Ma Jennie Z, Beuten Joke, Payne Thomas J, Dupont Randolph T, Elston Robert C, Li Ming D
Program in Genomics and Bioinformatics on Drug Addiction, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Hum Mol Genet. 2005 Jun 15;14(12):1691-8. doi: 10.1093/hmg/ddi177. Epub 2005 May 6.
DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.
多巴脱羧酶（DDC；也称为L-氨基酸脱羧酶；AADC）参与多巴胺、去甲肾上腺素和5-羟色胺的合成。由于中脑边缘多巴胺能系统与包括尼古丁在内的许多药物的强化作用有关，因此DDC基因被认为是参与尼古丁依赖（ND）易感性发展的一个合理候选基因。此外，该基因位于7p11区域，在我们之前对弗雷明汉心脏研究人群进行的全基因组扫描中，该区域显示出与ND的“提示性连锁”。在本研究中，我们检测了DDC基因内的8个单核苷酸多态性（SNP）与ND的关联性，ND通过吸烟量（SQ）、吸烟严重指数（HSI）和尼古丁依赖的Fagerstrom测试（FTND）评分来评估，研究对象为来自602个核心家庭的2037名吸烟者和非吸烟者，这些家庭分别具有非洲裔或欧洲裔美国人（分别为AA或EA）血统。使用PBAT-GEE程序对单个SNP进行的关联分析表明，SNP rs921451与EA样本中三项经调整的ND测量指标中的两项显著相关（P = 0.01 - 0.04）。基于单倍型的关联分析在AA样本中发现了rs921451 - rs3735273 - rs1451371 - rs2060762的一种保护性T - G - T - G单倍型，在进行多重检验校正后，该单倍型与所有三项经调整的ND测量指标均显著相关（HSI的最小Z值 = -2.78，P = 0.006）。相比之下，我们在EA样本中发现了rs921451 - rs3735273 - rs1451371 - rs3757472这一不同SNP组合的一种高风险T - G - T - G单倍型，在进行Bonferroni校正后，该单倍型与SQ和FTND评分显著相关（FTND的最大Z值 = 2.73，P = 0.005）。总之，我们的研究结果为DDC参与ND易感性提供了首个证据，并且进一步揭示了其影响的种族特异性。
