Sequence variations of the human MPDZ gene and association with alcoholism in subjects with European ancestry.
Sequence variations of the human MPDZ gene and association with alcoholism in subjects with European ancestry.
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DOI：
10.1111/j.1530-0277.2008.00888.x
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Choi DS
中科院分区：
文献类型：
--
作者：
Karpyak VM;Kim JH;Biernacka JM;Wieben ED;Mrazek DA;Black JL;Choi DS
Mpdz 基因变异是导致小鼠急性酒精戒断严重程度和癫痫发作的已知因素。为了调查这些发现与人类酗酒的相关性，我们对 61 名有酒精戒断性癫痫发作 (AWS) 病史的受试者、59 名有酒精戒断史但无 AWS 的受试者以及来自自我报告的非酒精性受试者 [所有欧洲裔美国人 (EA) 血统] 的 64 份 Coriell 样本的人类 MPDZ 基因 5' 区域的 46 个外显子、外显子-内含子边界和 2 kilobase 进行了重新测序，并与 Mpdz 进行了比较具有不同 AWS 倾向的 3 种小鼠品系的序列。为了探索人类 MPDZ 基因与酗酒和 AWS 的潜在关联，使用 13 种常见变异进行了单 SNP 和单倍型分析。在人类 MPDZ 基因中发现了 67 个新的、大多数罕见的变异。序列比较显示，人类基因不具有与小鼠中与AWS相关的Mpdz基因单倍型相同的变异。我们还发现 MPDZ 单倍型与人类 AWS 之间没有显着关联。然而，单倍型关联的全球测试显示，没有 AWS 的酒精依赖受试者和 Coriell 对照之间的单倍型频率存在显着差异 (p = 0.015)，这表明 MPDZ 在酒精中毒和/或 AWS 以外的相关表型中具有潜在作用。对最常见单倍型（频率 > 0.05）进行的单倍型特异性测试揭示了一种特定的高风险单倍型（p = 0.006，最大统计量 p = 0.051），包含 rs13297480G 等位基因，还发现与非酒精性 Coriell 受试者相比，在没有 AWS 的酗酒者中更为普遍（p = 0.019）。对具有 EA 血统的个体的 MPDZ 基因进行测序，发现与小鼠中与 AWS 相关的位点没有相同的变化。探索性单倍型和单一 SNP 关联分析表明 MPDZ 基因与酒精依赖之间可能存在关联，但与 AWS 无关。对 MPDZ 变异体进行进一步的功能基因组分析，并研究它们与更广泛的酗酒相关表型的关联，可以揭示酗酒的其他遗传标记。
Mpdz gene variations are known contributors of acute alcohol withdrawal severity and seizures in mice. To investigate the relevance of these findings for human alcoholism, we resequenced 46 exons, exon–intron boundaries, and 2 kilobases in the 5′ region of the human MPDZ gene in 61 subjects with a history of alcohol withdrawal seizures (AWS), 59 subjects with a history of alcohol withdrawal without AWS, and 64 Coriell samples from self-reported nonalcoholic subjects [all European American (EA) ancestry] and compared with the Mpdz sequences of 3 mouse strains with different propensity to AWS. To explore potential associations of the human MPDZ gene with alcoholism and AWS, single SNP and haplotype analyses were performed using 13 common variants. Sixty-seven new, mostly rare variants were discovered in the human MPDZ gene. Sequence comparison revealed that the human gene does not have variations identical to those comprising Mpdz gene haplotype associated with AWS in mice. We also found no significant association between MPDZ haplotypes and AWS in humans. However, a global test of haplotype association revealed a significant difference in haplotype frequencies between alcohol-dependent subjects without AWS and Coriell controls (p = 0.015), suggesting a potential role of MPDZ in alcoholism and or related phenotypes other than AWS. Haplotype-specific tests for the most common haplotypes (frequency > 0.05), revealed a specific high-risk haplotype (p = 0.006, maximum statistic p = 0.051), containing rs13297480G allele also found to be significantly more prevalent in alcoholics without AWS compared with nonalcoholic Coriell subjects (p = 0.019). Sequencing of MPDZ gene in individuals with EA ancestry revealed no variations in the sites identical to those associated with AWS in mice. Exploratory haplotype and single SNP association analyses suggest a possible association between the MPDZ gene and alcohol dependence but not AWS. Further functional genomic analysis of MPDZ variants and investigation of their association with a broader array of alcoholism-related phenotypes could reveal additional genetic markers of alcoholism.
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影响因子：
17.7
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通讯作者：
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