Human Molecular Genetics Advance Access originally published online on June 12, 2007
Human Molecular Genetics 2007 16(16):1931-1939; doi:10.1093/hmg/ddm140
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
In vitro assays fail to predict in vivo effects of regulatory polymorphisms
Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA
* To whom correspondence should be addressed at: Institute for Genome Sciences and Policy, Duke University, PO Box 3471, Durham, NC 27710, USA. Tel: +1 9196840896; Fax: +1 9196686787; Email: d.goldstein{at}duke.edu
Received May 8, 2007; Revised May 8, 2007; Accepted May 16, 2007
A typical paradigm in the investigation of complex human disease is to assess the effects of cis-regulatory polymorphisms implicated in association studies on transcription in cellular expression systems. Evidence from in vitro transfection studies is often assumed to be sufficient evidence for the in vivo functional importance of a polymorphism in the context of human disease, even though many confounding effects (e.g. temporal regulation, tissue specificity, genetic background) are not considered. In this study, we evaluate this assumption directly by examining the translation of in vitro results on allele-specific expression to an in vivo system using four genes that have been well documented through reporter assays to have promoter polymorphisms affecting transcription level: monoamine oxidase A (MAOA), neuropeptide Y (NPY), endothelial nitric oxide synthase (NOS3), and prodynorphin (PDYN). In our study, MAOA was found to have large allelic imbalances, which indicates that there is in vivo variation in the expression of this gene. However, the imbalances observed were not correlated with genotype at the putatively functional polymorphism. PDYN, NOS3 and NPY did not have large allelic imbalances. Overall, there was no statistically significant effect of these polymorphisms on expression level as measured by imbalance ratios in any of these genes. These results suggest that the functional effects of a polymorphism on gene expression may be more complicated and context dependent than is often assumed and also imply that the use of cell-based expression studies to support the role of such polymorphisms in disease etiology should be treated with caution.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Wang, H. Chen, K. M. Momary, L. H. Cavallari, J. A. Johnson, and W. Sadee Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement Blood, August 15, 2008; 112(4): 1013 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Bray Gene Expression in the Etiology of Schizophrenia Schizophr Bull, May 1, 2008; 34(3): 412 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.L. Crawford, T. Blomquist, D.N. Mullins, Y. Yoon, D.R. Hernandez, M. Al-Bagdhadi, J. Ruiz, J. Hammersley, and J.C. Willey CEBPG regulates ERCC5/XPG expression in human bronchial epithelial cells and this regulation is modified by E2F1/YY1 interactions Carcinogenesis, December 1, 2007; 28(12): 2552 - 2559. [Abstract] [Full Text] [PDF]
|
|