Nicotinic α5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms.
- Authors
- Smith, Ryan M; Alachkar, Houda; Papp, Audrey C; Wang, Danxin; Mash, Deborah C; Wang, Jen-Chyong; Bierut, Laura J; Sadee, Wolfgang
- Year
- 2011
- Journal
- European journal of human genetics : EJHG
- PMID
- 20700147
- DOI
- 10.1038/ejhg.2010.120
- PMCID
- PMC2995013
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 (LD), 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 LD across the CHRNA5 locus require consideration of upstream enhancer variants when testing clinical associations.
Polymorphisms genotyped in the CHRNA5 locus, including SNPs used to establish haplotype structure, marker SNPs (*), and putative functional enhancer SNPs (#).
AEI ratios in brain tissues heterozygous for both marker SNPs rs16969968 (rs968) and rs615470 (rs470). In all, 9 of 10 samples display consistent AEI across the two marker SNPs, whereas one sample (101) shows differences in AEI, a possible indicator of RNA processing leading to different mRNA isoforms (eg, alternative splicing), or analysis error in this sample. Note: Solid line at 0 indicates no difference between gDNA and mRNA ratios; dotted lines indicate a 2.5-fold change in allelic mRNA expression (normalized to gDNA), taken here as strong evidence for AEI; error bars=SEM.
Combined rs16969968 and rs615470 allelic mRNA expression ratios for 42 prefrontal cortex tissues. A total of 27 of 42 samples display >2.5-fold AEI (represented by dotted lines). Bars represent mean AEI, with error bars indicating SEM.
(a) One-way analysis of varience shows a significant effect of rs905740 genotype on totalCHRNA5 mRNA expression in prefrontal cortex tissue (P<0.001). Bonferroni-corrected post hoc analysis shows a significant increase in T/T expression (indicated by lower CT values) compared with either C/C or C/T genotype. **P<0.001; *P<0.05. CT: RT-PCR cycle threshold, with each unit corresponding to a twofold change. (b) CHRNA5 mRNA expression in lymphocytes when compared across the rs905740 genotype. No significant difference is observed. CT: RT-PCR cycle threshold.
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