Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations
Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations
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DOI：
10.1038/sj.npp.1300997
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发表时间：
2006-03-01
影响因子：
7.6
通讯作者：
Li, MD
中科院分区：
文献类型：
--
作者：
Beuten, J;Payne, TJ;Li, MD
儿茶酚-O-甲基转移酶（COMT）基因在药物奖赏中枢多巴胺能回路中起着重要作用。因此，COMT基因内的等位基因变异是检查尼古丁依赖（ND）易感性个体间差异的潜在候选者。我们分析了5个单核苷酸多态性（SNPs），包括瓦尔/Met变异（rs 4680），它导致COMT内酶活性的三到四倍差异，与三个ND措施，SQ，HSI和FTND，在602个核心家庭的非洲裔美国人（AA）或欧洲裔美国人（EA）的起源。瓦尔/Met变异体显示与合并样本和EA样本中的三种ND测量值以及AA样本中的FTND显著相关。单倍型分析揭示了一个主要的保护性A-G-T单倍型AA样本中rs740603-rs 4680-rs 174699（频率23.6%）（FTND的最小Z = -3.35; P = 0.0005），主要保护性T-G-T单倍型（频率15.2%;最小Z = -2.92; FTND P = 0.003），以及高风险C-A-T单倍型（频率16.9%;最小Z = 3.16; SQ的P = 0.002）。此外，我们发现COMT中的显著单倍型具有性别特异性，并且显著相关的A-G-T仅在AA女性中具有保护性，而T-G-T仅在EA男性中具有保护性。此外，我们发现了一个主要的高风险T-A-T单倍型（频率56.7%），显示显着关联的三个ND措施在EA男性。对两种保护性单倍型（AA中的A-G-T和EA中的T-G-T）的进一步检查表明，低COMT酶活性Met等位基因对尼古丁依赖具有保护作用。总之，我们的研究结果提供了COMT在ND易感性中的作用的证据，并进一步证实其作用具有种族和性别特异性。
The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three- to fourfold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. The Val/Met variant showed a significant association with the three ND measures in the pooled and EA samples and with FTND in the AA sample. Haplotype analysis revealed a major protective A-G-T haplotype (frequency 23.6%) for rs740603-rs4680-rs174699 in the AA sample (minimum Z = -3.35; P = 0.0005 for FTND), a major protective T-G-T haplotype (frequency 15.2%; minimum Z = -2.92; P = 0.003 for FTND) in the EA sample, and a high-risk C-A-T haplotype (frequency 16.9%; minimum Z = 3.16; P = 0.002 for SQ) in the AA sample for rs933271-rs4680-rs174699. Furthermore, we found that the significant haplotypes within COMT were gender-specific and the significantly associated A-G-T is protective in AA females only, whereas T-G-T is protective in EA males only. Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.