In-vivo repeatability of three intra-oral spectrophotometers.

OBJECTIVE: The objective was to assess the repeatability of three spectrophotometers, based on the CIELCh factors and shadeguide reference measurements. MATERIALS AND METHODS: Color analysis was performed using three devices: Rayplicker, Easyshade 4, and Easyshade V. Five repeated measures were performed by the same operator, on the right central maxillary incisor of 30 patients. The CIELCh factors were retrieved and the intra-class correlation was calculated. The Vita Classical and Vita 3D Master shadeguides were used to evaluate the respective Fleiss' Kappa factors. RESULTS: Rayplicker and Easyshade V demonstrated strong intra-class correlation based on the CIELCh factors: 0.98, 0.99, and 0.91 for Rayplicker, and 0.95, 0.99, and 0.93 for Easyshade V, for the L*, C*, and h* parameters, respectively. Regarding the repeatability of the shadeguide data, while Easyshade 4 had the best repeatability when using the Vita Classical as a reference, Rayplicker and Easyshade V showed better repeatability when using the Vita 3D Master. CONCLUSION: These findings suggest that both Rayplicker and Easyshade V are reliable devices for measuring CIELCh parameters. In terms of shadeguide references, the reliability of spectrophotometers is generally lower compared to the CIELCh measurements. CLINICAL SIGNIFICANCE: Given their good repeatability, both the Rayplicker and the Easyshade V spectrophotometers are reliable tools for prosthetic dental practices.

Operator versus material influence on film thickness using adhesive resin cement or pre-heated resin composite.

OBJECTIVE: There is a growing interest in using pre-heated composites instead of dual-cured cements when luting indirect restorations. This study evaluated the film thickness obtained from two pre-heated composites and two resin cements, by two different operators. The influence of the materials and the level of expertise of the operator were analyzed. MATERIALS AND METHODS: Forty specimens of human dentin and composite discs were prepared and divided into four groups depending on the luting process. Each group was randomly equally divided to be handled by two operators with different levels of experience. Two of the initial four groups were luted using dual-cured cements and the two remaining groups using light-cured pre-heated composites. Specimen discs were cut after luting, and film thickness was measured using a Digital microscope. Data were analyzed using a 2-way ANOVA with the Holm-Sidak pairwise multiple comparison procedure (p < 0.05). RESULTS: Mean film thickness ranged from 156.16 ± 4.7 to 33.82 ± 0.7 µm. Significant differences (p < 0.001) were noticed between expert and novice results with pre-heated composites. CONCLUSION: Within the limits of this study, using pre-heated composites as a luting cement requires a better level of expertise to achieve a clinically acceptable film thickness. CLINICAL SIGNIFICANCE: Using pre-heated composites as luting agent for indirect restorations requires an experimented skill level to achieve a clinically recommended film thickness.

Effects of DRD2 splicing-regulatory polymorphism and DRD4 48 bp VNTR on crack cocaine addiction.

There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2-DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of DRD2 rs2283265 and DRD4 48 bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the DRD2 T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of DRD2-T allele and concomitant absence of DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of DRD2 and DRD4 variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2-DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2-DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.

Association between the Intron 8 VNTR Polymorphism of the DAT1 Gene and Crack Cocaine Addiction.

BACKGROUND: This study aims to compare allele and genotype frequencies of a 30-bp variable number of tandem repeats (VNTR) polymorphism of the DAT1 gene, located at intron 8, between adult crack cocaine users and nonaddicted individuals. Due to its involvement in drug addiction, this gene is a good candidate for molecular studies. METHODS: A cross-sectional sample of 239 current adult crack abusers or dependents from in- and outpatient clinics and 211 control individuals was collected in Brazil. They were evaluated using ASRS, ASI-6, WAIS-III, and MINI assessments. DNA samples extracted from whole blood were genotyped for the intron 8 VNTR in DAT1. RESULTS: Logistic regression analysis was performed and controlled for gender, age, ethnicity, educational level, and comorbidities of clinical interest (generalized anxiety disorder, suicide risk, major depressive episode, and attention deficit/hyperactivity disorder). This analysis showed that the 6R6R genotype was associated with crack cocaine addiction (OR = 1.844; CI = 1.101-3.089; p = 0.020). CONCLUSIONS: Our results are consistent with the role of DAT1 in the neurobiology of drug addiction. Nevertheless, the study of other genes, environmental factors, and their interactions is also important to gain a broader understanding of this condition.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene.

Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Crack cocaine users show differences in genotype frequencies of the 3' UTR variable number of tandem repeats of the dopamine transporter gene (DAT1/SLC6A3).

BACKGROUND: Due to the mechanism of action of the dopamine transporter (DAT) in drug addiction, the DAT1 gene is a potential candidate for molecular studies. This paper aims to compare the prevalence of allele and genotype frequencies created by the 3' UTR variable number of tandem repeats (VNTR) of this gene between crack cocaine users and controls. METHODS: A cross-sectional sample of 237 current adult crack cocaine abusers or dependents (DSM-IV TR criteria) from in- and outpatient clinics in southern Brazil and 205 community controls were compared. The subjects were evaluated using the Adult ADHD Self-Report Scale, the Mini-International Neuropsychiatric Interview - short version, and the Wechsler Intelligence Scale. DNA samples were genotyped for the DAT1 3' VNTR. RESULTS: Logistic regression analysis was performed to compare the frequency of the 10.10 genotype (the putative risk genotype) to those of other genotypes. A significant difference (p = 0.04, OR = 1.758, CI = 1.026-3.012) indicating an increased frequency of the 10.10 genotype in the cases (59.9%) compared to the controls (49.3%) was verified using clinical and demographic covariates. CONCLUSIONS: This is one of the first genetic association studies on crack cocaine users in the literature. The results suggest an influence of the DAT1 gene, namely the 3' VNTR 10.10 genotype. However, more analyses will confirm and clarify its contribution as a possible risk factor for crack cocaine dependence.

Exploring potential impacts of pregnancy-related maternal immune activation and extracellular vesicles on immune alterations observed in autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders usually observed in early life, with impacts on behavioral and social skills. Incidence of ASD has been dramatically increasing worldwide, possibly due to increase in awareness/diagnosis as well as to genetic and environmental triggers. Currently, it is estimated that ∼1% of the world population presents ASD symptoms. In addition to its genetic background, environmental and immune-related factors also influence the ASD etiology. In this context, maternal immune activation (MIA) has recently been suggested as a component potentially involved in ASD development. In addition, extracellular vesicles (EVs) are abundant at the maternal-fetal interface and are actively involved in the immunoregulation required for a healthy pregnancy. Considering that alterations in concentration and content of EVs have also been associated with ASD, this article raises a debate about the potential roles of EVs in the processes surrounding MIA. This represents the major differential of the present review compared to other ASD studies. To support the suggested correlations and hypotheses, findings regarding the roles of EVs during pregnancy and potential influences on ASD are discussed, along with a review and update concerning the participation of infections, cytokine unbalances, overweight and obesity, maternal anti-fetal brain antibodies, maternal fever, gestational diabetes, preeclampsia, labor type and microbiota unbalances in MIA and ASD.

Association between NKG2/KLR gene variants and epilepsy in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders mainly characterized by repetitive, restrictive and stereotypical behaviors, and impaired communication skills. Several lines of evidence indicate that alterations of the immune system account for ASD development, including the presence of brain-reactive antibodies, abnormal T cell activation, altered cytokine levels in brain, cerebrospinal fluid and peripheral blood circulation, increased levels of circulating monocytes, and dysregulation in Natural Killer (NK) cells activity. Regarding NK cells, a lower cytotoxic activity, a higher level of activation and an increased number of these cells in individuals with ASD have been described. In 2019, a study showed that NK cells derived from patients with ASD show a characteristic pattern of NKG2C overexpression, highlighting the importance of the NK cell pathway in ASD. In fact, the study of genes related to NK cell activity has proven to be an excellent research target, both in terms of susceptibility as well as a marker for the different clinical manifestations observed in ASD individuals. Here, we evaluated the influence of KLRC2 gene deletion as well as KLRK1 rs1049174 and rs2255336 variants in a cohort of 185 children diagnosed with ASD and their respective biological parents in southern Brazil. Of note, this is the first study concerning genetic variants of the KLRC2 and KLRK1 genes in an ASD sample. The KLRC2 gene deletion (p = 0.001; pc = 0.009), KLRK1 rs1049174 (p = 0.005; pc = 0.045) and KLRK1 rs2255336 (p = 0.001; pc = 0.009) were associated with epilepsy in ASD patients. The results indicate that KLRC2 deletion, KLRK1 rs2255336, and KLRK1 rs1049174 could be involved in epilepsy manifestation in ASD patients, possibly impacting the NK dysregulation already described in ASD and epileptic patients.

