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Michael J Lucht,
Sven Barnow,
Christine Sonnenfeld,
Ines Ulrich,
Hans Joergen Grabe,
Winnie Schroeder,
Henry Völzke,
Harald J Freyberger,
Ulrich John,
Falko H Herrmann,
Heyo Kroemer, Dieter Rosskopf
[show abstract]
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ABSTRACT: Background/aims: The application of intranasal oxytocin enhances facial emotion recognition in normal subjects and in subjects with autism spectrum disorders (ASD). In addition, various features of social cognition have been associated with variants of the oxytocin receptor gene (OXTR). Therefore, we tested for associations between mind-reading, a measure for social recognition and OXTR polymorphisms. Methods: 76 healthy adolescents and young adults were tested for associations between OXTR rs53576, rs2254298, rs2228485 and mind-reading using the "Reading the Mind in the Eyes Test" (RMET). Results: After Bonferroni correction for multiple comparisons, rs2228485 was associated with the number of incorrect answers when subjects evaluated male faces (P =0.000639). There were also associations between OXTR rs53576, rs2254298 and rs2228485 and other RMET dimensions according to P <0.05 (uncorrected). Conclusion: This study adds further evidence to the hypothesis that genetic variations in the OXTR modulate mind-reading and social behaviour.
Nordic journal of psychiatry 07/2012; · 0.99 Impact Factor
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ABSTRACT: Associations between thyroid function and hepatic steatosis defined by enzymatic and sonographic criteria are largely unknown in the general population. Thus, the aim of the present study was to investigate the association between thyroid function tests and sonographic as well as enzymatic criteria of liver status in a large population-based study, the Study of Health in Germany (SHIP).
Data from 3661 SHIP participants without a self-reported history of thyroid or liver disease were analyzed. Hepatic steatosis was defined as the presence of a hyperechogenic ultrasound pattern of the liver and increased serum alanine transferase concentrations. Serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) concentrations were associated with hepatic steatosis using multinomial regression models adjusted for sex, age, physical activity, alcohol consumption, waist circumference, and food intake pattern.
We detected no consistent association of serum TSH and FT3 concentrations with hepatic steatosis. In contrast, serum FT4 concentrations were inversely associated with hepatic steatosis in men (odds ratio (OR)=0.04 [95% confidence interval (CI)=0.01; 0.17]) and women (OR=0.06 [95% CI=0.01; 0.42]).
Results from the present cross-sectional study suggest that low FT4 concentrations are associated with hepatic steatosis. Longitudinal and intervention studies are warranted to investigate whether hypothyroidism increases the risk of hepatic steatosis or vice versa.
Thyroid: official journal of the American Thyroid Association 05/2012; 22(6):568-74. · 2.60 Impact Factor
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[show abstract]
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ABSTRACT: Wir konnten kürzlich einen C825T-Polymorphismus im Gen GNB3 nachweisen, das für die Gβ3-Untereinheit heterotrimerer G-Proteine
kodiert. Das 825T-Allel verusacht ein alternatives Spleißen des Gens und die Expression einer funktionell aktiven Deletionsvariante
von Gβ3, welche als Gβ3s bezeichnet wird. Eine Genotypisierung bezüglich des C825T-Polymorphismus ermöglicht eine Vorhersage
über die Stärke der Aktivierbarkeit von G-Proteinen und nachgeschalteter Zellfunktionen.
Das 825T-Allel ist mit einem erhöhten Risiko für Hypertonie bei Weißen assoziiert, vermutlich mit der sogenannten Form der
„Low-Renin-Hypertension”, und es akkumuliert besonders stark bei Hypertonikern mit einer positiven Familienanamnese. Die höchsten
Frequenzen des 825T-Allels (bis zu 80%) findet man bei Schwarzafrikanern, Afroamerikanern, Buschmännern und bei australischen
Ureinwohnern. Somit könnte eine gesteigerte Aktivierbarkeit von G-Proteinen in Urzeiten ein Überlebensvorteil gewesen sein.
Die Frequenzen des 825T-Allels sind dagegen bei Asiaten (ca. 40 bis 50%) und bei Kaukasiern (30%) deutlich niedriger. Das
825T-Allel ist bei jungen Weißen, Chinesen und Schwarzafrikanern mit einem erhöhten Risiko für Adipositas assoziiert. Somit
ist eine genotypisierung am GNB3-Lokus ideal für die Präventivmedizin geeignet, um Risikopatienten frühzeitig zu identifizieren,
die dann durch Lebensstiländerung dieser genetischen Prädisposition gezielt entgegenwirken können. Bei Grenzwerthypertonie
kann der Nachweis einer genetischen Prädisposition die Entscheidung für eine medikamentöse antihypertensive Therapie begünstigen.
