ReviewAssociation between major depressive disorder and the norepinephrine transporter polymorphisms T-182C and G1287A: A meta-analysis
Introduction
The norepinephrine transporter (NET) is a target for the tricyclic antidepressants, selective norepinephrine reuptake inhibitors (NRIs), and serotonin−norepinephrine reuptake inhibitors (SNRIs) used to treat major depressive disorder (MDD) (Benmansour et al., 2004, Vaishnavi et al., 2004, Min et al., 2009a). Transporter mRNA, NET protein, and norepinephrine binding sites are also lower in the brains of MDD patients (Klimek et al., 1997, Hahn and Blakely, 2007), suggesting that dysfunctional regulation of synaptic norepinephrine (NE) is involved in the pathogenesis of MDD. Furthermore, clinical studies suggest that NET gene polymorphisms may also confer differential sensitivity to specific antidepressant treatments (Owens et al., 2008, Jeannotte et al., 2009, Sekine et al., 2010). Indeed, different combinations of NET polymorphisms may be associated with distinct subphenotypes of MDD (Hahn et al., 2008).
The human NET gene, located on chromosome 16q12.2, spans approximately 45 kb and consists of 16 exons (Brüss et al., 1993, Hahn and Blakely, 2002). Among the several known NET polymorphisms, most studies on the etiology of psychiatric disorders like MDD have focused on T-182C and G1287A. The T-182C polymorphism is located in the NET promoter region and may regulate transcriptional activity by modifying the DNA binding affinity of transcription factors. The G1287A polymorphism is a silent mutation located in exon 9. Studies have concluded that the G and A alleles are functionally identical (Yang et al., 2004, Song et al., 2011), the G allelic variant was associated with a higher concentration of the principal NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) of healthy volunteers (Jönsson et al., 1998), suggesting that the G/A allele regulates norepinephrine transmission.
Several case-control studies have investigated the potential association between these two polymorphisms and MDD, but the results have been inconsistent and often contradictory, possibly due to insufficient sample sizes, ethic variability, different sampling strategies, or to the small effects of single polymorphisms on complex and heterogeneous phenotypes like MDD. We have therefore conducted a meta-analysis to estimate the influence of the T-182C and G1287A polymorphisms on MDD. Meta-analysis is a powerful method that can detect small genetic contributions and reduce false negative results by increasing the sample size and statistical power (Choi et al., 2003). After retrieving all relevant studies and including only case-control studies of patients with MDD as defined by the DMS-IV, we found no significant association between MDD and either T-182C or G1287A.
Section snippets
Inclusion criteria
We included all studies that tested the potential association between MDD and the T-182C and/or G1287A polymorphisms. Only case-control studies of patients who fulfilled the DSM-IV diagnosis of major depressive disorder were included in the analysis. The frequencies of each allele and genotype meet the criteria for Hardy-Weinberg disequilibrium in both case and control groups.
Search strategy
Relevant studies published before May 2012 were retrieved from the PUBMED and EMBASE databases using full-text searching
Results
Database searches identified 10 studies meeting our inclusion criteria. Two studies used the same sample population (Min et al., 2009a, Min et al., 2009b), so only the former (Min et al., 2009a) was included. Similarly, a study by Sun et al. (2008) was excluded, while a study using the same population (Xu et al., 2009) was included. Three studies examined the association between MDD and both the T-182C and G1287A polymorphism distributions in a population of Chinese MDD patients and controls (
Discussion
To our knowledge, this is the first meta-analysis evaluating the relationship between MDD risk and the T-182C and G1287A polymorphisms. By including all relevant case-control studies up to May 2012, our meta-analysis represents the most up-to-date quantitative synthesis of gene-psychiatric disorder association studies, encompassing several thousand participants across different racial groups. Our main finding is that these two NET polymorphisms are not associated with major depression. Our
Role of funding source
This study was supported by a Grant from project of Liaoning SHIBAIQIAN high-end talent, a Grant from Liaoning Science & Technology project (2011408004), and a National Natural Science Foundation of China (81271442) for Prof. Gang Zhu.
Conflicts of interest
None of the authors have any interests to declare in relation to this submission.
Acknowledgement
None.
References (41)
- et al.
Regulation of the norepinephrine transporter by chronic administration of antidepressants
Biological Psychiatry
(2004) The promoter of the serotonin transporter genotype, environment and depression: a hypothesis supported?
Journal of Affective Disorders
(2012)- et al.
A CDE/CHR-like element mediates repression of transcription of the mouse RB2 (p130) gene
FEBS Letters
(2000) - et al.
Desipramine induced changes in the norepinephrine transporter, alpha- and gamma-synuclein in the hippocampus, amygdala and striatum
Neurosci. Lett.
(2009) - et al.
Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationships to monoamine metabolite concentrations in CSF of healthy volunteers
Psychiatry Research
(1998) - et al.
A previously undescribed intron and extensive 5′ upstream sequence, but not Phox2a-mediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene
Journal of Biological Chemistry
(1999) The genetics of depression: a review
Bio. Psychiatry
(2006)- et al.
A case-control and family-based association study of the 5-HTTLPR in pediatric-onset depressive disorders
Biological Psychiatry
(2004) - et al.
Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression
Psychiatry Research
(1999) - et al.
Obstacles and opportunities in meta-analysis of genetic association studies
Genetics in Medicine
(2005)
Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity
Biological Psychiatry
The norepinephrine transporter gene modulates the relationship between urban/rural residency and major depressive disorder in a Chinese population
Psychiatry Research
Association of norepinephrine transporter gene with methylphenidate response
Journal of the American Academy of Child and Adolescent Psychiatry
Identification of a naturally occurring polymorphism in the promoter region of the norepinephrine transporter and analysis in major depression
Neuropsychopharmacology
Operating characteristics of a rank correlation test for publication bias
Biometrics
Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter
Human Genetics
Lack of association between the norepinephrine transporter gene and major depression in a Han Chinese population
Journal of Psychiatry and Neuroscience
Combining multiple microarray studies and modeling interstudy variation
Bioinformatics
Research review: gene-environment interaction research in youth depression - a systematic review with recommendations for future research
Journal of Child Psychology and Psychiatry
Bias in meta-analysis detected by a simple, graphical test
British Medical Journal
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