Validation of serotonin transporter mRNA as a quantitative biomarker of heavy drinking and its comparison to ethyl glucuronide/ethyl sulfate: A randomized, double-blind, crossover trial.
Validation of serotonin transporter mRNA as a quantitative biomarker of heavy drinking and its comparison to ethyl glucuronide/ethyl sulfate: A randomized, double-blind, crossover trial.
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DOI：
10.1111/acer.14931
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发表时间：
2022-10
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5-羟色胺转运体(SERT)基因是恩丹西酮治疗的5HTTLPR：LL基因携带者大量饮酒的定量和基于病理生理学的生物标志物。在这里，我们进一步验证了SERT mRNA在定量预测近期饮酒(在没有治疗的情况下)的潜在用途，并与已知的生物标记物乙基葡萄糖醛酸脂(EtG)和硫酸盐(ETS)进行了比较。年龄在21-65岁的欧洲血统的狂饮男性和女性参加了一项为期12天的住院、随机、双盲、交叉研究，其中三种饮料剂量(安慰剂、0.5g/kg(男性/女性)和1g/kg(女性))在三个为期四天的时期(实验)中单独服用，间隔至少七天。在住院试验期间，控制饮食、睡眠和体力活动。29名参与者被随机分配到按SERT基因5HTTLPR：LL+rs25531：AA(LALA)与5HTTLPR：LS/SS进行分层的亚组中，接受平衡的治疗顺序和性别。每天采集外周静脉血，(1)采用定量逆转录聚合酶链式反应(qRT-PCR)测定SLC6A4mRNA的含量；(2)采用串联质谱仪测定血浆EtG和ETS水平。用线性混合模型评估至少一项为期四天的实验(N=18)的受试者的SERT信使核糖核酸与饮品剂量之间的关联没有统计学意义。饮品剂量与血浆ETG、ETS及ETG/ETS比值呈显著正相关(β=5.8，SE=1.2，p&t；0.0001；β=1.3，SE=0.6，p=0.023；β=3，SE=0.7，p<；0.0001；C统计量分别为0.97，0.8，0.92)。此外，我们观察到在第一次实验中给药时SERT mRNA的序列效应和更大的安慰剂效应(p=0.0009)，但对EtG/ETS测量没有影响。需要更大和更具创新性的研究来解决安慰剂、种族、性别和对5-羟色胺能药物治疗的反应的影响，以全面评估SERT，以及可能是酗酒和酗酒的其他信使核糖核酸生物标志物。
The serotonin transporter (SERT) mRNA was previously reported as a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we further validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared with known biomarkers ethyl glucuronide (EtG) and sulfate (EtS). Binge drinking men and women of European ancestry aged 21–65 years were enrolled in a 12-day, in-patient, randomized, double-blind, crossover study, where three beverage doses (placebo, 0.5g/kg (0.4g/kg), and 1g/kg (0.9g/kg) for men (women)) were administered individually in three four-day periods (experiments), separated by minimum of seven-day washout. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty-nine participants were randomized to receive beverage doses counterbalancing sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (LALA) vs 5HTTLPR:LS/SS. Peripheral venous blood was collected daily for (1) quantification of SLC6A4 mRNA (primary outcome measure) using qRT-PCR and (2) plasma EtG and EtS levels using tandem mass-spectrometry. The association between administered beverage dose and SERT mRNA from completers of at least one four-day experiment (N=18) assessed by a linear mixed model was not statistically significant. Significant positive associations were found with beverage dose and plasma EtG, EtS and EtG/EtS ratio (beta=5.8, SE=1.2, p<0.0001; beta=1.3, SE=0.6, p=0.023; and beta=3.0, SE=0.7, p<0.0001, respectively; C-statistic for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with greater placebo effect on SERT mRNA when administered during the first experiment (p=0.0009), but not on EtG/EtS measures. Larger and more innovative studies addressing effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess SERT, and possibly other mRNA biomarkers of heavy and binge drinking.
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