Following a classical candidate gene approach we have detected a C825T polymorphism in the gene GNB3 which encodes the Gβ3
subunit of heterotrimeric G proteins. The 825T allele causes alternative splicing of the gene and the generation of a truncated
but functionally active splice variant of Gβ3 which is referred to as Gβ3s. Thus, genotyping for the C825T polymorphism is
predictive for the activation of certain G proteins in humans.
The 825T allele is significantly associated with an increased risk for hypertension in Caucasians, most likely “low renin
hypertension” and it accumulates significantly in individuals with a strong family history of hypertension. Highest frequencies
of the 825T allele (up to 80%) are found in old ethnicities, e. g. black Africans, African Americans, bushmen, and Australian
aborigines. This suggests that enhanced G protein activation represents a thrifty genotype which might have facilitated survival
in our ancestors. Frequencies of the 825T allele are significant lower in Asians (approximately 40 to 50%) and Caucasians
(20%). More recent studies show that young 825T allele carriers are predisposed for obesity and this association could be
confirmed across different ethnicities including young Germans, as well as Chinese and black African individuals. Thus, genotyping
at the GNB3 locus represents an ideal tool for preventive medicine in that individuals at risk for obesity and hypertension
can be identified early and counteract their genetic predisposition through changes in lifestyle. In individuals with borderline
hypertension genotyping can facilitate the decision for medical treatment as a positive test result confirms an inherited
form of hypertension.
Herz 04/2012; 25(1):26-33. · 0.92 Impact Factor
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Hans Jörgen Grabe,
Christian Schwahn,
Jessie Mahler,
Andrea Schulz,
Carsten Spitzer,
Kristin Fenske,
Katja Appel,
Sven Barnow,
Matthias Nauck,
Georg Schomerus,
Reiner Biffar, Dieter Rosskopf,
Ulrich John,
Henry Völzke,
Harald Jürgen Freyberger
[show abstract]
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ABSTRACT: The impact of the promoter polymorphisms of the serotonin transporter (5-HTTLPR) on mood has been studied by two-way interaction models comprising one environmental factor and genotype variants. However, childhood abuse is assumed to be associated with different psychobiological long-term effects than adult traumatic events. Both types of trauma may interact on an individual basis throughout the lifespan moderating the impact of the 5-HTTLPR s allele on depressive disorders. Therefore, the hypothesis of a three-way interaction among the 5-HTTLPR, childhood abuse and adult traumatic experience was tested. Caucasian subjects (1,974) from the general population in Germany (Study of Health in Pomerania (SHIP)) were analyzed. Depressive symptoms were measured with the Beck Depression Inventory (BDI-II). Childhood abuse was assessed with the Childhood Trauma Questionnaire. Adult traumatic events were derived from the SCID interview (DSM-IV) on posttraumatic stress disorder (PTSD). Global three-way interactions among the 5-HTTLPR, adult traumatic experiences and childhood abuse (P = 0.0007) were found. Carriers of the ss or sl genotypes who had been exposed to childhood abuse and to more than two adult traumatic events had higher mean BDI-II scores (16.0 [95% CI 8.4-23.6]) compared to those carrying the ll genotype (7.6 [4.5-10.7]). These results were supported using a second, more severe definition of childhood abuse (P = 0.02). No two-way interactions were observed (P > 0.05). Childhood abuse and adult traumatic events may act synergistically in interaction with the s allele of the 5-HTTLPR to increase the risk for depressive symptoms independently from the lifetime diagnosis of PTSD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2012; 159B(3):298-309. · 3.70 Impact Factor
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Hans Jörgen Grabe,
Christian Schwahn,
Jessie Mahler,
Katja Appel,
Andrea Schulz,
Carsten Spitzer,
Kristin Fenske,
Sven Barnow,
Harald Jürgen Freyberger,
Alexander Teumer,
Astrid Petersmann,
Reiner Biffar, Dieter Rosskopf,
Ulrich John,
Henry Völzke
[show abstract]
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ABSTRACT: Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene-gene-environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms.
