Nicotinic α5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms.
Nicotinic α5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms.
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DOI：
10.1038/ejhg.2010.120
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发表时间：
2011-01
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影响因子：
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编码烟碱α5亚基的CHRNA5与多种疾病有关，包括尼古丁成瘾和肺癌。先前的研究表明启动子多态性和CHRNA5 mRNA表达之间存在显着关联，但负责的序列变异仍然不确定。为了寻找顺式调节变体，我们测量了人类前额皮质尸检组织中CHRNA5的等位基因特异性mRNA表达，并扫描了CHRNA5基因座的调节变体。一组六个常见的单核苷酸多态性（rs1979905，rs1979906，rs1979907，rs880395，rs905740和rs7164030），在完全连锁不平衡中，完全解释了>2.5倍的等位基因表达差异和总CHRNA5 mRNA表达的四倍增加。这个拟议的增强子区域位于CHRNA 5转录起始位点上游超过13千碱基处。相同的上游变异体不能影响外周血淋巴细胞中CHRNA5 mRNA的表达，表明组织特异性基因调控。其他启动子多态性也与脑中CHRNA5 mRNA的总体表达相关，但与等位基因mRNA表达率不一致，这是顺式调节变体的一个可靠和近似的测量。增强子区域和非同义多态性rs16969968产生了三种主要的单倍型，改变了尼古丁依赖的风险。当测试临床关联时，跨CHRNA5位点的连锁不平衡的种族差异需要考虑上游增强子变体。
CHRNA5, encoding the nicotinic α5 subunit, is implicated in multiple disorders, including nicotine addiction and lung cancer. Previous studies demonstrate significant associations between promoter polymorphisms and CHRNA5 mRNA expression, but the responsible sequence variants remain uncertain. To search for cis-regulatory variants, we measured allele-specific mRNA expression of CHRNA5 in human prefrontal cortex autopsy tissues and scanned the CHRNA5 locus for regulatory variants. A cluster of six frequent single nucleotide polymorphisms (rs1979905, rs1979906, rs1979907, rs880395, rs905740, and rs7164030), in complete linkage disequilibrium, fully account for a >2.5-fold allelic expression difference and a fourfold increase in overall CHRNA5 mRNA expression. This proposed enhancer region resides more than 13 kilobases upstream of the CHRNA5 transcription start site. The same upstream variants failed to affect CHRNA5 mRNA expression in peripheral blood lymphocytes, indicating tissue-specific gene regulation. Other promoter polymorphisms were also correlated with overall CHRNA5 mRNA expression in the brain, but were inconsistent with allelic mRNA expression ratios, a robust and proximate measure of cis-regulatory variants. The enhancer region and the nonsynonymous polymorphism rs16969968 generate three main haplotypes that alter the risk of developing nicotine dependence. Ethnic differences in linkage disequilibrium across the CHRNA5 locus require consideration of the upstream enhancer variants when testing clinical associations.
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DOI：
10.1002/ajmg.b.30828
发表时间：
2009-06-05
期刊：
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
影响因子：
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作者：
Saccone NL;Saccone SF;Hinrichs AL;Stitzel JA;Duan W;Pergadia ML;Agrawal A;Breslau N;Grucza RA;Hatsukami D;Johnson EO;Madden PA;Swan GE;Wang JC;Goate AM;Rice JP;Bierut LJ
通讯作者：
Bierut LJ
影响因子：
11.2
作者：
Liu P;Yang P;Wu X;Vikis HG;Lu Y;Wang Y;Schwartz AG;Pinney SM;de Andrade M;Gazdar A;Gaba C;Mandal D;Lee J;Kupert E;Seminara D;Minna J;Bailey-Wilson JE;Spitz M;Amos CI;Anderson MW;You M
通讯作者：
You M
DOI：
10.1161/hypertensionaha.109.133033
发表时间：
2009-07
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Kumar P;Pandey KN
通讯作者：
Pandey KN
影响因子：
5.8
作者：
Johnson, Andrew D.;Handsaker, Robert E.;de Bakker, Paul I. W.
通讯作者：
de Bakker, Paul I. W.
影响因子：
11.2
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
通讯作者：
Bierut LJ