Childhood maltreatment history and trauma-specific predictors of parenting stress in new fathers.

For new fathers, parenting stress is a risk factor for impaired early parenting and child maltreatment perpetration. Predictors of parenting stress, including fathers' own experiences of trauma, could be useful intervention targets to support new fathers. We aim to examine associations between new fathers' own histories of child maltreatment, and their perinatal mental health, relationships, and parenting stress. We recruited 298 first-time fathers for a survey that measured child maltreatment history, trauma sequelae including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), interpersonal reactivity, substance use, anger expression, coparenting quality, and parenting stress. On the Parenting Stress Index (PSI) (from 36 to 180), bivariate analysis demonstrated that new fathers who experienced child maltreatment (n = 94) had significantly higher parenting stress (x̅ = 85.3, σ = 18.7) than those who did not (n = 204; x̅ = 76.0, σ = 16.6; P < .000). Hierarchical linear regression modeling indicated that a child maltreatment history, PTSD, and MDD were significantly associated with parenting stress. The strongest predictors of parenting stress were coparenting quality and complex trauma sequelae-interpersonal reactivity and anger expression. Interventions to reduce fathers' parenting stress by targeting known mental health and relationship sequelae of maltreatment are promising avenues to breaking intergenerational transmission of child maltreatment and psychiatric vulnerability.

Para nuevos papás, el estrés de crianza es un factor de riesgo para la deficiente crianza temprana y para cometer maltrato infantil. Los factores de predicción del estrés de crianza, incluyendo las propias experiencias de trauma de los papás, pueden ser útiles metas de intervención para apoyar a los nuevos papás. Nos propusimos examinar las asociaciones entre las propias historias de maltrato de los nuevos papás, y su salud mental perinatal, relaciones y estrés de crianza. Reclutamos 298 papás primerizos para una encuesta que medía la historia de maltrato infantil, la secuela de trauma incluyendo el trastorno de estrés postraumático (PTSD), el trastorno depresivo serio (MDD), la reactividad interpersonal, el uso de sustancias, la expresión de ira, la calidad de la crianza compartida, así como el estrés de crianza. En el Índice de Estrés de Crianza (de 36-180), los análisis bivariantes demostraron que los nuevos papás que habían experimentado maltrato infantil (N = 94) tenían significativamente un mayor estrés de crianza (x̅ = 85.3, σ = 18.7) que aquellos que no habían tenido tal experiencia (N = 204; x̅ = 76.0, σ = 16.6; P<.000). El modelo de regresión lineal jerárquica indicó que una historia de maltrato infantil, PTSD y MDD estaban significativamente asociados con el estrés de crianza. Los más fuertes factores de predicción del estrés de crianza fueron la calidad de la crianza compartida y la compleja secuela de trauma-la reactividad interpersonal y la expresión de la ira. Las intervenciones para reducir el estrés de crianza de los papás por medio del enfoque en la salud mental conocida y las secuelas en la relación del maltrato son una vía prometedora para romper la transmisión intergeneracional del maltrato infantil y la vulnerabilidad siquiátrica.

Pour les nouveaux pères le stress de parentage est un facteur de risque pour le parentage précoce compromis et la perpétration de maltraitance de l'enfant. Les prédicteurs de stress de parentage, y compris les propres expériences de trauma des pères, pourraient être des cicles d'intervention utiles afin de soutenir les nouveaux pères. Nous nous sommes donné pour but d'examiner les liens entre le propre passé de maltraitance de l'enfant des nouveaux pères et leur santé mentale périnatale, leurs relations et le stress de parentage. Nous avons recruté 298 nouveaux pères (pères pour la première fois) pour un sondage mesurant l'histoire de la maltraitance de l'enfant, les séquelles de trauma y compris les troubles de stress post-traumatique (TSPT), les troubles dépressifs majeurs (MDD en anglais), la réactivité interpersonnelle, la toxicomanie, l'expression de colère et la qualité du co-parentage ainsi que le stress parental. Pour l'Index de Stress de Parentage (de 36-180), une analyse bivariée a montré que les nouveaux pères qui avaient fait l'expérience de maltraitance de l'enfance (N = 94) avaient un stress de parentage bien plus élevé (x̅ = 85,3, σ = 18,7) que ceux n'en ayant pas fait l'expérience (N = 204; x̅ = 76,0, σ = 16,6; P<,000). Un modèle de régression linéaire hiérarchique a indiqué qu'un passé de maltraitance de l'enfant, le TSPT et le MDD étaient fortement liés au stress de parentage. Les facteurs de prédiction les plus forts de stress de parentage étaient la qualité du co-parentage et les séquelles de trauma complexes - réactivité interpersonnelle et l'expression de la colère. Les interventions pour réduire le stress de parentage des pères en ciblant la santé mentale connue et les séquelles de maltraitance sont un chemin prometteur pour casser la transmission intergénérationnelle de la maltraitance de l'enfant et la vulnérabilité psychiatrique.

