Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations
Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations
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DOI：
10.1001/archpsyc.61.6.597
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发表时间：
2004-06-01
影响因子：
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通讯作者：
Goldman, D
中科院分区：
文献类型：
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作者：
Xu, K;Lichtermann, D;Goldman, D
背景：多巴胺受体介导的通路在成瘾机制中起着关键作用。目的：确定D-2多巴胺受体基因(DRD2)是否存在易感部位。设计：采用10个单核苷酸多态(SNPs)对两个不同人群进行病例对照分析。研究地点：德国美因茨大学和波恩大学，以及中国西南地区的3家医院。患者：病例和对照对象分别来自中国(486例，313例对照)和德国(471例，192例对照)。干预：采用5‘-核酸内切酶荧光法对10个SNP进行基因分型。用期望最大化算法计算连锁不平衡和单倍型的D‘值。主要结果指标：通过为每个群体构建的X(2)检验比较病例和对照之间的基因型、等位基因和单倍型频率。结果：从5‘端的8个SNPs(TaqIB)延伸到3’端10kb的SNP10位点(TaqIA)，确定了一个25.8kb的单倍型片段(Kb)。其中，携带TaqIB1等位基因的单倍型簇A与中国海洛因依赖的高危相关(P=1.425×10(-22)；优势比为52.8；8-SNP分析95%可信区间为7.290~382.5)。在SNP6(内含子6Ins/del G)附近发现了一个可能的重组热点，创造了两个新的女儿单倍型，这两种单倍型与德国人海洛因依赖的风险较低有关(8-SNP分析的P=1.94×10(-11))。结论：这些结果有力地支持了DRD2基因作为中国人海洛因依赖易感基因的作用，并与德国人海洛因依赖的低风险有关。
Context: Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D-2 dopamine receptor gene (DRD2) with substance abuse are controversial.Objective: To determine whether susceptibility sites re sided at DRD2.Design: Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence.Setting: Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China.Patients: Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls).Interventions: Genotyping for 10 SNPs by 5'-exonuclease fluorescence assays. The D' value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm.Main Outcome Measures: Genotype, allele, and haplotype frequencies were compared between cases and controls by chi(2) tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations.Results: A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3, (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10 kb distal to the 3' end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 x 10(-22); odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 x 10(-11) for 8-SNP analysis). There was no evidence of population stratification in either population.Conclusions: These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.