Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism
Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism
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DOI：
10.1038/sj.mp.4001409
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发表时间：
2004-03-01
影响因子：
11
通讯作者：
Vicente, AM
中科院分区：
文献类型：
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作者：
Coutinho, AM;Oliveira, G;Vicente, AM
血清素系统在自闭症谱系障碍（ASD）的病因和发病机制中的作用尚未明确界定。在一部分患者中一直发现血小板血清素（5 - HT）水平较高，并且已知特定的5 - HT转运体基因（SLC6A4）变体可调节转运体的再摄取功能，因此可能影响一部分自闭症患者高血清素血症的发生。我们在105名ASD患者、他们的父母以及52名对照儿童的样本中，研究了血小板血清素水平与SLC6A4的两种多态性的关联，即启动子中的5 - HTT基因连锁多态性区域（HTTLPR）和内含子2的可变数目串联重复序列（VNTR）。定量传递不平衡检验（QTDT）结果显示，每个SLC6A4标记（HTTLPR的P = 0.017；内含子2 VNTR的P = 0.047）以及这两种标记的单倍型（P = 0.017）对5 - HT水平都有显著影响，其中L.Stin2.10单倍型的贡献较大（P = 0.0013）。高血清素血症范围内的5 - HT平均值与纯合的L.Stin2.10单倍型相关（H(1,N = 97)=7.76，P = 0.0054），该单倍型在33%的高血清素血症患者中出现，而在5 - HT水平正常的患者中仅占6%（费舍尔精确检验：P = 0.013，优势比 = 8）。在HTTLPR位点发现了等位基因相互作用，对5 - HT水平有显著的显性方差效应。我们未发现ASD中任何SLC6A4变体存在传递不平衡。我们的结果表明，SLC6A4基因是决定5 - HT水平的一个重要因素，并且特定的SLC6A4变体与我们的自闭症患者样本中高血清素血症风险增加有关。然而，其生物学机制不太可能仅涉及SLC6A4基因。相关的SLC6A4等位基因可能与其他基因或环境因素相互作用，导致在这部分自闭症患者中观察到异常高的5 - HT水平，这些患者可能代表一个独立的病因群体。
The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L. Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L. Stin2.10 haplotype (H(1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.