2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms.
Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p=0.02). Emotional abuse carried the main effect of the interaction (p=0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles.
Our results point to a gene-gene-environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2012; 36(2):264-70. · 3.25 Impact Factor
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[show abstract]
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ABSTRACT: Background: Associations between thyroid function and hepatic steatosis defined by enzymatic and sonographic criteria are largely unknown in the general population. Thus, the aim of the present study was to investigate the association between thyroid function tests and sonographic as well as enzymatic criteria of liver status in a large population-based study, the Study of Health in Germany (SHIP). Methods: Data from 3661 SHIP participants without self-reported history thyroid or liver disease were analyzed. Hepatic steatosis was defined as the presence of a hyperechogenic ultrasound pattern of the liver and increased serum alanine transferase concentrations. Serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) concentrations were associated with hepatic steatosis using multinomial regression models adjusted for sex, age, physical activity, alcohol consumption, waist circumference, and food intake pattern. Results: We detected no consistent association of serum TSH and FT3 concentrations with hepatic steatosis. In contrast, serum FT4 concentrations were inversely associated with hepatic steatosis in males (odds ratio 0.04, 95% confidence interval 0.01; 0.17) and females (odds ratio 0.06, 95% confidence interval 0.01; 0.42). Conclusions: Results from the present cross-sectional study suggest that low FT4 concentrations are associated with hepatic steatosis. Longitudinal and intervention studies are warranted to investigate whether hypothyroidism increase the risk of hepatic steatosis or vice versa.
Thyroid: official journal of the American Thyroid Association 03/2012; · 2.60 Impact Factor
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ABSTRACT: CYP2C19 is a polymorphic enzyme that plays a pivotal role in the metabolism of 10% of clinically used drugs worldwide. The CYP2C19*3 allele is characterized by a premature stop codon that leads to a truncated nonfunctional protein and consequently a poor metabolizer phenotype. Aminoglycoside antibiotics have been shown to induce readthrough of premature stop codons and partial restoration of protein function. We investigated the ability of the aminoglycosides gentamicin and G418 to induce readthrough of CYP2C19*3 premature stop codon in human cells.
A CYP2C19*3 expression model in HeLa cells was used in all experiments. CYP2C19-EGFP expression was assessed by flow cytometry, immunoblotting, and fluorescence microscopy, whereas CYP2C19 enzymatic activity was quantified by hydroxylation of 3-cyano-7-ethoxycoumarin.
G418 and gentamicin promoted readthrough of the CYP2C19*3 premature stop codon in a concentration-dependent manner. Flow cytometry revealed a maximum 23% protein restoration with the highest aminoglycoside concentrations tested, namely 300 mg/ml G418 and 1000 mg/ml gentamicin. At these concentrations, G418 was more effective than gentamicin in restoring CYP2C19 expression in immunoblotting and fluorescence microscopy assays, as well as in restoring CYP2C19 enzymatic activity.
This is the first demonstration of readthrough of a stop codon in a pharmacogenetic target of clinical relevance, namely CYP2C19*3. The experimental models may be adapted to explore readthrough of stop codons in other genes of pharmacogenetic interest.
Pharmacogenetics and Genomics 09/2011; 21(11):694-700. · 3.48 Impact Factor
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ABSTRACT: An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated.
To investigate this association among Caucasians.
Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value <.004 as significant.
Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03).
Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies.
Headache The Journal of Head and Face Pain 10/2010; 51(2):201-7. · 2.52 Impact Factor
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Praveen K Nambaru,
Tobias Hübner,
Kathleen Köck,
Steffen Mews,
Markus Grube,
Léa Payen,
Jérôme Guitton,
Matthias Sendler,
Gabriele Jedlitschky,
Christian Rimmbach, Dieter Rosskopf,
Dariusz W Kowalczyk,
Heyo K Kroemer,
Frank U Weiss,
Julia Mayerle,
Markus M Lerch,
Christoph A Ritter
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ABSTRACT: Pancreatic adenocarcinoma is one of the malignancies that is highly resistant to therapy and among the leading causes of cancer-related death. Several factors may influence pancreatic cancer resistance, and expression of ATP-binding cassette transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux nucleoside analogs used in the treatment of pancreatic cancer. Expression of MRP1, MRP3, MRP4, and MRP5 in human pancreas and pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of pancreatic cancer are not fully understood. MRP5 mRNA expression in pancreatic adenocarcinoma cell lines correlated significantly with cellular sensitivity to 5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with 5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC(50) values for control and 5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 ± 5.3 and 33.2 ± 6.9 μM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of 5-FU related radioactivity and 5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of 5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to 5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic adenocarcinoma cell lines to 5-FU. Further investigations using models that resemble human pancreas tumors are necessary to prove a causative relation between expression and activity of MRP5 and tumor resistance to 5-FU.
