Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies.
Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies.
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DOI：
10.1038/tp.2016.22
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发表时间：
2016-03-01
影响因子：
6.8
通讯作者：
Mickey BJ
中科院分区：
文献类型：
--
作者：
Gluskin BS;Mickey BJ
D2多巴胺受体介导神经精神症状，是药物治疗的靶点。D2受体密度的个体间差异被认为会影响疾病风险和药理学反应。许多分子成像研究已经测试了常见的遗传变异是否会影响人类的D2受体结合潜力（BP），但由于样本量小，证明了强大的影响。我们对已发表的人类体内分子成像研究进行了系统检索，以估计常见遗传变异对纹状体D2受体BP的影响大小。我们确定了21项研究，检查了11个基因中的19个变异。最常研究的变异是ANKK 1的单核苷酸多态性（rs 1800497，Glu 713 Lys，也称为“Taq 1A”）。对该变体的固定和随机效应荟萃分析（5项研究，共194例受试者）显示，相对于主要等位基因纯合子，次要等位基因（Lys 713）携带者的纹状体BP显著且稳健地较低。在固定效应模型下，加权标准化均值差为-0.57（95%置信区间=（-0.87，-0.27），P=0.0002）。rs 1800497与血压之间的正常关系在神经精神疾病的受试者中不明显。据报道，四种DRD 2变体（rs 1079597，rs 1076560，rs6277和rs 1799732）和PER 2重复多态性与基线纹状体D2受体BP显著相关，但尚未在两个以上的独立样本中进行测试。我们的研究结果解决了文献中的明显差异，并确定rs 1800497强烈影响纹状体D2受体的可用性。这种遗传变异可能导致人类纹状体功能、神经精神疾病风险和药理学反应的重要个体差异。
The D2 dopamine receptor mediates neuropsychiatric symptoms and is a target of pharmacotherapy. Inter-individual variation of D2 receptor density is thought to influence disease risk and pharmacological response. Numerous molecular imaging studies have tested whether common genetic variants influence D2 receptor binding potential (BP) in humans, but demonstration of robust effects has been limited by small sample sizes. We performed a systematic search of published human in vivo molecular imaging studies to estimate effect sizes of common genetic variants on striatal D2 receptor BP. We identified 21 studies examining 19 variants in 11 genes. The most commonly studied variant was a single-nucleotide polymorphism in ANKK1 (rs1800497, Glu713Lys, also called ‘Taq1A'). Fixed- and random-effects meta-analyses of this variant (5 studies, 194 subjects total) revealed that striatal BP was significantly and robustly lower among carriers of the minor allele (Lys713) relative to major allele homozygotes. The weighted standardized mean difference was −0.57 under the fixed-effect model (95% confidence interval=(−0.87, −0.27), P=0.0002). The normal relationship between rs1800497 and BP was not apparent among subjects with neuropsychiatric diseases. Significant associations with baseline striatal D2 receptor BP have been reported for four DRD2 variants (rs1079597, rs1076560, rs6277 and rs1799732) and a PER2 repeat polymorphism, but none have yet been tested in more than two independent samples. Our findings resolve apparent discrepancies in the literature and establish that rs1800497 robustly influences striatal D2 receptor availability. This genetic variant is likely to contribute to important individual differences in human striatal function, neuropsychiatric disease risk and pharmacological response.