Early life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13–14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.

早期生活压力与编码糖皮质激素受体的核受体亚科 3 组 C 成员 1 ( NR3C1 ) 基因甲基化增加有关。此外，早期生活压力与年轻时开始使用物质有关，这是发展物质使用障碍的风险因素。然而，迄今为止还没有研究调查NR3C1甲基化是否可以预测年轻人的物质使用。这项研究包括 13-14 岁的青少年，他们在基线时没有报告药物使用史，（N = 1041; 男性 = 46%）。参与者提供了唾液 DNA 样本，并在青春期中期作为 KUPOL 的一部分进行了跟踪，KUPOL 是一项针对瑞典 7 年级学生的前瞻性队列研究。结果变量是 (i) 最近使用、(ii) 终生使用和 (iii) (a) 酒精、(b) 烟草制品、(c) 大麻或 (d) 任何物质的使用持续时间的自我报告。结果连续三年每年测量一次。预测变量是NR3C1的外显子 1 F 基因座的 DNA 甲基化。风险和比率比被计算为关联的度量，有或没有内化症状和父母精神疾病的调整。对于个体的一个子集（N = 320），也有上午和下午唾液皮质醇测量值可用，这些测量值与NR3C1甲基化水平相关。基线NR3C1高甲基化与未来自我报告最近使用和任何物质的使用持续时间相关，在调整潜在混杂因素之前和之后。在考虑终生使用时，总体估计值有所减弱。性别分层分析揭示了男性吸烟与吸烟的最强关联。皮质醇分析揭示了NR3C1甲基化与早晨皮质醇水平之间的关联。这项研究的结果表明，唾液NR3C1高甲基化可以预测青春期中期的物质使用。有必要进行额外的纵向研究来证实这些发现。