Drug metabolism and disposition: the biological fate of chemicals 10/2010; 39(1):132-9. · 3.74 Impact Factor
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Marcus Dörr,
Carsten O Schmidt,
Thomas Spielhagen,
Alexa Bornhorst,
Katharina Hentschel,
Christina Franz,
Klaus Empen,
Thomas Kocher,
Scott R Diehl,
Heyo K Kroemer,
Henry Völzke,
Ralf Ewert,
Stephan B Felix, Dieter Rosskopf
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ABSTRACT: Impaired heart rate (HR) response to exercise is associated with increased cardiovascular morbidity and mortality. We analyzed whether common variants (rs5443/C825T and rs5442/G814A) in the G-protein β3 subunit (GNB3) gene modulate interindividual variation in β-blocker responses with respect to HR.
Among 1614 subjects (347 current β-blocker users) of a population-based study, HR during symptom-limited exercise testing was analyzed by multilevel linear regression models adjusted for potential confounders.
In β-blocker users, but not in nonusers, HR was attenuated in rs5443 T allele carriers (TC/TT vs CC) with lower adjusted HR over the entire exercise period from rest to peak workload (3.5 bpm; 95% CI: 1.1-5.8; p < 0.01), and during recovery (4.2 bpm; 95% CI: 0.6-7.8; p = 0.02). The genotype-related HR reducing effect at peak exercise varied by up to 7.5 bpm (CC vs TT), more than a third (35.9%) of the total β-blocker effect (20.9 bpm). By contrast, rs5442 had no impact on any HR-related parameter.
In this population-based sample, a common GNB3 polymorphism (C825T) was significantly related with response to β-blocker therapy with respect to HR during exercise and HR recovery, respectively. Further prospective studies are needed to confirm these associations and to examine their potential clinical relevance.
Pharmacogenomics 09/2010; 11(9):1209-21. · 3.97 Impact Factor
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André Scherag,
Christian Dina,
Anke Hinney,
Vincent Vatin,
Susann Scherag,
Carla I G Vogel,
Timo D Müller,
Harald Grallert,
H-Erich Wichmann,
Beverley Balkau, [......],
Markus M Nöthen,
Thomas W Mühleisen,
Raimund Erbel,
Karl-Heinz Jöckel,
Susanne Moebus,
Tanja Boes,
Thomas Illig,
Philippe Froguel,
Johannes Hebebrand,
David Meyre
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ABSTRACT: Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
PLoS Genetics 04/2010; 6(4):e1000916. · 8.69 Impact Factor
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ABSTRACT: We previously showed that the MRP4 (ABCC4) transporter is expressed in human platelet delta-granules and may be involved in ADP transport. We now demonstrate by immunoblotting and immunofluorescence microscopy that platelet MRP4 is absent in two patients with a platelet delta-storage pool deficiency (delta-SPD)-like phenotype with reduced platelet adenine nucleotide (AN) but normal serotonin levels, whereas their other membrane marker proteins of platelet granules were normally expressed and localized. In these patients, MRP4 was present in lymphocytes, and the coding region of their MRP4/ABCC4 gene did not show any mutation that explained the lack of expression. In platelets with "classic" delta-SPD (low AN and serotonin levels), MRP4 was quantitatively (immunoblot) normal, but, like other delta-granules membrane marker proteins (eg, LAMP2), was mostly displaced from delta-granules to patches at the plasma membrane, suggesting that platelets with classic delta-SPD have an abnormality that impairs the assembly of normal delta-granules. Thus, defective expression of platelet MRP4 is associated with selective defect in AN storage. The genetic basis of the new delta-SPD phenotype remains to be elucidated.
