主动注射吸毒的全表观基因组关联分析。

Epigenome-wide association analyses of active injection drug use.

作者信息

Shu Chang, Jaffe Andrew E, Sabunciyan Sarven, Ji Hongkai, Astemborski Jacquie, Sun Jing, Bakulski Kelly M, Sosnowski David W, Mehta Shruti H, Kirk Gregory D, Maher Brion S

机构信息

Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.

Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

出版信息

Drug Alcohol Depend. 2022 Jun 1;235:109431. doi: 10.1016/j.drugalcdep.2022.109431. Epub 2022 Mar 29.

DOI:10.1016/j.drugalcdep.2022.109431

PMID:35395503

Abstract

BACKGROUND

Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized.

METHODS

401 participants (M = 47.9; 68% male; 90% African American) over several timepoints (1054 visits) were drawn from a longitudinal cohort of people who inject drugs. DNA methylation was measured among buffy coat samples from the 1054 visits. Compared to samples collected after ≥ 6 months of abstinence, separate EWAS were conducted for active injecting of any drug, quantitative injection frequency, injecting of heroin and injecting of cocaine. Linear mixed effect models were used and analyses were adjusted for repeated measurements and key technical, biological, and sociodemographic characteristics.

RESULTS

We found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10) and injection intensity (cg13117953, p = 4.30 × 10). We found converging evidence that cg10636246 (AIM2), cg23110600 (PRKCH), cg03546163 (FKBP5), cg04590956 (GMCL1), and cg16317961 (MAPRE2) were among the top 0.1% significantly differentially methylated CpG sites shared across the five EWAS. Top ranked CpGs among the five EWAS were enriched (p < 0.0001) in AIM2 inflammasome complex, T cell migration, insulin regulation and epinephrine synthesis pathways. During periods of active injection, samples had 0.46 years of epigenetic age acceleration relative to the abstinence period, within the same subject (p = 0.03).

CONCLUSIONS

Findings from this study demonstrate modest, common, and specific effects on DNA methylation during a relatively short time between periods of active drug injection and abstinence.

摘要

背景

注射吸毒在美国很普遍，且与血源性感染、发病率和死亡率的重大风险相关。然而，其对血液中DNA甲基化的生物学影响范围尚未得到充分表征。

方法

从一个注射吸毒者的纵向队列中选取401名参与者（平均年龄47.9岁；68%为男性；90%为非裔美国人），在多个时间点（共1054次访视）进行研究。对1054次访视的血沉棕黄层样本进行DNA甲基化测量。与禁欲≥6个月后采集的样本相比，分别针对任何药物的主动注射、定量注射频率、海洛因注射和可卡因注射进行了全表观基因组关联研究（EWAS）。使用线性混合效应模型，并针对重复测量以及关键的技术、生物学和社会人口学特征进行了分析调整。

结果

我们发现了全表观基因组范围内与主动注射（cg10636246，AIM2，p = 2.33×10）和注射强度（cg13117953，p = 4.30×10）相关的显著CpG位点。我们发现有一致的证据表明，cg10636246（AIM2）、cg23110600（PRKCH）、cg03546163（FKBP5）、cg04590956（GMCL1）和cg16317961（MAPRE2）是五个EWAS中共同的前0.1%显著差异甲基化的CpG位点。五个EWAS中排名靠前的CpG在AIM2炎性小体复合物、T细胞迁移、胰岛素调节和肾上腺素合成途径中富集（p < 0.0001）。在主动注射期间，同一受试者的样本相对于禁欲期有0.46年的表观遗传年龄加速（p = 0.03）。