Transcriptional analysis of sodium valproate in a serotonergic cell line reveals gene regulation through both HDAC inhibition-dependent and independent mechanisms.

Sodium valproate (VPA) is a histone deacetylase (HDAC) inhibitor, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for this drug are not fully understood. After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression. Analysis by four bioinformatic pipelines revealed as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated. A subset of 23 differentially expressed genes was selected for validation using the nCounter® platform, and of these we obtained robust validation for ADAM23, LSP1, MAOB, MMP13, PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We investigated the effect of lithium on this subset and found four genes, CDKN1C, LSP1, SERPINB2, and WNT6 co-regulated by lithium and VPA. We also explored the effects of other HDAC inhibitors and the VPA analogue valpromide on the subset of 23 selected genes. Expression of eight of these genes, CDKN1C, MAOB, MMP13, NGFR, SHANK3, VGF, WNT6 and ZCCHC12, was modified by HDAC inhibition, whereas others did not appear to respond to several HDAC inhibitors tested. These results suggest VPA may regulate genes through both HDAC-dependent and independent mechanisms. Understanding the broader gene regulatory effects of VPA in this serotonergic cell model should provide insights into how this drug works and whether other HDAC inhibitor compounds may have similar gene regulatory effects, as well as highlighting molecular processes that may underlie regulation of mood.

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BACKGROUND: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder. METHODS: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). DISCUSSION: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .

A multiplex pharmacogenetics assay using the MinION nanopore sequencing device.

OBJECTIVES: The MinION nanopore sequencing device opens the opportunity to cost-effective and point-of-care DNA sequencing. As a proof of principle, we developed a multiplex assay targeting pharmacogenetic variants related to clopidogrel and warfarin, the two commonly used drugs that show response variability due to genetic polymorphisms. METHODS: Six reference and 78 clinical DNA samples were amplified by PCR to generate 15 amplicons targeting 27 key variants. These products were then barcoded to enable sample multiplexing in one sequencing run. Four variant calling tools (marginCaller, VarScan 2, nanopolish, Clairvoyante) were used to compare genotyping accuracy. RESULTS: In our cohort, 81 out of 84 samples were successfully sequenced and genotyped. Using nanopolish as the variant calling tool achieved accuracy >95% for all except two variants. A known single base deletion (CYP2C9*6) was successfully detected. CONCLUSION: While minor misgenotyping issues exist, this work demonstrates that drug-specific or broad pharmacogenetic screening assays using small PCR amplicons are possible on the MinION sequencing device.

Choice of PCR microtube can impact on the success of long-range PCRs.

We compared four brands of microtubes with respect to their suitability for long-range polymerase chain reactions (PCRs). One of the four brands was found to have an inhibitory effect, decreasing PCR yields. The effect was universal across different PCR or enzyme systems. Increased ultraviolet absorbance suggests leaching of unknown chemical species into PCR mixtures. However, this could not be confirmed by high-performance liquid chromatography-mass spectrometry analysis. Nevertheless, our article demonstrates a clear impact of the choice of microtubes on long-range PCR success. Due consideration should be given to the PCR microtubes when determining optimal reaction conditions for long-range PCR.

