BACKGROUNDS:Deiodinase type 2 (DIO2) is a selenoenzyme involved in the synthesis of thyroid hormones. Chemerin is a newly investigated adipokine known also as novel chemokine. Both molecules have been recently expected and found to play an important role in inflammation and immunity. DIO2, for example, is upregulated during acute and chronic inflammation. In addition, inflammation-induced expression of DIO2 in macrophages has been confirmed, while chemerin modulates the activation and chemotaxis of immune cells. It is widely known that chronic obstructive pulmonary disease (COPD) - the most common lung disease in the world - is accompanied by an inflammatory process and immune activation. There are no studies demonstrating an association between DIO2, chemerin and COPD. The aim of this study was to estimate DIO2 and chemerin concentration in serum collected from patients suffering from COPD and to compare it with healthy subjects, as well as to correlate with basic and clinical characteristics. METHODS:The study group included 50 patients with COPD and 30 healthy subjects. DIO2 and chemerin serum levels as well as c-reactive protein levels were determined in all the subjects using commercial enzyme-linked immunosorbent assay kits. The association between serum DIO2 and chemerin with sociodemographic and clinical variables was assessed. RESULTS:DIO2 serum levels were significantly higher in the patients with COPD as compared to the control group (50.3±23.2 U/L vs. 13.3±13.1; p<0.00001). No differences were observed in serum chemerin levels between the patients and controls (107.559±86.695.6 vs. 100.701±53.805; p=0.54). Furthermore, there was no association between DIO2 and chemerin levels and other variables, and no correlation between both molecules. CONCLUSIONS:This study demonstrated that DIO2 levels were higher in the patients with COPD than in the control subjects. The examined molecules should be further investigated if they are intended to be considered markers of processes involved in COPD mechanisms.

Purpose: Chronic obstructive pulmonary disease is the most common chronic lung disease, which may be caused by different pathological processes, including inflammation. Furthermore, signs of changes in thyroid hormone levels are found in some patients. Deiodinases (DIOs) are selenoproteins (enzymes) involved in the synthesis of thyroid hormones. It has been found that these molecules are involved in inflammatory processes. We carried out this preliminary study to investigate the levels of two deiodinases, i.e. type 1 deiodinase (DIO1) and type 3 deiodinase (DIO3), and their possible association with COPD and specific clinical parameters. Patients and methods: Serum levels of DIO1 and DIO3 as well as lung function parameters were measured in 50 patients suffering from COPD and 30 healthy control subjects. The Mann-Whitney U test and Pearson's correlation coefficient were used to compare and correlate data. Results: Serum levels of DIO1 and DIO3 were significantly elevated in COPD patients (97.9 +/- 55.6 versus 28.2 +/- 28.3 U/L for DIO1 and 19.6 +/- 10.7 versus 6.4 +/- 6.3 U/L for DIO3; p < 0.001). No correlation between serum levels of the examined DIOs and other sociodemographic and clinical parameters was identified in this study. Conclusion: For the first time we observed that peripheral DIO1 and DIO3 concentrations were elevated in COPD; hence, we may cautiously begin considering these molecules as potential circulating biomarkers of COPD. It may also be beneficial to conduct further studies to confirm and clarify their potential role.

BACKGROUND:Thyroid hormones (TH) are involved in modulation of the immune system and inflammation. TH dysregulation is associated with depressive disorders. The iodothyronine deiodinases (DIOs), the key enzymes for TH synthesis, can be affected and induced by pro-inflammatory cytokines. We aimed to investigate the levels of and correlation between type 2 DIO (DIO2) and interferon-gamma (IFN-ɣ) in patients with recurrent depressive disorders (rDD).METHODS:Data from 91 rDD patients and 105 healthy controls were analyzed. The diagnoses are based on the ICD-10 criteria (F33.0-F33.8). Expression levels of DIO2 and IFN-ɣ were estimated using the method based on the polymerase chain reaction and the enzyme-linked immunosorbent assay (ELISA).RESULTS:The DIO2 expression on mRNA/protein levels in rDD patients (both female and males) was reduced as compared with the control subjects. No correlation between DIO2 and IFN-ɣ expression was observed.CONCLUSION:This is the first study to reveal that one may cautiously suggest that DIO2 may be involved in the development and/or progression of rDD. The mechanisms of TH regulation on depression, however, need further investigation.

