The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.
The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.
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DOI：
10.1158/0008-5472.can-09-0786
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Bierut LJ
中科院分区：
文献类型：
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作者：
Saccone NL;Wang JC;Breslau N;Johnson EO;Hatsukami D;Saccone SF;Grucza RA;Sun L;Duan W;Budde J;Culverhouse RC;Fox L;Hinrichs AL;Steinbach JH;Wu M;Rice JP;Goate AM;Bierut LJ
遗传关联研究已经证明了染色体15q24 - 25.1上的CHRNA5-CHRNA3-CHRNB 4胆碱能烟碱受体亚单位基因簇中的变体在欧洲血统人群中尼古丁依赖、吸烟和肺癌风险中的重要性。我们现在已经在欧洲和非洲裔美国人中使用密集基因分型对该区域进行了详细的研究。我们对75个已知的单核苷酸多态性（SNP）和一个测序发现的SNP在非洲裔美国人（AA）样本（N = 710）和欧洲裔美国人（EA）样本（N = 2062）进行基因分型。例尼古丁依赖和控制非依赖吸烟者。在2772名受试者的完整样本中，非同义CHRNA 5 SNP rs16969968是与尼古丁依赖相关的最重要SNP（p = 4.49 × 10 - 8，OR 1.42（1.25 - 1.61））以及仅AAs（p = 0.015，OR = 2.04（1.15 - 3.62））和仅EAs（p = 4.14 × 10 - 7，OR = 1.40（1.23 - 1.59））。已显示影响EA中CHRNA5 mRNA水平的其他SNP与AA中的尼古丁依赖相关，但与EA无关。CHRNA3 SNP rs578776与rs16969968的相关性较低，与EA中的尼古丁依赖相关，但与AA无关。不太常见的SNP（频率≤ 5%）也与尼古丁依赖相关。总之，该基因簇中的多个变体导致尼古丁依赖风险，其中一些还与CHRNA5的功能效应相关。非同义SNP rs16969968是欧洲血统人群中已知的风险变体，也与非洲裔美国人的风险显著相关。额外的SNP以不同的方式对这两个人群的风险做出贡献。
Genetic association studies have demonstrated the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 in risk for nicotine dependence, smoking, and lung cancer in populations of European descent. We have now carried out a detailed study of this region using dense genotyping in both European- and African-Americans. We genotyped 75 known single-nucleotide-polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American (AA) sample (N = 710) and European-American (EA) sample (N = 2062). Cases were nicotine-dependent and controls were non-dependent smokers. The non-synonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2772 subjects (p = 4.49×10−8, OR 1.42 (1.25–1.61)) as well as in AAs only (p = 0.015, OR = 2.04 (1.15–3.62)) and EAs only (p = 4.14×10−7, OR = 1.40 (1.23–1.59)). Other SNPs that have been shown to affect mRNA levels of CHRNA5 in EAs are associated with nicotine dependence in AAs but not in EAs. The CHRNA3 SNP rs578776, which has low correlation with rs16969968, is associated with nicotine dependence in EAs but not in AAs. Less common SNPs (frequency ≤ 5%) also are associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5. The non-synonymous SNP rs16969968, a known risk variant in European-descent populations, is also significantly associated with risk in African-Americans. Additional SNPs contribute in distinct ways to risk in these two populations.