Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism
Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism
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DOI：
10.1038/sj.mp.4000509
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发表时间：
1999-05-01
影响因子：
11
通讯作者：
Hietala, J
中科院分区：
文献类型：
--
作者：
Tiihonen, J;Hallikainen, T;Hietala, J
儿茶酚-O-甲基转移酶（COMT）是一种在多巴胺代谢中起关键作用的酶。有研究表明，COMT基因中常见的功能遗传多态性导致COMT酶活性的3 - 4倍差异（1，2），这可能有助于精神障碍（如双相情感障碍和酒精中毒）的病因学。(1)由于乙醇诱导的欣快与边缘区多巴胺的快速释放有关，因此可以想象，遗传了编码低活性COMT变体的等位基因的受试者将具有相对低的多巴胺失活率，因此更容易发展为乙醇依赖。本研究的目的是在1型（晚发性）酗酒者中检验这一假设。在图尔库（n = 67）和库奥皮奥（n = 56）的两个独立的男性晚发型（1型）酒精人群中测定COMT多态性。将高（H）和低（L）活性COMT基因型和等位基因频率与先前发表的来自3140名芬兰献血者（一般人群）和267名种族和性别匹配对照的数据进行比较。低活性等位基因（L）在图尔库和库奥皮奥患者中的频率均显著高于普通人群（P = 0.023和P = 0.005）。当所有患者与一般人群（献血者）进行比较时，差异甚至更显著（P = 0.0004）。将123例酗酒者的基因型与对照组基因型进行比较，发现LL基因型与HH基因型酗酒的OR值为2.51，95%CI为1.22-5.19，P = 0.006。此外，L等位基因频率显着高于酗酒者与对照组相比（P = 0.009）。酒精中毒中LL基因型的人群病因（归因）分数估计为13.3%（95%CI 2.3-25.7%）。结果表明，COMT基因多态性有助于晚发性酒精中毒的发展显着。
Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopamine. It has been suggested that a common functional genetic polymorphism in the COMT gene, which results in 3 to 4-fold difference in COMT enzyme activity,(1,2) may contribute to the etiology of mental disorders such as bipolar disorder and alcoholism.(1) Since ethanol-induced euphoria is associated with the rapid release of dopamine in limbic areas, it is conceivable that subjects who inherit the allele encoding the low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of ethanol dependence. The aim of this study was to test this hypothesis among type 1 (late-onset) alcoholics. The COMT polymorphism was determined in two independent male late onset (type 1) alcoholic populations in Turku (n = 67) and Kuopio (n = 56). The high (H) and low (L) activity COMT genotype and allele frequencies were compared with previously published data from 3140 Finnish blood donors (general population) and 267 race- and gender-matched controls. The frequency of low activity allele (L) was markedly higher among the patients both in Turku (P = 0.023) and in Kuopio (P = 0.005) when compared with the general population. When all patients were compared with the general population (blood donors), the difference was even more significant (P = 0.0004). When genotypes of all alcoholics (n = 123) were compared with genotypes of matched controls, the odds ratio (OR) for alcoholism for those subjects having the LL genotype vs those with HH genotype was 2.51, 95% CI 1.22-5.19, P = 0.006. Also, L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiological (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI 2.3-25.7%). The results indicate that the COMT polymorphism contributes significantly to the development of late-onset alcoholism.