A depressive disorder is a disease characterized by a heterogenous background. The important processes observed and diagnosed in depressed patients indicate that the etiology of depression may include disturbances in thyroid hormone (TH) levels and the occurrence of immune-inflammatory activation. Type 1 (DIO1) and type 3 (DIO3) iodothyronine deiodinases are the enzymes which determine the peripheral and tissue levels of TH, but also interfere with immunological cells and inflammatory processes. We aimed to investigate the levels of DIO1 and DIO3 in the patients suffering from recurrent depressive disorders (rDD). Data collected from 91 rDD patients and 105 healthy controls were analyzed. The diagnoses were made based on the ICD-10 criteria (F33.0-F33.8). The expression levels of DIO1 and DIO3 were estimated using the polymerase chain reaction method and the enzyme-linked immunosorbent assay (ELISA). The expression of DIO1 on mRNA/protein levels in the rDD patients was reduced in comparison to the control subjects, while the expression of DIO3 was higher in the patients suffering from depression. No significant relationship was found between the investigated DIOs and other clinical parameters. Our results indicate and suggest a role of DIO1 and DIO3-related pathways in the pathophysiology of depression. The results represent a promising way to investigate the biological markers of depression.

Neuroinflammation is a known factor in the pathogenesis of recurrent depressive disorders. Depression is accompanied by activated immune-inflammatory pathways including increased levels of TNFα, sTNFR1and sTNFR2.The purpose of this study was to analyse the TNF-α, TNFRSF1A and TNFRSF1B genes on both mRNA and protein levels in patients with rDD, and to investigate the relationship between TNF-α,TNFRSF1A and TNFRSF1B gene expression and cognitive performance. The study comprised 158 subjects: patients with recurrent depressive disorder (n=89) and healthy subjects (n=69). Cognitive function assessment was based on: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. Both mRNA and protein expression levels of all genes were significantly higher in rDD subjects when compared to healthy controls. No statistically significant correlations were observed between the analysed variables in both the rDD group and the HS test group. The only exception was noticed in the HS test group, where increased expression of TNFRSF1A and TNFRSF1B gene negatively affected the performance of the AVLT test. However, statistically significant correlations between TNF, TNFRSF1A, TNFRSF1B mRNA gene expression levels and all the neuropsychological tests used in the survey for the entire group were observed.CONCLUSIONS:1.The results of our study show increased expression of the TNF, TNFRSF1A and TNFRSF1B genes on both mRNA and protein levels in depression. 2. Elevated expression of TNF-α, TNFRSF1A and TNFRSF1B negatively correlates with cognitive efficiency: working memory, executive functions, attention, auditory-verbal memory, effectiveness of learning processes and verbal fluency.

BACKGROUND:Depressive disorder is characterized by disturbances in the hypothalamic-pituitary-thyroid (HPT) axis and in the metabolism of thyroid hormones (TH). The evidence for changes in TH levels is observed in human sera and cerebrospinal fluid as well as in animal model studies. Iodothyronine deiodinases (DIOs) type 1, 2 and 3 (DIO1, DIO2, DIO3) are important enzymes for the synthesis and determination of TH concentration. This study aims to examine the link between recurrent depressive disorders (rDD) and two functionally known polymorphisms DIO1a-C/T (rs11206244) and DIO1b-A/G (rs12095080) within the DIO1 gene encoding DIO1 and two polymorphisms DIO3-C/T (rs17716499), DIO3-A/C (rs7150269) within the DIO3 gene encoding DIO3.METHODS:Both variants were genotyped in 254 rDD patients and 197 healthy subjects using polymerase chain reaction. Basic methods and statistical analyses were used to estimate genetic variants in the risk of the disease.RESULTS:No significant associations were found between the polymorphisms examined here and rDD. There were no significant associations between genotypes distribution and demographic/medical variables. Odds ratios (ORdis) and corresponding 95% confidence interval (95% CI) were calculated, for example: for CC genotype of DIO1a C/T (ORdis=0.86, 95% CI: 0.59, 1.25).CONCLUSION:Functional variants within the DIO1 gene, which affect TH levels and polymorphisms in DIO3, are not confirmed to be associated with rDD. Nevertheless, considering previous data which indicate that the DIO1 gene is related to the depression, further studies on a larger sample size are recommended.