HLA-G*14 bp indel variant in autism spectrum disorder in a population from southern Brazil.

Altered immune response during pregnancy has been associated with ASD susceptibility. HLA-G is expressed by the trophoblast at the maternal/fetal interface and induces allogenic tolerance toward the fetus. A 14-bp insertion in the HLA-G 3'UTR (rs371194629) was associated with reduced levels of HLA-G. We aimed to assess the influence of the HLA-G*14 bp indel variant in ASD susceptibility and symptomatology in a Brazilian admixed sample. The insertion genotype (14 bp+/14 bp+) was firstly associated with hetero aggression, but statistical significance was lost after correction (p = 0.035, pcorrected = 0.35). No association between the HLA-G variant and susceptibility to ASD or differential clinical manifestations were observed.

Cathechol-O-methyltransferase Val(158)Met polymorphism is associated with disruptive behavior disorders among children and adolescents with ADHD.

COMT Val(158)Met polymorphism has been associated with both symptoms of attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBD): that is, oppositional defiant disorder (ODD) and conduct disorder (CD) often comorbid with ADHD. The aim of this study was to test the association between COMT Val(158)Met polymorphism and the presence of DBD in children with ADHD (n = 516). Homozygous Val/Val children showed a higher prevalence of ADHD comorbid with DBD (χ(2) = 5.762; p = 0.016; OR = 1.58; CI(95%) = 1.07-2.35). Our findings replicate previous results and suggest a role for COMT in the etiology of DBD in children and adolescents with ADHD.

The Brazilian contribution to Attention-Deficit/Hyperactivity Disorder molecular genetics in children and adolescents.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric condition of children worldwide. This disorder is defined by a combination of symptoms of inattention and hyperactivity/impulsivity. Diagnosis is based on a sufficient number of symptoms causing impairment in these two domains determining several problems in personal and academic life. Although genetic and environmental factors are important in ADHD etiology, how these factors influence the brain and consequently behavior is still under debate. It seems to be consensus that a frontosubcortical dysfunction is responsible, at least in part, for the ADHD phenotype spectrum. The main results from association and pharmacogenetic studies performed in Brazil are discussed. The investigations performed so far on ADHD genetics in Brazil and elsewhere are far from conclusive. New plausible biological hypotheses linked to neurotransmission and neurodevelopment, as well as new analytic approaches are needed to fully disclose the genetic component of the disorder.

Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs. METHODS: Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype. RESULTS: The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56). CONCLUSIONS: In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response.

MAOA is associated with methylphenidate improvement of oppositional symptoms in boys with attention deficit hyperactivity disorder.

The monoamine oxidase A (MAOA) gene has been extensively related to aggressive, impulsive and violent behaviours. Previous studies have documented the improvement of oppositional symptoms in attention deficit hyperactivity disorder (ADHD) patients with methylphenidate (MPH). However, the effect of the MAOA gene in response to MPH has not been investigated. A sample of 85 boys from an ADHD outpatient service was genotyped for the MAOA-uVNTR polymorphism. The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale - version IV. The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months of treatment. A significant interaction between the presence of MAOA high-activity genotype and treatment with MPH over time on oppositional scores was detected during the 3 months' treatment (n=85, F2,136=4.83, p=0.009). These results suggest an effect of the MAOA-uVNTR high-activity genotype on the improvement of oppositional symptoms with MPH treatment.

Further evidence for the association between attention deficit/hyperactivity disorder and the serotonin receptor 1B gene.

Several evidences suggested that the serotonin 5-HT1B receptor gene (HRT1B) might be involved in the susceptibility to attention deficit/hyperactivity disorder (ADHD). Prior studies reported excess transmissions of the HRT1B gene 861G allele to affected ADHD children and of a haplotype block containing this variant and two functional promoter SNPs to probands with ADHD-inattentive subtype. However, some investigations did not replicate these findings. Therefore, we tested for biased transmissions of haplotypes derived from the 861G > C, -161A > T, and -261T > G SNPs from parents to 343 families with ADHD children. We also sought to replicate findings from the literature that the association between HTR1B is preferentially with ADHD-Inattentive subtype. Using a transmission disequilibrium test we found evidence for an excess transmission of haplotype. -261G/-161T/861G (P = 0.014) for affected children in the total sample. When the analysis was repeated with 143 families with ADHD-Inattentive subtype no significant associations were observed. Our results provide additional evidence that HRT1B gene may be an important risk factor for the development of ADHD, but this effect seems not to be attributable to inattentive cases.

