Association between major depressive disorder and the norepinephrine transporter polymorphisms T-182C and G1287A: A meta-analysis

Abstract

Background

Previous studies have implicated norepinephrine transporter (NET) gene polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide NET polymorphisms, T-182C (rs2242446) in the promoter region and G1287A (rs5569) in exon 9, were found to be associated with MDD in different populations. However, inconsistent and inconclusive results have also been obtained.

Methods

In this study, we examined whether rs2242446 and rs5569 genetic variants are related to the etiology of MDD using a meta-analysis. Relevant case-control studies were retrieved by database searching and selected according to established inclusion criteria.

Results

Eight articles were identified that tested the relationship between the NET T-182C and/or G1287A polymorphism and MDD. Statistical analyses revealed no significant association between these polymorphisms and MDD (OR=1.23, 95% CI=0.77−1.97, P=0.38 for T-182C; OR=1.00, 95% CI=0.78−1.29, P=0.99 for G1287A).

Limitations

The results must be treated with caution because of the small sample sizes of several included studies.

Conclusions

Our findings suggest that the NET T-182C and G1287A polymorphisms are not susceptibility factors for MDD.

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.