Purpose: Significant impairment of some psychological functions, including cognitive functioning, has been characteristically found in depressed patients. Memory disturbances may be related to the levels of thyroid hormones (TH) that are under the influence of different mechanisms and molecules, including deiodinase type 1(D1) - an important determinant of circulating triiodothyronine (T3). We investigated the relationship between two functionally known polymorphisms within the DIO1 gene, i.e. DIO1a-C/T and DIO1b-A/G, and cognitive functioning in patients diagnosed with recurrent depressive disorder (rDD). In the planned analysis we mainly concentrated on the frontal function: working memory, executive functions and verbal fluency.Materials and methods: Genetic variants were genotyped in 128 patients using a method based on polymerase chain reaction (PCR). Cognitive functions were assessed by the Trail Making Test, the Stroop Test and the Verbal Fluency Test (VFT).Results: No significant associations were found between DIO1 polymorphisms and cognitive functioning in rDD. Only the CT and TT genotypes of the DIO1a variant were significantly related to verbal fluency. There were no significant differences between the distribution of the genotypes and demographic/medical variables.Conclusions: Based on the study, the examined polymorphisms are not an important risk or protective factor for cognitive impairment in depressive patients. Functional variants within the DIO1 gene that affect triiodothyronine (T3) levels seem not to be associated with cognitive functions. Nevertheless, considering the fact that the DIO1 gene is related to the course and management of depression, further studies on a larger sample size might be suggested. (C) 2016 Medical University of Bialystok. Published by Elsevier Sp. z o.o. All rights reserved.

Depressive disorders are increasingly more often linked with social cognition deficits, mainly in the scope of detecting subtle nonverbal signals. These skills are particularly important because of the fact that adequate identification of nonverbal emotional expression is a fundamental condition for effective interpersonal communication. The aim of this study is to evaluate expression on the mRNA level for the human neuropsin gene (hNP) in the group of patients with diagnosed depression, treated for the first time and treated for many years due to recurrent episodes of the disease.

Genetic factors may play a role in the etiology of depressive disorder. The type 2 iodothyronine deiodinase gene (DIO2) encoding the enzyme catalyzing the conversion of T4 to T3 is suggested to play a role in the recurrent depressive disorder (rDD). The current study investigates whether a specific single nucleotide polymorphism (SNP) of the DIO2 gene, Thr92Ala (T/C); rs 225014 or ORFa-Gly3Asp (C/T); rs 12885300, correlate with the risk for recurrent depression. Genotypes for these two single nucleotide polymorphisms (SNPs) were determined in 179 patients meeting the ICD-10 criteria for rDD group and in 152 healthy individuals (control group) using a polymerase chain reaction (PCR) based method. The specific variant of the DIO2 gene, namely the CC genotype of the Thr92Ala polymorphism, was more frequently found in healthy subjects than in patients with depression, what suggests that it could potentially serve as a marker of a lower risk for recurrent depressive disorder. The distribution of four haplotypes was also significantly different between the two study groups with the TC (Thr-Gly) haplotype more frequently detected in patients with depression. In conclusion, data generated from this study suggest for the first time that DIO2 gene may play a role in the etiology of the disease, and thus should be further investigated.

OBJECTIVES Deterioration of the working memory is regarded as one of the most important deficits in a number of somatic diseases. The purpose of the present study was to compare the effectiveness of working memory in 4 groups of patients: 1) diagnosed with recurrent depressive disorder (rDD), 2) with diabetes type 1 (DM1), 3) with diabetes type 2 (DM2), 4) with arterial hypertension (HA) and in healthy controls (HC). METHODS The study comprised 300 subjects: rDD (n=99), DM1 (n=31), DM2 (n=31), HA (n=30) and HC (n=109).Cognitive function assessment was based on Trail Making Test (TMT) and the Stroop test. RESULTS Analysis of variance (ANOVA) indicated statistically significant differences of the mean values among particular groups for each of the analysed results of the Stroop Test and TMT (p<0.0001). Patients with DM1 performed better in both TMT and Stroop tests, when compared to those diagnosed with HA. Patients with HA obtained better results than patients with DM2. Patients with rDD performed significantly worse than those with DM1 in both parts of TMT (A/time: p=0.022, B/time: p<0.001) and in the Stroop test (RCNb/time: p<0.001; NCWd/time: p=0.001; NCWd/errors: p=0.443). They also obtained worse results than patients with DM2 and HA, however, the differences were not statistically significant. CONCLUSIONS 1) Our study has confirmed previous results showing association between depressive disorder and cognitive impairment. 2) Patients with rDD had worse performance on working memory tasks than the patients with DM type 1, DM type 2 and HA. 3) Further investigation is needed to clarify the role of inflammatory and oxidative and nitrosative stress (O&NS) processes in neurocognitive dysfunctions occurring in recurrent depression and somatic disease.

