In vitro assays fail to predict in vivo effects of regulatory polymorphisms - PubMed (original) (raw)
. 2007 Aug 15;16(16):1931-9.
doi: 10.1093/hmg/ddm140. Epub 2007 Jun 12.
Affiliations
- PMID: 17566082
- DOI: 10.1093/hmg/ddm140
In vitro assays fail to predict in vivo effects of regulatory polymorphisms
Elizabeth T Cirulli et al. Hum Mol Genet. 2007.
Abstract
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.
Similar articles
- Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain: dissection of epigenetic and genetic factors.
Pinsonneault JK, Papp AC, Sadée W. Pinsonneault JK, et al. Hum Mol Genet. 2006 Sep 1;15(17):2636-49. doi: 10.1093/hmg/ddl192. Epub 2006 Aug 7. Hum Mol Genet. 2006. PMID: 16893905 - Multiple Functional Variants in cis Modulate PDYN Expression.
Babbitt CC, Silverman JS, Haygood R, Reininga JM, Rockman MV, Wray GA. Babbitt CC, et al. Mol Biol Evol. 2010 Feb;27(2):465-79. doi: 10.1093/molbev/msp276. Epub 2009 Nov 12. Mol Biol Evol. 2010. PMID: 19910384 - A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer's disease patients.
Wu YH, Fischer DF, Swaab DF. Wu YH, et al. Brain Res. 2007 Sep 5;1167:13-9. doi: 10.1016/j.brainres.2007.06.053. Epub 2007 Aug 9. Brain Res. 2007. PMID: 17692293 - Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias.
Pereira TV, Rudnicki M, Cheung BM, Baum L, Yamada Y, Oliveira PS, Pereira AC, Krieger JE. Pereira TV, et al. J Hypertens. 2007 Sep;25(9):1763-74. doi: 10.1097/HJH.0b013e3281de740d. J Hypertens. 2007. PMID: 17762636 Review. - Functional polymorphisms in dopamine and serotonin pathway genes.
D'Souza UM, Craig IW. D'Souza UM, et al. Hum Mutat. 2006 Jan;27(1):1-13. doi: 10.1002/humu.20278. Hum Mutat. 2006. PMID: 16320307 Review.
Cited by
- Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review.
Chan AML, Cheah JM, Lokanathan Y, Ng MH, Law JX. Chan AML, et al. Int J Mol Sci. 2023 Feb 16;24(4):4026. doi: 10.3390/ijms24044026. Int J Mol Sci. 2023. PMID: 36835438 Free PMC article. Review. - An Interdisciplinary Approach to Studying Gene-Environment Interactions: From Twin Studies to Gene Identification and Back.
Dick DM. Dick DM. Res Hum Dev. 2011;8(3-4):211-226. doi: 10.1080/15427609.2011.625317. Epub 2011 Nov 18. Res Hum Dev. 2011. PMID: 34385894 Free PMC article. - The role of monoamine oxidase A in the neurobiology of aggressive, antisocial, and violent behavior: A tale of mice and men.
Kolla NJ, Bortolato M. Kolla NJ, et al. Prog Neurobiol. 2020 Nov;194:101875. doi: 10.1016/j.pneurobio.2020.101875. Epub 2020 Jun 20. Prog Neurobiol. 2020. PMID: 32574581 Free PMC article. Review. - Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A.
Rafehi M, Faltraco F, Matthaei J, Prukop T, Jensen O, Grytzmann A, Blome FG, Berger RG, Krings U, Vormfelde SV, Tzvetkov MV, Brockmöller J. Rafehi M, et al. Front Pharmacol. 2019 Oct 30;10:1297. doi: 10.3389/fphar.2019.01297. eCollection 2019. Front Pharmacol. 2019. PMID: 31736764 Free PMC article. - Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution.
Kircher M, Xiong C, Martin B, Schubach M, Inoue F, Bell RJA, Costello JF, Shendure J, Ahituv N. Kircher M, et al. Nat Commun. 2019 Aug 8;10(1):3583. doi: 10.1038/s41467-019-11526-w. Nat Commun. 2019. PMID: 31395865 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous