions causing excess morbidity and mortality among people with HIV (PWH). A handful of single-trait epigenome-wide association studies (EWAS) have suggested that inflammation is associated with DNA methylation (DNAm) among PWH. Multi-trait EWAS may further improve statistical power and reveal pathways in common between different inflammatory markers.

We conducted single-trait EWAS of three inflammatory markers (soluble CD14, D-dimers, and interleukin 6) in the Veteran Aging Cohort Study (n = 920). The study population was all male PWH with an average age of 51 years, and 82.3% self-reported as Black. We then applied two multi-trait EWAS methods—CPASSOC and OmniTest—to combine single-trait EWAS results.

CPASSOC and OmniTest identified 189 and 157 inflammation-associated DNAm sites respectively, of which 112 overlapped. Among the identified sites, 56% were not significant in any single-trait EWAS. Top sites were mapped to inflammation-related genes including IFITM1, PARP9 and STAT1. These genes were significantly enriched in pathways such as “type I interferon signaling” and “immune response to virus”.

We demonstrate that multi-trait EWAS can improve the discovery of inflammation-associated DNAm sites, genes, and pathways. These DNAm sites suggest molecular mechanisms in response to inflammation associated with HIV and might hold the key to addressing persistent inflammation in PWH.