BACKGROUND: Depressive disorders are multifactorial diseases in which cognitive impairments are one of typical features. Thiol protein groups (TPGs) are elements of chemical structure of compounds having antioxidative properties (glutathione peroxidase, metallothioneins) and their oxidation reflects the lost of compensatory capacity of antioxidative mechanisms. The purpose of this study was to determine the level of TPGs in patients with recurrent depressive disorder (rDD) and to define relationship between plasma levels of TPGs and the cognitive performance.MATERIAL AND METHODS: The study comprised 76 subjects: patients with rDD (n=43) and healthy subjects (comparison group, CG - n=33). Cognitive function assessment was based on the following 4 tests: the Trail Making Test (TMT), the Stroop Test, Verbal Fluency Test (VFT) and Auditory Verbal Learning Test (AVLT).RESULTS: The level of TPGs was higher in patients with rDD. In rDD group, the elevated concentration of TPGs in plasma was associated with a decrease in efficiency of declarative-memory, working memory and verbal fluency. The higher was the concentration of plasma TPGs, the greater was the severity of depressive symptoms measured by 21-item Hamilton Depression Rating Scale (HDRS), before and after pharmacotherapy. In CG group, the elevated TPGs levels were associated with worse cognitive test performance (AVLT and VFT tests).CONCLUSIONS: 1) Our study confirms previous results showing increased TPGs level in depression. 2) Our data suggest relation between increased plasma TPGs level in depression and cognitive impairment. 3) The elevated levels of plasma TPGs are related to impairment of the short-term and delayed declarative memory, verbal fluency and working memory.

Recurrent depressive disorder (rDD) is a multifactorial disease. Vascular endothelial growth factor (VEGF) is one of the factors that have been suggested to play a role in the etiology and/or development of this disease. Limited information related to the role of VEGFA gene polymorphism in depressive disorder is available. The aim of the study was to analyze the association between VEGFA gene polymorphisms (+405G/C; rs2010963, +936C/T; rs 3025039), VEGFA gene expression, and its serum protein levels in rDD in the Caucasian population. In the current study, 268 patients and 200 healthy controls of the Caucasian origin were involved. Genotyping and gene expression were performed using polymerase chain reaction (PCR)-based methods. Enzyme-linked immunosorbent assay (ELISA) was used for detection of circulating serum VEGF levels. The distribution of VEGFA polymorphism +405G/C differed significantly between rDD patients and healthy subjects. The results of this study indicated that the C allele and CC genotype of VEGFA are risk factors for rDD. Haplotypes CC and TG are the important factors for depression development. Further, VEGFA mRNA expression and VEGF levels were higher in rDD patients than in controls. The VEGFA gene polymorphism may serve as a prognostic factor for rDD development. Our study showed higher levels of both VEGFA mRNA in the peripheral blood cells and serum VEGF in patients diagnosed with rDD than in healthy controls. The obtained results suggest VEGF and the gene encoding the molecule play a role in the etiology of the disease and should be further investigated.

Depressive disorder is a disease characterized by disturbances in the hypothalamo-pituitary-adrenal axis. Abnormalities include the increased level of glucocorticoids (GC) and changes in sensitivity to these hormones. The changes are related to glucocorticoid receptors gene (NR3C1) variants. The NR3C1 gene is suggested to be a candidate gene affecting depressive disorder risk and management. The aim of this study was to investigate polymorphisms within the NR3C1 gene and their role in the susceptibility to recurrent depressive disorder (rDD). 181 depressive patients and 149 healthy ethnically matched controls were included in the study. Single nucleotide polymorphisms were assessed using polymerase chain reaction/restriction fragment length polymorphism method. Statistical significance between rDD patients and controls was observed for the allele and genotype frequencies at three loci: BclI, N363S, and ER22/23EK. The presence of C allele, CC, and GC genotype of BclI polymorphism, G allele and GA genotype for N363S and ER22/23EK variants respectively were associated with increased rDD risk. Two haplotypes indicated higher susceptibility for rDD, while haplotype GAG played a protective role with OR(dis) 0.29 [95 % confidence interval (CI) = 0.13-0.64]. Data generated from this study support the earlier results that genetic variants of the NR3C1 gene are associated with rDD and suggest further consideration on the possible involvement of these variants in etiology of the disease.