Analysis of a Protein Network Related to Copy Number Variations in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, with strong genetic influences as evidenced by its high heritability. Submicroscopic variations (ranging from one kilobase to several megabases) in DNA, called copy number variations (CNVs), have been associated with psychiatric diseases, including ASD. We aimed to identify CNVs in children diagnosed with idiopathic ASD. We used microarray-based comparative genomic hybridization analysis to detect the CNVs, and bioinformatic tools to evaluate their pathogenic potential, based on predicted functional aspects. Using combined cytogenetic and bioinformatic tools, we identified an autism network of genes/proteins related to the CNVs. Among the 40 children analyzed, we found 14 potentially pathogenic CNVs, including those previously associated with ASD (located at 16p11.2, 15q11.2, and 7p21 regions). We suggest that the most relevant biological process and functional attributes involve olfactory receptors. The CNV-related autism network comprised 90 proteins and 754 nodes and indicated the family of olfactory receptors as a significant pathway in ASD. Olfactory receptors were previously associated with neurologic diseases, and they are possibly related to cognition. This integrative analysis that combines cytogenetics and bioinformatics is a promising approach to understand complex conditions such as ASD.

22q11.2 deletion syndrome in patients admitted to a cardiac pediatric intensive care unit in Brazil.

The 22q11.2 deletion syndrome (22q11DS) is one of the most recognizable causes of congenital heart defects (CHDs), but the frequency varies in non-selected populations. The purpose of this study was to determine the incidence and clinical features of patients with CHD and 22q11DS admitted to a pediatric cardiology intensive care unit in Brazil. In a prospective study, we evaluated a consecutive series of 207 patients with a CHD following a clinical protocol and cytogenetic analysis by high resolution karyotype and fluorescent in situ hybridization (FISH). 22q11DS was identified in four patients (2%), a frequency similar to studies that evaluated subjects with major CHDs in other countries. Despite this similarity, we believe that the low rate of prenatal identification of CHDs and the limited access of these patients to appropriate diagnosis and care, which occur in our region, could have had an influence on this frequency. It is possible that 22q11DS patients with a severe CHD could have died before having a chance to access a tertiary hospital, leading to an underestimate of its frequency.

Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder.

CONTEXT: Preclinical studies have demonstrated the relevance of adrenergic alpha2A receptor on the attentional process and the mechanism of action of methylphenidate hydrochloride. Several molecular genetic investigations suggest a role for the adrenergic alpha2A receptor gene (ADRA2A) in attention-deficit/hyperactivity disorder (ADHD), especially in the inattentive dimension. However, the effect of ADRA2A in the response to methylphenidate in humans has not been previously investigated, to our knowledge. OBJECTIVE: To evaluate the association between the ADRA2A -1291 C>G polymorphism and the clinical response to methylphenidate treatment in children and adolescents with ADHD. DESIGN: A pharmacogenomic study was undertaken between November 1, 2002, and May 1, 2004, using a nonrandom assignment, quasi-experimental design. SETTING: An ADHD outpatient program at a university hospital in Brazil. Patients One hundred six patients consecutively diagnosed as having ADHD were genotyped for the ADRA2A -1291 C>G polymorphism and were included in the analyses. Intervention Short-acting methylphenidate administered in increasing dosages until no further clinical improvement was detected or until limited adverse effects occurred. MAIN OUTCOME MEASURES: The primary outcome measure was the parent-rated inattentive subscale of the Swanson, Nolan, and Pelham Scale version IV. Secondary outcome measures included the Barkley Side Effect Rating Scale and the parent-rated hyperactivity-impulsivity subscale of the Swanson, Nolan, and Pelham Scale version IV. Scales were applied by child psychiatrists blinded to genotype at baseline and at 1 and 3 months of treatment. RESULTS: A significant interaction effect between the presence of the G allele and treatment with methylphenidate over time on inattentive scores was detected during the 3 months of treatment (n = 106; F(2,198) = 4.30; P = .02). CONCLUSIONS: We documented the effect of the G allele at the ADRA2A -1291 C>G polymorphism on the improvement of inattentive symptoms with methylphenidate treatment in children and adolescents with ADHD. Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylphenidate action.

