Proudnikov Dmitri, Hamon Sara, Ott Jurg, Kreek Mary Jeanne
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Neurosci Lett. 2008 Apr 25;435(3):234-9. doi: 10.1016/j.neulet.2008.02.042. Epub 2008 Feb 26.
The melanocortin receptor type 2 (MC2R or adrenocorticotropic hormone, ACTH receptor) gene (MC2R) encodes a protein involved in regulation of adrenal cortisol secretion, important in the physiological response to stressors. A variant of MC2R, -179A>G, results in reduction of promoter activity and less adrenal action. We hypothesize that altered stress responsivity plays a key role in the initiation of substance abuse. By direct resequencing of the promoter region and exons 1 and 2 of the MC2R gene in 272 subjects including Caucasians, Hispanics and African Americans with approximately equal numbers of former heroin addicts and normal volunteers, we identified five novel variants each with allele frequency <2%. Previously reported polymorphisms -184G>A (rs2186944), -179A>G, 833A>C (rs28926182), 952T>C (rs4797825), 1005C>T (rs4797824) and 1579T>C (rs4308014) were each in allelic frequency >/=2% in one or more ethnic groups. These polymorphisms were genotyped in 632 subjects (260 Caucasians, 168 Hispanics, 183 African Americans and 21 Asians) using TaqMan assays. Significant differences in genotype frequency among ethnic groups studied were found for each of the six variants analyzed. We found a significant association (p=0.0004, experiment-wise p=0.0072) of the allele -184A with a protective effect from heroin addiction in Hispanics. Also, in Hispanics only we found the haplotype GACT consisting of four variants (-184G>A, -179A>G, 833A>C and 1005C>T) to be significantly associated with heroin addiction (p=0.0014, experiment-wise p=0.0168), whereas another haplotype, AACT, consisting of the same variants, was associated with a protective effect from heroin addiction (p=0.0039, experiment-wise p=0.0468).
黑素皮质素2型受体（MC2R，即促肾上腺皮质激素，ACTH受体）基因（MC2R）编码一种参与调节肾上腺皮质醇分泌的蛋白质，这在对应激源的生理反应中很重要。MC2R的一种变体，-179A>G，会导致启动子活性降低以及肾上腺作用减弱。我们推测应激反应性改变在药物滥用的起始过程中起关键作用。通过对272名受试者（包括白种人、西班牙裔和非裔美国人，前海洛因成瘾者和正常志愿者人数大致相等）的MC2R基因启动子区域以及外显子1和2进行直接测序，我们鉴定出5种新变体，每种变体的等位基因频率均<2%。先前报道的多态性-184G>A（rs2186944）、-179A>G、833A>C（rs28926182）、952T>C（rs4797825）、1005C>T（rs4797824）和1579T>C（rs4308014）在一个或多个种族群体中的等位基因频率均≥2%。使用TaqMan分析对632名受试者（260名白种人、168名西班牙裔、183名非裔美国人和21名亚洲人）的这些多态性进行基因分型。在所研究的种族群体中，分析的6种变体中的每一种在基因型频率上均存在显著差异。我们发现等位基因-184A与西班牙裔人群中海洛因成瘾的保护作用存在显著关联（p = 0.0004，实验性p = 0.0072）。此外，仅在西班牙裔人群中，我们发现由4种变体（-184G>A、-179A>G、833A>C和1005C>T）组成的单倍型GACT与海洛因成瘾显著相关（p = 0.0014，实验性p = 0.0168），而由相同变体组成的另一种单倍型AACT与海洛因成瘾的保护作用相关（p = 0.0039，实验性p = 0.0468）。
