Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol

The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.     

MAOA and MAOB polymorphisms and anger-related traits in suicidal participants and controls

MAOA and, to a lesser extent, MAOB polymorphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was composed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring factors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI “anger-out” subscale) in male suicidal patients compared to controls (p < 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale (“anger out”) (p = 0.002). Allele frequencies of the MAOA rs909525 were associated with suicidality (p < 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relationship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted.     

Die Einwilligung in die medizinische Behandlung minderjähriger Patienten und die Neuregelung der Patientenverfügung

Ohne Zusammenfassung     

Impact of left ventricular assist device therapy on the cardiac proteome and metabolome composition in ischemic cardiomyopathy

The changes in the myocardial proteome and metabolome associated with left ventricular assist device (LVAD) therapy in patients with ischemic cardiomyopathy (ICM) are poorly characterized. We investigated the impact of mechanical unloading following LVAD therapy on the myocardial proteome and metabolome. Matched samples of 5 patients’ myocardial tissue, harvested at the time of LVAD implant (“pre-LVAD”) or heart transplant (“post-LVAD”), were studied by quantitative proteomics and metabolomics as well as being probed for T-tubule structure and connexin-43 distribution. Moreover, pre-LVAD proteome profiles of ICM context were bioinformatically compared to pre-LVAD proteome profiles of dilated cardiac myopathy (DCM). More than 2120 proteins were reliably identified and quantified in paired patient samples. LVAD therapy led to proteomic remodeling, including reduced levels of α-1-antichymotrypsin together with an overall decrease of immune response proteins and an increase of proteins involved in membrane biology. Metabolomics highlighted increased glucose and glucose-6-phosphate levels in the left ventricle upon LVAD therapy. Wheat germ agglutinin staining demonstrated improved T-tubule structure. Connexin-43 displayed a trend for more pronounced intercalated disc localization. In comparing pre-LVAD proteome profiles of ICM context with pre-LVAD proteome profiles of dilated cardiac myopathy (DCM), we noticed an overrepresentation in ICM of proteins associated with humoral immune response. Our findings underline an impact of LVAD therapy on left ventricular biology in ICM. The proteomic, metabolomic, and structural alterations described here are typically associated with cardiac recovery. On the molecular level, our findings indicate the possibility of cardiac remodeling under LVAD therapy in ICM.