Novel CYP2D6 and CYP2C19 variants identified in a patient with adverse reactions towards venlafaxine monotherapy and dual therapy with nortriptyline and fluoxetine.

We present a case report of novel variants of CYP2D6 and CYP2C19 identified in a patient who experienced adverse effects during antidepressant therapy. CYP2D6 DNA sequencing revealed that the patient was most likely an intermediate metabolizer, owing to the presence of a novel variant (2579C>T), which gives rise to a premature stop codon in exon 5. Because defects in CYP2C19 may also be important, we sequenced the promoter region and all exons of CYP2C19 and identified a cluster of three novel variants (-13G>A, 7C>T and 10T>C) around exon 1, as well as the more common CYP2C19*2 allele. The presence of multiple genetic lesions in CYP2C19 implies that this patient is potentially a CYP2C19 poor metabolizer, and this was confirmed by haplotype analysis. Combined impairment of CYP2D6 and CYP2C19 activities, we believe, may have contributed to the development of the observed drug responses in the present report.

Opposing roles of membrane and soluble forms of the receptor for advanced glycation end products in primary respiratory syncytial virus infection.

Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.

Omeprazole Treatment Failure in Gastroesophageal Reflux Disease and Genetic Variation at the CYP2C Locus.

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to investigate the association between these genetic variants and omeprazole treatment failure in GERD. We recruited predominantly New Zealand European GERD patients who either did not respond to omeprazole or experienced breakthrough heartburn symptoms despite at least 8 weeks of omeprazole (≥40 mg/day). The GerdQ score was used to gauge symptomatic severity. A total of 55 cases were recruited with a median age (range) of 56 years (19-82) and GerdQ score of 11 (5-17). Of these, 19 (34.5%) were CYP2C19*17 heterozygotes and two (3.6%) were CYP2C19*17 homozygotes. A total of 30 (27.3%) CYP2C:TG haplotypes was identified in our cohort, with seven (12.7%) CYP2C:TG homozygotes, and 16 (29%) CYP2C:TG heterozygotes. No significant differences were observed for overall CYP2C19*17 alleles, CYP2C19*17/*17, overall CYP2C:TG haplotypes, and CYP2C:TG heterozygotes (p > 0.05 for all comparisons). Gastroscopy and 24-h esophageal pH/impedance tests demonstrated objective evidence of GERD in a subgroup of 39 (71%) cases, in which the CYP2C:TG/TG was significantly enriched (p = 0.03) when compared with the haplotype frequencies in a predominantly (91%) New Zealand European reference population, but not the CYP2C19*17/*17 (p > 0.99), when compared with the allele frequencies for the non-Finnish European subset of gnomAD. We conclude that omeprazole treatment failure in GERD is associated with CYP2C:TG/TG, but not CYP2C19*17.

Allelic diversity of the pharmacogene CYP2D6 in New Zealand Maori and Pacific peoples.

The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with many Indigenous and minority populations, such as those from Oceania, greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Maori and Pacific people living in Aotearoa (New Zealand). We carried out long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified twelve variants which have previously not been reported in the PharmVar CYP2D6 database, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining five variants were identified in two samples each. Identified variants formed twelve new CYP2D6 suballeles and four new star alleles, now recorded in the PharmVar database. One striking finding was that CYP2D6*71, an allele of uncertain functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (8.9%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.

Life stress, 5-HTTLPR and mental disorder: findings from a 30-year longitudinal study.

BACKGROUND: Recent meta-analyses have raised concerns about the replicability of gene × environment interactions involving the serotonin transporter gene (5-HTTLPR) in moderating the associations between adverse life events and mental disorders. AIMS: To use data gathered over the course of a 30-year longitudinal study of a New Zealand birth cohort to test the hypothesis that the presence of short ('s') alleles of 5-HTTLPR are associated with an increased response to life stress. METHOD: Participants were 893 individuals from the Christchurch Health and Development Study who had complete data on: the 5-HTTLPR genotype; psychiatric disorders up to the age of 30; and exposure to childhood and adult adverse life events. RESULTS: A series of 104 regression models were fitted to four mental health outcomes (depressive symptoms, major depression, anxiety disorder and suicidal ideation) observed at ages 18, 21, 25 and 30 using 13 measures of life-course stress that spanned childhood and adult stressors. Both multiplicative and additive models were fitted to the data. No evidence was found that would support the hypothesis that 's' alleles of 5-HTTLPR are associated with increased responsivity to life stressors. CONCLUSIONS: The present findings add to the evidence suggesting that it is unlikely that there is a stable gene × environment interaction involving 5-HTTLPR, life stress and mental disorders.

