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GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis.

ABSTRACT: This study aimed to evaluate the relationship between a human GRIK4 gene polymorphism (rs1954787) and responsiveness to antidepressant treatment in depressed patients.A meta-analysis was carried out on five studies. Pooled odds ratios (ORs), 95% CIs and a ?(2) test measuring heterogeneity were calculated. A test of publication bias was also conducted.Alleles and genotypes from a total of 2169 depressed patients were analyzed. The results showed that the C allele appeared more frequently than the T allele in responders to treatment (OR: 1.22; 95% CI: 1.035-1.445; z = 2.36; p = 0.018). Similarly, CC homozygotes were more likely than TT homozygotes to respond to treatment (OR: 1.45; 95% CI: 1.107-1.913; z = 2.69; p = 0.007). No evidence of publication bias was detected.Subjects possessing the C allele or CC genotype of the GRIK4 polymorphism rs1954787 are more likely to respond to antidepressant treatment relative to subjects harboring the T allele and TT genotype. Additional replication of this result is required before this association can be considered definitive, after which it may become possible to employ this marker in conjunction with other known predictors in order to anticipate the outcomes of treatment with antidepressant medications.

SUBMITTER: Kawaguchi DM

PROVIDER: S-EPMC4208722 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis.

Kawaguchi Daniel M DM Glatt Stephen J SJ

Pharmacogenomics 20140801 11

<h4>Aim</h4>This study aimed to evaluate the relationship between a human GRIK4 gene polymorphism (rs1954787) and responsiveness to antidepressant treatment in depressed patients.<h4>Methods</h4>A meta-analysis was carried out on five studies. Pooled odds ratios (ORs), 95% CIs and a χ(2) test measuring heterogeneity were calculated. A test of publication bias was also conducted.<h4>Results</h4>Alleles and genotypes from a total of 2169 depressed patients were analyzed. The results showed that th ...[more]

PMID: 25303296

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Project description:BackgroundBrain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms.AimTo investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression.MethodsParticipants of 18-70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model.ResultsA total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 -0.042 ln(pg/ml) (95%CI -0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI -0.117; 0.130). No other association reached statistical significance.ConclusionWe observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes.

Project description:Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR(*)D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR(*)D (rs1954787, p=0.076, p(corrected)=0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR(*)D (rs7997012, allelic, p=0.043, p(corrected)=0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p=0.0019, p(corrected)=0.12) and the HTR2A SNP (rs17288723, genotypic, p=0.0011, p(corrected)=0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p=0.022) or HTR2A (genotypic, p=0.012) locus using the Fisher's product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p=0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p=0.002) and cortisol (p=0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR(*)D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.

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GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis.

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GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis.

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