Evaluation of Adenosine A2A receptor gene polymorphisms as risk factors of methamphetamine use disorder susceptibility and predictors of craving degree

The adenosine A2A receptor (ADORA2A) is highly expressed in the central nervous system and plays vital roles in drug addiction. In this study, we aimed to explore the susceptibility of ADORA2A to methamphetamine use disorder (MUD) and the craving degree based on a two-stage association analysis. A total of 3,542 (1,216 patients with MUD and 2,326 controls) and 1,740 participants (580 patients with MUD and 1,160 controls) were recruited in discovery and replication stage, respectively. Significant SNPs identified in the discovery stage were genotyped in the replication samples. Serum levels of ADORA2A were measured using enzyme-linked immu-nosorbent assay kits. The genetic association signal of each SNP was examined using Plink. A linear model was fitted to investigate the relationship between craving scores and genotypes of significant SNPs. SNP rs5751876 was significantly associated with MUD in the discovery samples and this association signal was then further replicated in the replication samples. Significant associations were also identified between serum levels of ADORA2A and the genotypes of rs5751876 (P = 0.0002). The craving scores in patients with MUD were strongly correlated with rs5751876 genotypes. Our results suggest that polymorphisms of the ADORA2A gene could affect the susceptibility to MUD and its craving degree.

腺苷A2A受体（ADORA2A）在中枢神经系统中高度表达，在药物成瘾中起着至关重要的作用。在本研究中，我们旨在基于两阶段关联分析来探究ADORA2A对甲基苯丙胺使用障碍（MUD）的易感性以及渴求程度。在发现阶段和复制阶段分别招募了总共3542人（1216名MUD患者和2326名对照）以及1740名参与者（580名MUD患者和1160名对照）。在发现阶段确定的显著单核苷酸多态性（SNP）在复制样本中进行基因分型。使用酶联免疫吸附测定试剂盒测量ADORA2A的血清水平。使用Plink检验每个SNP的遗传关联信号。拟合线性模型以研究渴求分数与显著SNP基因型之间的关系。SNP rs5751876在发现样本中与MUD显著相关，并且该关联信号随后在复制样本中进一步得到复制。还发现ADORA2A的血清水平与rs5751876的基因型之间存在显著关联（P = 0.0002）。MUD患者的渴求分数与rs5751876基因型密切相关。我们的结果表明，ADORA2A基因的多态性可能影响对MUD的易感性及其渴求程度。