Background: There is evidence that inflammation, oxidative and nitrosative stress (IO&NS) play a role in the pathophysiology of depression. There are also data indicating altered inflammatory gene expression in depressive disorder and that genetic variants of IO&NS genes are associated with increased risk of the disease in question. The aim of this study was to explore mRNA expression of four IO&NS genes PTGS2, MPO, NOS2A, and PLA2G2A coding respectively: cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and secretory phospholipase A2 type IIA (sPLA2-IIA).Method: Expression of the mRNA was determined using quantitative real-time PCR, in peripheral blood cells of patients with recurrent depressive disorder (rDD) and normal controls.Results: The mRNA expressions of the genes encoding for COX-2, MPO, iNOS and sPLA2-IIA were significantly increased in the peripheral blood cells of depressed patients versus controls. Limitations: Patients were treated with antidepressants.Conclusion: Our results indicate and may confirm the role of peripheral IO&NS pathways in the pathophysiology of depression. The results represent a promising way to investigate biological markers of depression. (C) 2012 Elsevier B.V. All rights reserved.

Recent research findings suggest that vascular endothelial growth factor (VEGF) participates in the development of depressive disorder. VEGF is involved in neurogenesis and neuroprotection processes, mediated by vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 also plays a role in angiogenesis, a process related to neurogenesis and other biological processes. We examined VEGFR2 (KDR) gene polymorphism, mRNA expression levels, as well as VEGFR2 protein levels in 268 patients diagnosed with a recurrent depressive disorder (rDD) using the ICD-10 criteria, and in 200 healthy controls. Genotyping and gene expression level analysis was performed using polymerase chain reaction (PCR)-based methods. An Enzyme-Linked Immunosorbent Assay (ELISA) was used for measurement of KDR protein levels. Our study found that distribution of KDR polymorphism +1416T/A differs significantly in patients with rDD when compared to healthy subjects, while A allele and AA genotype are risk factors for rDD. KDR mRNA and protein expression are higher in patients with rDD. We also observed a significant association between the -271A/G variant and gene and protein levels. Our study is the first to demonstrate that the KDR gene may serve as a novel genetic marker that could participate in the etiology of rDD. This new pathway may play a role in the inflammatory pathophysiology of depression.

Polymorphisms (rs 4753426 and rs 794837) and expression of the melatonin MT(2) receptor gene were evaluated in 181 patients with recurrent depressive disorder (rDD) and 149 healthy subjects of Polish origin. We found an increased risk for rDD in patients with the C allele and a decreased risk in patients with the T allele (rs4753426). Patients with the AT heterozygote (rs794837) had an increased mRNA level. The significance of the MT(2) receptor gene and the risk of rDD are suggested.

Background COX-2 is an enzyme isoform that catalyses the formation of prostanoids from arachidonic acid. An increased COX-2 gene expression is believed to participate in carcinogenesis. Recent studies have shown that COX-2 up-regulation is associated with the development of numerous neoplasms, including skin, colorectal, breast, lung, stomach, pancreas and liver cancers. COX-2 products stimulate endothelial cell proliferation and their overexpression has been demonstrated to be involved in the mechanism of decreased resistance to apoptosis. Suppressed angiogenesis was found in experimental animal studies as a consequence of null mutation of COX-2 gene in mice. Despite the role of COX-2 expression remains a subject of numerous studies, its participation in carcinogenesis or the thyroid cancer progression remains unclear. Methods Twenty three (23) patients with cytological diagnosis of PTC were evaluated. After FNAB examination, the needle was washed out with a lysis buffer and the obtained material was used for COX-2 expression estimation. Total RNA was isolated (RNeasy Micro Kit), and RT reactions were performed. β-actin was used as endogenous control. Relative COX-2 expression was assessed in real-time PCR reactions by an ABI PRISM 7500 Sequence Detection System, using the ΔΔC T method. Results COX-2 gene expression was higher in patients with PTC, when compared to specimens from patients with non-toxic nodular goitre (NTG). Conclusions The preliminary results may indicate COX-2 role in thyroid cancer pathogenesis, however the observed variability in results among particular subjects requires additional clinical data and tumor progression analysis.