MAOA, abuse exposure and antisocial behaviour: 30-year longitudinal study.

BACKGROUND: Recent studies have raised issues concerning the replicability of gene × environment (G × E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between abuse or maltreatment exposure and antisocial behaviour. This study attempted to replicate the findings in this area using a 30-year longitudinal study that has strong resemblance to the original research cohort. AIMS: To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to abuse exposure. METHOD: Participants were 398 males from the Christchurch Health and Development Study who had complete data on: MAOA promoter region variable number tandem repeat genotype; antisocial behaviour to age 30; and exposure to childhood sexual and physical abuse. RESULTS: Regression models were fitted to five antisocial behaviour outcomes (self-reported property offending; self-reported violent offending; convictions for property/violent offending; conduct problems; hostility) observed from age 16 to 30, using measures of childhood exposure to sexual and physical abuse. The analyses revealed consistent evidence of G × E interactions, with those having the low-activity MAOA variant and who were exposed to abuse in childhood being significantly more likely to report later offending, conduct problems and hostility. These interactions remained statistically significant after control for a range of potentially confounding factors. Findings for convictions data were somewhat weaker. CONCLUSIONS: The present findings add to the evidence suggesting that there is a stable G × E interaction involving MAOA, abuse exposure and antisocial behaviour across the life course.

Generation of a novel system for studying spleen tyrosine kinase function in macrophages and B cells.

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is expressed primarily in hematopoietic cells. Because this protein has been implicated in processes such as Fc-mediated phagocytosis, BCR signaling, oxidative burst, degranulation, cytokine secretion, and integrin-mediated outside-in signaling, it is hypothesized that Syk may be a viable target in the treatment of a variety of autoimmune and inflammatory diseases. Because efforts to design a small-molecule therapeutic that specifically inhibits Syk have been largely unsuccessful, and genetic studies of Syk have been hampered by the fact that syk-/- mice die in utero, we have taken a chemical genetic approach to study the function of Syk. Specifically, we have created a mutant form of Syk that retains its wild-type function, but is susceptible to inhibition by enlarged derivatives of the tyrosine kinase inhibitor, PP1. We report in this study that Syk M442A S505A reconstituted wild-type function when introduced into murine syk-/- bone marrow-derived macrophages and syk-/- DT40 chicken B cells, as determined by functional and biochemical assays. Furthermore, after screening a series of PP1 derivatives, we identified one compound, namely 2,3-DMB-PP1, that specifically inhibited Syk M442A S505A, but not wild-type Syk. This system provides us with the power to characterize immune functions that are Syk specific, and furthermore, it provides us with a tool to assess how inhibition of Syk may alter an immune response and influence disease pathogenesis and/or progression.

Genome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells.

BACKGROUND: Environmental factors, such as oxidative stress, have the potential to modify the epigenetic landscape of cells. We have previously shown that DNA methyltransferase (DNMT) activity can be inhibited by sublethal doses of hydrogen peroxide (H2O2). However, site-specific changes in DNA methylation and the reversibility of any changes have not been explored. Using bead chip array technology, differential methylation was assessed in Jurkat T-lymphoma cells following exposure to H2O2. RESULTS: Sublethal H2O2 exposure was associated with an initial genome-wide decrease in DNA methylation in replicating cells, which was largely corrected 72 h later. However, some alterations were conserved through subsequent cycles of cell division. Significant changes to the variability of DNA methylation were also observed both globally and at the site-specific level. CONCLUSIONS: This research indicates that increased exposure to H2O2 can result in long-term alterations to DNA methylation patterns, providing a mechanism for environmental factors to have prolonged impact on gene expression.

