先前有报道称,5-羟色胺转运蛋白(SERT)mRNA是用昂丹司琼治疗的5HTTLPR:LL基因型携带者大量饮酒的定量和基于病理生理学的生物标志物。这里,我们验证了SERTmRNA在定量预测近期饮酒(在无治疗的情况下)中的潜在用途,并将其与已知的生物标志物葡萄糖醛酸乙酯(EtG)和硫酸乙酯(EtS)进行了比较.
年龄在21至65岁之间的欧洲血统的狂饮男性和女性参加了为期12天的比赛,在病人中,随机化,双盲,交叉研究,他们服用了三剂饮料(安慰剂,0.5g/kg[0.4g/kg]乙醇,和1g/kg[0.9g/kg]乙醇的男性[女性])在三个4天的时间内单独(实验),由最少7天的清除期分隔。饮食,睡眠,在整个住院实验中,体力活动都得到了控制。29名参与者被随机分配接受饮料剂量,以平衡SERT基因型5HTTLPR:LLrs25531:AA(LALA)与5HTTLPR:LS/SS分层的亚组中的治疗顺序和性别。每天收集外周静脉血,用于(1)使用qRT-PCR定量SERTmRNA(主要结果测量)和(2)使用串联质谱的血浆EtG和EtS水平。
通过线性混合模型评估的至少一个4天实验(N=18)的施用饮料剂量与来自完成者的SERTmRNA之间的关联在统计学上不显著。发现与饮料剂量和血浆EtG显著正相关,EtS和EtG/EtS比率(β=5.8,SE=1.2,p<0.0001;β=1.3,SE=0.6,p=0.023;和β=3.0,SE=0.7,p<0.0001;区分结果的C统计量分别为0.97,0.8和0.92)。此外,我们观察到序列效应与更大的安慰剂效应对SERTmRNA时,在第一个实验(p=0.0009),但不是EtG/EtS措施。
这些发现并不能验证SERT作为重度饮酒的生物标志物。更大、更具创新性的研究解决了安慰剂的影响,种族,性别,需要对5-羟色胺能药物治疗的反应来全面评估SERT作为重度和暴饮暴食的生物标志物的效用。
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 (LA LA ) 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.