A common haplotype at the dopamine transporter gene 5' region is associated with attention-deficit/hyperactivity disorder.

The dopamine transporter (DAT) is the major site of methylphenidate action, which is one of the main drugs used to treat attention-deficit/hyperactivity disorder (ADHD). Most association studies with ADHD focused in a VNTR at the 3'-untranslated region of the gene (3'UTR) presenting conflicting results. However, the most common explanation to inconsistent results is variable linkage disequilibrium with an adjacent functional variant, just a few number of DAT1 studies have reported LD structure across the gene. In this study, we screened 16 polymorphisms across the DAT1 gene to understand LD structure in a Brazilian sample of families with ADHD probands and to verify if there were evidence for a biased transmission of alleles and haplotypes from parents to their 243 children with ADHD. In the DSM-IV combined subtype, we observed a preferential transmission of the haplotype A/C/C/C/A derived from five SNPs (rs2550948, rs11564750, rs261759, rs2652511, rs2975223) in 5' region (P corrected = 0.018) and no association with any allele/haplotype at the 3' region of the gene, including the 3' VNTR and the VNTR of intron 8. These results suggest a role for the promoter region in ADHD susceptibility and that allele heterogeneity should be highly considered in DAT1 gene association studies highlighting the importance of this gene in the genetics of the disorder.

Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes.

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by impairments in social behaviors and communication. Oxytocin and its signaling pathway are related to a range of human behaviors, from facial expression recognition to aggressive behaviors, and have been suggested as involved in the etiology of ASD. Our aim was to evaluate the influence of two polymorphisms (rs1042778, rs53576) at the oxytocin receptor gene (OXTR) on ASD diagnosis and on specific ASD-related clinical symptoms (seizures, panic, and aggressive behaviors). We also assessed if these SNPs could be related to changes in OXTR availability and functionality using a bioinformatic approach. The sample was composed by 209 probands with ASD and their biological parents. Family-based approach and logistic regression models were used to investigated the outcomes. We observed that panic and aggressive behaviors were nominally associated with presence of rs1042778 T allele (P = 0.019/Pcorr = 0.114; P = 0.046/Pcorr = 0.276 respectively). Also, in the family-based analysis, a trend towards association with ASD susceptibility was observed for rs1042778 (G allele) (P = 0.066). In a bioinformatic approach, we demonstrated that rs1042778 G allele is determinant for the binding of the transcription factor MAZ, suggesting that when the T allele is present, the absence of MAZ binding might be associated with lower transcription levels of the OXTR gene. The overall findings suggest that the OXTR gene may play a role in ASD diagnosis and some of its clinical phenotypes, supported by previous animal and clinical studies. Further investigations are necessary to replicate our findings and fully understand the effects of the oxytocin pathway on ASD.

Effects of crack cocaine addiction and stress-related genes on peripheral BDNF levels.

This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor 1 (CRHR1), and brain-derived neurotrophic factor (BDNF) genes on susceptibility to crack cocaine addiction and BDNF levels. Crack addicted patients who sought treatment (n = 280) and non-addicted individuals (n = 241) were assessed. Three SNPs in NR3C1 (rs6198, rs41423247, and rs10052957), three in CRHR1 (rs12944712, rs110402, and rs878886), and one in BDNF (rs6265) were genotyped. No significant effect was seen in the case-control analyses. Crack cocaine addicted patients showed significantly lower serum BDNF levels. Significant effects were observed for NR3C1 rs41423247 and rs10052957. These effects were restricted to non-addicted individuals and they were supported by significant gene-by-disease status interactions. For CRHR1, all SNPs were associated with BDNF levels. Although there were significant effects only in the analysis restricted to non-addicted individuals, the lack of significant results in the gene-by-disease status interaction analyses suggest a general effect on BDNF levels. The haplotype analyses presented the same effect seen in the single marker analyses. This study suggests that SNPs in the NR3C1 and CRHR1 genes may influence BDNF levels, but this effect is blunted in the context of crack cocaine addiction. Therefore, our data may be interpreted in light of several studies showing pronounced effects of crack cocaine on BDNF levels. Since peripheral BDNF is a biomarker for several psychiatric phenotypes, our results may be useful in interpreting previous associations between stress-related SNPs, drug addiction, and depression.