The Three Ps: Psychiatry, Pharmacy, and Pharmacogenomics, a Brief Report From New Zealand.

We describe a case series of 22 individuals who were referred to our laboratory by a pharmacist based in a mental health hospital, for pharmacogenetic analysis due to severe or unexpected adverse drug reactions (ADRs) to psychiatric medication. The participants were genotyped for common variation in the CYP2D6, CYP2C19, and CYP2C9 genes, using Sanger sequencing. We tested variants in these genes as they have the strongest evidence with respect to altering the pharmacokinetics of commonly prescribed psychiatric medicine. Looking specifically at the subset of 18 European study participants, we observed a comparatively high but non-significant rate of pharmacogenetic variants, compared to allele frequency surveys in unselected population samples. For CYP2D6, we observed an elevated frequency of both poor (17%) and intermediate (33%) metabolizers when compared with previously reported frequencies (6% and 12% respectively). For CYP2C19, we observed an increased frequency of intermediate (33%) and ultra-rapid (17%) metabolizers compared to expected frequencies (21% and 4% respectively). For CYP2C9, the frequency of intermediate metabolizers (22%) was elevated compared to the expected population frequency (11%). While sample size is a major limitation of this brief report, we can conclude that patients with adverse reactions to antidepressant or antipsychotic drugs selected by a specialist mental health pharmacist appear to have a relatively high rate of genetic variants in pharmacogenes known to affect the pharmacokinetics of these drugs. The selective application of such pharmacogenetic tests by clinical pharmacists may be a valuable approach to clarify the basis for adverse or unusual responses to medication, and to guide ongoing prescribing decisions for this group of patients.

Nanopore sequencing of the pharmacogene CYP2D6 allows simultaneous haplotyping and detection of duplications.

Aim: Long read sequencing offers the promise of overcoming some of the challenges in accurate genotyping of complex genes, along with the advantage of straightforward variant phasing. We have established methods for sequencing and haplotyping of the whole CYP2D6 gene using nanopore sequencing. Materials and methods: 32 samples covering various haplotypes including gene duplication were sequenced on the GridION platform. Results: Haplotypes of 52 alleles matched accurately to known star (*) allele subvariants, with the remaining 12 being assigned as new alleles, or new subvariants of known alleles. Duplicated alleles could be detected by analyzing the allelic balance. Conclusion: Nanopore sequencing of CYP2D6 offers a high throughput method for accurate haplotyping, detection of new variants and determination of duplicated alleles.

Common CYP2D6, CYP2C9, and CYP2C19 Gene Variants, Health Anxiety, and Neuroticism Are Not Associated With Self-Reported Antidepressant Side Effects.

Many patients prescribed an antidepressant stop taking it because of side effects. Genetic factors and psychological factors including state or trait anxiety, may explain variation in side effect outcomes. Our aim was to examine the relative contribution of genetic and psychological factors in people with self-reported antidepressant side effects. We undertook a case control study (n = 194) of people who took a selective serotonin reuptake inhibitor (SSRI) or serotonin/noradrenaline reuptake inhibitor (SNRI) in the past 2 years, recruited via social media advertising. Cases had previously not tolerated at least one trial of an SSRI or SNRI, evidenced by stopping the drug or reducing the dose by at least 50% because of a side effect. Control participants had taken an SSRI or SNRI but did not meet case criteria. Variation in the genes CYP2D6, CYP2C19, and CYP2C9 was analyzed by Sanger sequencing on DNA extracted from blood or saliva. Participants completed the Short Health Anxiety Inventory-18, K10, and NEO-FFI-3 personality questionnaire. Participants were 87.1% female. 70.8% had a current K10 score of 22 or more. There was no consistent evidence that cases had higher psychological distress, health anxiety, or neuroticism. There was low correspondence between participants' CYP2D6, CYP2C19, and CYP2C9 phenotypes and their history of antidepressant tolerability. For this cohort of patients a history of not tolerating SSRI or SNRI therapy was not associated with variation in the pharmacogenes we tested, nor was it associated with health anxiety or neuroticism.