Depressive disorder (DD) is characterised by disturbances in blood melatonin concentration. It is well known that melatonin is involved in the control of circadian rhythms, sleep included. The use of melatonin and its analogues has been found to be effective in depression therapy. Melatonin synthesis is a multistage process, where the last stage is catalysed by acetylserotonin methyltransferase (ASMT), the reported rate-limiting melatonin synthesis enzyme. Taking into account the significance of genetic factors in depression development, the gene for ASMT may become an interesting focus for studies in patients with recurrent DD. The goal of the study was to evaluate two single-nucleotide polymorphisms (SNPs) (rs4446909; rs5989681) of the ASMT gene, as well as mRNA expression for ASMT in recurrent DD-affected patients. We genotyped two polymorphisms in a group of 181 recurrent DD patients and in 149 control subjects. The study was performed using the polymerase chain reaction/restriction fragment length polymorphism method. The distribution of genotypes in both studied SNPs in the ASMT gene differed significantly between DD and healthy subjects. The presence of AA genotype of rs4446909 polymorphism and of GG genotype of rs5989681 polymorphism was associated with lower risk for having recurrent DD. In turn, patients with depression were characterised by reduced mRNA expression for ASMT. In addition, ASMT transcript level in both recurrent DD patients and in healthy subjects depended significantly on genotype distributions in both polymorphisms. In conclusion, our results suggest the ASMT gene as a susceptibility gene for recurrent DD.

Evidence indicates that depressive disorder is a heterogenic disease, and oxidative stress, inflammation and impairment of neurogenesis play a role in its aetiology. Moreover, there are data suggesting that genetic factors affect the development of depression. Nitric oxide (NO) is a biological molecule with both a beneficial and a detrimental role in brain. One of the three enzymes generating NO is inducible nitric oxide synthase (iNOS). Recent studies have shown that depressed patients are characterised by excessive NO production. In addition, iNOS inhibitors are effective in depression treatment. This study investigated the importance of a functional single nucleotide polymorphism (SNP), -1026C/A, located in the promoter region of the human NOS2A gene, for the risk of recurrent depressive disorder (RDD) vulnerability. The study was carried out in a group of 181 patients with RDD and 149 ethnically matched controls. Genotyping was performed by direct sequencing of the polymerase chain reaction (PCR) products. The genotype distribution of the -1026C/A polymorphism between depressed patients and healthy controls was significantly different. Individuals who were homozygous for the CC genotype exhibited an increased risk of developing RDD. In conclusion we cautiously conclude that polymorphism in the NOS2A gene promoter may play a role in the background of RDD.

Background: Major depression is characterised by increased nitric oxide (NO) levels. Inhibition of the NO synthesizing enzymes, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), results in antidepressant-like effects, whereas the expression of iNOS and nNOS is increased in depression. Recent studies have indicated that NOS participates in the mechanisms of antidepressants.The aim of this study was to examine whether a single nucleotide polymorphism (SNP) present in the genes encoding iNOS and nNOS can contribute to the risk of developing recurrent depressive disorder (rDD).Methods: The study was carried out in a group of 181 depressive patients and 149 control subjects of Polish origin. SNPs were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses.Results: The genotype distributions of the polymorphisms in exon 22 of the NOS2A gene and in exon 29 of the nNOS gene were significantly different between rDD patients and controls. The results showed that the G/A SNP of the gene encoding iNOS was associated with an increased susceptibility to rDD, whereas A/A homozygous carriers had a decreased risk of developing rDD. There was also a significant association between the C/T SNP of the gene encoding nNOS; the presence of the CC homozygous genotype decreased the risk of rDD, whereas the T allele and T/T homozygous genotype increased the vulnerability to rDD.Conclusions: Our results suggest that polymorphisms in the iNOS and nNOS genes confer an increased susceptibility or resistance to rDD. Future research should examine genetic variants and their associations to the expression of NOSs and NO level in depressive patients. (C) 2010 Elsevier B.V. All rights reserved.