کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6263753 1613910 2013 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Research ReportFunctional characterization of SNPs in CHRNA3/B4 intergenic region associated with drug behaviors
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب (عمومی)
پیش نمایش صفحه اول مقاله
Research ReportFunctional characterization of SNPs in CHRNA3/B4 intergenic region associated with drug behaviors
چکیده انگلیسی


- SNPs rs1948, rs8023462 and rs6495309 have been previously associated with drug-use.
- Luciferase assays show rs8023462 represses expression in certain genetic contexts.
- Electrophoretic mobility shift assays (EMSAs) show rs8023462 and rs6495309 bind nuclear proteins in an allele-specific way.
- rs8023462 interacts with GATA transcription factors in an allele-specific manner.

The cluster of human neuronal nicotinic receptor genes (CHRNA5/A3/B4) (15q25.1) has been associated with a variety of smoking and drug-related behaviors, as well as risk for lung cancer. CHRNA3/B4 intergenic single nucleotide polymorphisms (SNPs) rs1948 and rs8023462 have been associated with early initiation of alcohol and tobacco use, and rs6495309 has been associated with nicotine dependence and risk for lung cancer. An in vitro luciferase expression assay was used to determine whether these SNPs and surrounding sequences contribute to differences in gene expression using cell lines either expressing proteins characteristic of neuronal tissue or derived from lung cancers. Electrophoretic mobility shift assays (EMSAs) were performed to investigate whether nuclear proteins from these cell lines bind SNP alleles differentially. Results from expression assays were dependent on cell culture type and haplotype. EMSAs indicated that rs8023462 and rs6495309 bind nuclear proteins in an allele-specific way. Additionally, GATA transcription factors appeared to bind rs8023462 only when the minor/risk allele was present. Much work has been done to describe the rat Chrnb4/a3 intergenic region, but few studies have examined the human intergenic region effects on expression; therefore, these studies greatly aid human genetic research as it relates to observed nicotine phenotypes, lung cancer risk and potential underlying genetic mechanisms. Data from these experiments support the hypothesis that SNPs associated with human addiction-related phenotypes and lung cancer risk can affect gene expression, and are potential therapeutic targets. Additionally, this is the first evidence that rs8023462 interacts with GATA transcription factors to influence gene expression.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Brain Research - Volume 1529, 5 September 2013, Pages 1-15
نویسندگان
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