Contrasting signals of cardiovascular health among natriuretic peptides in subjects without heart disease.

Natriuretic Peptides (NP) are important in maintaining normal cardiac and metabolic status and have been used to predict cardiovascular events. Whether plasma concentrations of NP products within the normal range reflect cardio-metabolic health is unknown. Plasma NTproANP, NTproBNP and NTproCNP and their bioactive counterparts were measured in a random sample of 348 community dwellers aged 49-51 yr without heart disease and associations sought with established vascular risk factors, echocardiographic indices and a genetic variant previously linked with BNP. Stratified by sex, each of ten vascular risk factors were positively associated with NTproCNP whereas associations with NTproBNP and NTproANP were all negative. In both sexes, higher plasma NTproCNP was associated with higher arterial elastance, lower LV stroke volume and lower LV end diastolic volume. Exactly opposite associations were found with plasma NTproBNP or NTproANP. Sex specific differences were identified: positive association of NTproBNP with LV end systolic volume and the negative association with LV elastance were found only in males. The genetic variant rs198358 was independently associated with NTproBNP but not with NTproANP. In conclusion, higher NTproCNP is likely to be an adaptive response to impaired LV relaxation whereas genetic factors likely contribute to higher NTproBNP and improved cardio-metabolic health at midlife.

Tryptophan hydroxylase gene (TPH1) and peripheral tryptophan levels in depression.

BACKGROUND: Genetic variants have been discovered in two genes encoding for tryptophan hydroxylase (TPH)-TPH1 and TPH2. Low tryptophan (TRP) levels are associated with depression and may arise because of stress. Evidence suggests that hypothalamic and peripheral 5HT systems have a significant role in appetite regulation, possibly a homeostatic mechanism in regulating peripheral TRP levels. METHODS: We examined the association between a polymorphism in intron 7 of TPH1, 218A>C and plasma total TRP levels in 118 patients with major depression. RESULTS: There was an interaction between 218A>C and gender in determining plasma TRP whereby presence of the 218C allele, in women, was associated with markedly reduced plasma TRP. LIMITATIONS: The study investigated only the TRP1 gene and did not use a haplotype analysis. The results only apply to a population of subjects suffering from major depression. CONCLUSIONS: TPH1 may be associated with the regulation of peripheral tryptophan levels and therefore availability of tryptophan to the brain. This may have relevance to a range of neuropsychiatric conditions.

An association study of DRD2 and COMT polymorphisms with novelty seeking and harm avoidance scores, in two independent samples of depressed patients.

BACKGROUND: It was recently reported that an interaction of the dopamine D2 receptor (DRD2) and catechol-O-methyltransferase (COMT) influences the behavioural approach system--as measured using Carver and White's Behavioural Inhibition and Behavioural Approach System (BIS/BAS) scales--in a sample of healthy German subjects. The Temperament and Character Inventory (TCI), in particular the novelty seeking (NS) and harm avoidance (HA) scales, correlates moderately with the BIS/BAS measure. This study aimed to examine support for an association of DRD2 and COMT with behavioural activation, using the TCI within two independent samples of depressed outpatients (for both samples n = 146). METHODS: Two clinical samples of depressed patients were ascertained to assess the efficacy of two different pharmacotherapy and psychotherapy treatments. Analysis of variance (ANOVA) was used to analyse NS and HA scale and subscale scores with respect to gene loci within each clinical sample. Analysis of covariance were undertaken to examine the association of age and gender with NS and HA scores. An association of age group or gender with gene loci were explored using chi-squared tests, in each sample. RESULTS: No significant effect of DRD2 or COMT, either independently or as an interaction, on NS or HA scores was observed, within either sample. Whilst age was significantly negatively associated with NS scores, including age in the two- and three-way interactions did not affect the significance of the association of personality with gene loci. CONCLUSION: This study suggests that the COMT-DRD2 Equilibrium Model of Positive Emotionality recently proposed by Reuter and his colleagues is not applicable amongst currently depressed individuals, whose behavioural approach and inhibition tendencies have been assessed using the TCI.