Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Alcohol Clin Exp Res. 2022 Oct;46(10):1888-1899. doi: 10.1111/acer.14931. Epub 2022 Sep 11.
The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS).
Binge drinking men and women of European ancestry aged 21 to 65 years were enrolled in a 12-day, in-patient, randomized, double-blind, crossover study, where they were administered three beverage doses (placebo, 0.5 g/kg [0.4 g/kg] ethanol, and 1 g/kg [0.9 g/kg] ethanol for men [women]) individually in three 4-day periods (experiments), separated by minimum 7-day washout period. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty-nine participants were randomized to receive beverage doses counterbalancing the sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (L L ) versus 5HTTLPR:LS/SS. Peripheral venous blood was collected daily for (1) quantification of SERT mRNA (the 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 4-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 (β = 5.8, SE = 1.2, p < 0.0001; β = 1.3, SE = 0.6, p = 0.023; and β = 3.0, SE = 0.7, p < 0.0001, respectively; the C-statistics for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with a greater placebo effect on SERT mRNA when it was administered during the first experiment (p = 0.0009), but not on EtG/EtS measures.
The findings do not validate the use of SERT as a biomarker of heavy drinking. Larger and more innovative studies addressing the effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess the utility of SERT as a biomarker of heavy and binge drinking.
先前有研究报道，5HTTLPR：LL 基因型携带者在接受昂丹司琼治疗时，血清素转运体（SERT）mRNA 可作为衡量重度饮酒的一种基于定量和生理病理学的生物标志物。在此，我们验证了 SERT mRNA 用于定量预测近期饮酒（无治疗情况下）的潜力，并将其与已知生物标志物乙基葡萄糖醛酸（EtG）和乙基硫酸盐（EtS）进行了比较。
纳入年龄在 21 至 65 岁之间的、有 binge drinking 史的欧洲裔男性和女性，他们参加了一项为期 12 天的住院、随机、双盲、交叉研究，在三个 4 天的实验期间（实验）中，他们分别单独接受三种饮料剂量（安慰剂、0.5 g/kg [0.4 g/kg] 乙醇和 1 g/kg [0.9 g/kg] 乙醇，男性 [女性]），每个实验之间至少间隔 7 天的洗脱期。住院期间的实验过程中，对饮食、睡眠和身体活动进行了控制。将 29 名参与者随机分配，以平衡治疗顺序和按 SERT 基因型 5HTTLPR：LL+rs25531：AA（L L ）与 5HTTLPR：LS/SS 分层的性别内亚组内的饮料剂量。每天采集外周静脉血，用于：（1）使用 qRT-PCR 定量测定 SERT mRNA（主要观察指标），（2）使用串联质谱法测定血浆 EtG 和 EtS 水平。
至少完成一个 4 天实验的参与者（N=18）的线性混合模型评估显示，给予的饮料剂量与 SERT mRNA 之间的关联无统计学意义。结果发现，饮料剂量与血浆 EtG、EtS 和 EtG/EtS 比值呈显著正相关（β=5.8，SE=1.2，p<0.0001；β=1.3，SE=0.6，p=0.023；β=3.0，SE=0.7，p<0.0001；区分结局的 C 统计量分别为 0.97、0.8 和 0.92）。此外，我们观察到一个序列效应，即在第一个实验中给予安慰剂时，SERT mRNA 的安慰剂效应更大（p=0.0009），但 EtG/EtS 指标则没有这种效应。
这些发现并不支持 SERT 作为重度饮酒生物标志物的用途。需要更大规模和更具创新性的研究来解决安慰剂、种族、性别和对 5-羟色胺能药物治疗反应的影响等问题，以全面评估 SERT 作为重度和 binge drinking 生物标志物的效用。
