Common Genetic Polymorphisms in the ABCB1 Gene Are Associated with Risk of Major Depressive Disorder in Male Portuguese Individuals

Abstract

Major depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus-pituitary-adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR)=0.360, 95% confidence interval [CI]: [0.140-0.950], p=0.022; C3435T: OR=0.306, 95% CI: [0.096-0.980], p=0.042; and G2677TA: OR=0.300, 95% CI: [0.100-0.870], p=0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR=0.313, 95% CI: [0.118-0.832], p=0.016, FDR p=0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.

In-Silico Target Prediction for Hsa-Mir-27a and Identification of Genes Involved In Breast Cancer

“…In all studied participants, nine different haplotypes were identified, the most common of which were T-T-T and C-G-C. These results differ slightly from the ones obtained in Caucasians (Santos et al 2014) as well as Asian study populations (Kato et al 2008).…”

“…In this study, the genotype and allele frequencies of the first two of the above mentioned polymorphisms in Polish population were evaluated. The indicated frequency of particular genotypes and allele the synonymous C1236T, localized in exon 12 were comparable with Portuguese major depressive disorder (MDD) patients (Santos et al 2014) and relevantly different from Asian patients with depression (Kato et al 2008;Fujii et al 2012;Xie et al 2015). Similar observations were demonstrated for G2677T/A, nonsynonymous triallelic polymor-phism located in exon 21.…”

C3435T polymorphism of the MDR1 gene is not associated with blood levels of hypothalamus-pituitary-adrenal axis hormones in healthy male subjects

“…It has also been associated with major depression (Fujii et al, 2012;Ozbey et al, 2014;Santos et al, 2014). Furthermore, our recent study showed a significant association between the C3435T MDR1 polymorphism and interpersonal sensitivity, a depression-prone personality trait, in healthy subjects (Enokido et al, 2014).…”

Vascular and extravascular distribution of the ATP-binding cassette transporters ABCB1 and ABCC1 in aged human brain and pituitary

“…They are, for example, critically involved the clearance of Aβ thus being putative molecular targets for AD treatment (Cirrito et al, 2005; Gosselet et al, 2013; Kim et al, 2013; Koldamova et al, 2010; Krohn et al, 2011; Pahnke et al, 2013; Pahnke et al, 2009; Pahnke et al, 2008; Scheffler et al, 2012; Schumacher et al, 2012; Vogelgesang et al, 2002; Vogelgesang et al, 2004). Dysfunction of ABCB1 has been associated with Parkinson’s disease, progressive supranuclear palsy (PSP), multi-systems atrophy (MSA) and very recently genetic associations with depressive disorders were found (Bartels et al, 2008; Enokido et al, 2014; Li et al, 2014; Santos et al, 2014). In accordance with their function as “gatekeepers” at the BBB, ABCB1 and ABCC1 are localized in both the luminal and abluminal membranes of brain capillary endothelial cells, in adjacent pericytes and astrocytes as well as in choroid plexus epithelia and ventricular ependyma (for reviews see (Ballerini et al, 2002; Bendayan et al, 2002; Gazzin et al, 2008; Keep and Smith, 2011; Thiebaut et al, 1987; Wolf et al, 2012)).…”