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首页> 外文学位 >Effects of the Dopamine Receptor 2 (DRD2) and Its Genetic Variants on Smoking and Nicotine Dependence in African Americans.
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Effects of the Dopamine Receptor 2 (DRD2) and Its Genetic Variants on Smoking and Nicotine Dependence in African Americans.

机译：多巴胺受体2（DRD2）及其遗传变异对非裔美国人吸烟和尼古丁依赖性的影响。

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摘要

Nicotine dependence is highly heritable and influenced by increased expression of the dopamine receptor D2 (DRD2) gene and the Taq1A single nucleotide polymorphism (SNP). Previous research has demonstrated that, African-American smokers are more likely to be nicotine dependent and notably, the A1 allele of the Taq1A SNP is more prevalent in this population. Moreover, both DRD2 synonymous and non-synonymous SNPs have been found to affect the expression of the DRD2 gene. Therefore, SNPs were selected based on a modified version of the mapping by admixture linkage disequilibrium (MALD) algorithm, a theoretically powerful approach to mapping genetic variants that are involved in human disease. Using this approach, four SNPs that are more prevalent in populations of African descent were identified. These SNPs are found in functional regions of the gene, such as the 3' untranslated region (UTR) which may influence mRNA stability and gene expression.;Restriction fragment length polymorphism (RFLP) and pyrosequencing were used as methods to genotype DRD2 SNPs: rs6274, rs6276, and rs6279, as well as Taq1A (rs1800497) in a cohort of 473 African-American former and current smokers from Baltimore, MD (n = 378) and Washington, DC (n = 95). Clinical nicotine dependence was examined and measured in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), an independent and cumulative association of 3 or more clinical symptoms of nicotine dependence. Herein we report a significant association between rs1800497 and heavy smoking (OR=0.48 95% CI: 0.25--0.93; p=0.03) and number of cigarettes smoked per day (OR=0.16, 95%CI: 0.16--1.11; p=0.05). Additionally, rs1800497, rs6274, rs6276 were associated with quit attempts while rs6279 was associated with cumulative clinical nicotine dependence.;To determine the relationship between dopamine and DRD2 in vitro , DRD2 expression and cAMP activity was measured in SHSY5Y (D1-like) and Y-79 (D2-like cells) cell lines. The results indicate that, the D1-like cells are more sensitive to the effects of dopamine than the Y-79 cells. These data provide evidence for an association between DRD2 SNPs and nicotine dependence in African Americans and substantiates the hypothesis that, dopamine deficiency is a possible explanation for nicotine dependence observed in former and current smokers. Investigation of clinically-defined symptoms for nicotine dependence may further our understanding of genetic determinants that contribute to the biology of nicotine dependence and tobacco cessation in African-Americans smokers.
机译：尼古丁的依赖性是高度可遗传的，并受多巴胺受体D2（DRD2）基因和Taq1A单核苷酸多态性（SNP）表达增加的影响。先前的研究表明，非洲裔美国吸烟者更可能依赖尼古丁，尤其是Taq1A SNP的A1等位基因在该人群中更为普遍。而且，已经发现DRD2同义和非同义SNP都影响DRD2基因的表达。因此，基于通过混合连锁不平衡（MALD）算法绘制的映射的修改版本选择SNP，这是一种映射人类疾病涉及的遗传变异的理论上有效的方法。使用这种方法，确定了在非洲人后裔中更普遍的四个SNP。这些SNP位于基因的功能区域，例如可能影响mRNA稳定性和基因表达的3'非翻译区（UTR）;;限制性片段长度多态性（RFLP）和焦磷酸测序被用作基因型DRD2 SNP的方法：rs6274 ，rs6276和rs6279，以及Taq1A（rs1800497），来自马里兰州巴尔的摩（n = 378）和华盛顿特区（n = 95）的473名非裔美国人和现时吸烟者。根据《精神障碍诊断和统计手册》（DSM-IV），对尼古丁的临床依赖性进行了检查和测量，该手册是3种或多种尼古丁依赖性临床症状的独立且累积的关联。本文中我们报告了rs1800497与重度吸烟之间的显着相关性（OR = 0.48 95％CI：0.25--0.93; p = 0.03）和每天吸烟的数量（OR = 0.16，95％CI：0.16--1.11; p = 0.05）。此外，rs1800497，rs6274，rs6276与尝试戒烟有关，而rs6279与临床尼古丁累积依赖性有关。 -79（D2样细胞）细胞系。结果表明，与Y-79细胞相比，D1样细胞对多巴胺的效应更为敏感。这些数据为非裔美国人中DRD2 SNP与尼古丁依赖性之间的关联提供了证据，并证实了多巴胺缺乏是以前和现在吸烟者中尼古丁依赖性的一种可能解释。对尼古丁依赖的临床定义症状的调查可能会进一步使我们了解有助于非洲裔美国人吸烟者尼古丁依赖和戒烟生物学的遗传决定因素。

著录项

  • 作者

    Arrey, Benedict Nkongho.;

  • 作者单位

    Howard University.;

  • 授予单位 Howard University.;
  • 学科 African American Studies.;Health Sciences Pharmacy.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 117 p.
  • 总页数 117
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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