American Journal Of Pathology 03/2010; 176(3):1097-103. · 4.89 Impact Factor
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ABSTRACT: Neonatal health is of major concern to parents, midwives, physicians and society as a whole, yet a prospective population-based birth cohort to collect comprehensive data on multiple issues including medical, social, environmental and genetic aspects remains to be established in Germany. The survey of newborns in Pomerania (SNiP) described in this paper attempts to take up this goal. The objectives of SNiP are to establish (a) a population-based birth cohort providing detailed information about neonatal health, morbidity and mortality, (b) a biobank with newborn DNA and serum from cord blood, placenta tissue samples and DNA obtained from oral mucosal swabs of the mothers, (c) a prospective study design by re-examination of the SNiP population prior to attendance at primary school. From March 2003 until November 2008 all childbearing mothers in a well-defined region in North-Eastern Germany were asked to participate with their newborns. Detailed data on health status of the newborn, pregnancy, medical and family history, socio-economic status and maternal life style were obtained via face-to-face interview, standardised questionnaires and medical records. Placental tissue samples, cord blood plasma and DNA were continuously collected; sampling of maternal DNA from mouth swabs started in 2007. As a result, during the study period n = 6747 births and n = 6828 babies were enrolled. A population coverage of 95% was achieved. The active participation rate was 75%. A non-responder analysis revealed no meaningful selection bias. Thus, SNiP is a population-based, representative study in Germany that is able to describe the health and living conditions of newborns and their families comprehensively. It can contribute to existing knowledge and to similar cohort studies since data are accessible by researchers.
Paediatric and Perinatal Epidemiology 03/2010; 24(2):190-9. · 2.31 Impact Factor
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ABSTRACT: 1. Preconditioning has been proposed to protect the myocardium by inhibiting glycogen-synthase kinase (GSK) 3beta. The aim of the present study was to test whether transfection of ventricular myocytes with inactive GSK3 beta would mimic preconditioning and whether a constitutively active form of GSK3 beta would prevent protection by an opioid receptor agonist. 2. Isolated ventricular myocytes from adult rats were infected with live adenovirus containing either a wild-type (wtGSK), constitutively active (caGSK) or dominant-negative (dnGSK) GSK3 beta plasmid. Cells were loaded with tetramethylrhodamine ethyl ester (TMRE) and exposed to H(2)O(2) (100 micromol/L) for 40 min before mitochondrial membrane potential (Delta Psi(m)) was assessed using flow cytometric analysis. 3. Fluorescence intensity was reduced in H(2)O(2)-treated cells compared with untreated cells, presumably because oxidant injury opened mitochondrial permeability transition pores, causing mitochondria to lose TMRE. The selective GSK3 beta inhibitor SB216763, as well as the delta-opioid receptor agonist [d-Ala(2)-D-Leu(5)]-enkephalin (DADLE) (1 micromol/L), protected cells against peroxide-induced loss of Delta Psi(m). 4. Cells transfected with dnGSK (1 micromol/L) were equally protected against peroxide stress, when given throughout the TMRE and H(2)O(2) treatment, confirming a protective effect of GSK3 beta with a highly selective inhibition. Cells transfected with wtGSK did not show any difference in responses to H(2)O(2), SB216763 or DADLE compared with untransfected cells, suggesting that adenovirus infection itself had no effect. In contrast, caGSK-transfected myocytes could no longer be protected with DADLE, suggesting a role for GSK3 beta between the surface receptor and the mitochondria. 5. These experiments confirm that inhibition of GSK3 beta protects the myocytes, but also that the preconditioning mimetic DADLE loses its protective effect when a constitutively active GSK3 beta is present.
Clinical and Experimental Pharmacology and Physiology 03/2010; 37(7):684-8. · 1.85 Impact Factor
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Henry Völzke,
Dietrich Alte,
Carsten Oliver Schmidt,
Dörte Radke,
Roberto Lorbeer,
Nele Friedrich,
Nicole Aumann,
Katharina Lau,
Michael Piontek,
Gabriele Born, [......],
Birte Holtfreter,
Ines Polzer,
Thomas Kohlmann,
Hans J Grabe, Dieter Rosskopf,
Heyo K Kroemer,
Thomas Kocher,
Reiner Biffar,
Ulrich John,
Wolfgang Hoffmann
International Journal of Epidemiology 02/2010; 40(2):294-307. · 6.41 Impact Factor
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Monica Venner,
Jette Peters,
Nina Höhensteiger,
Birthe Schock,
Alexa Bornhorst,
Markus Grube,
Ulrike Adam,
Eberhard Scheuch,
Werner Weitschies, Dieter Rosskopf,
Heyo K Kroemer,
Werner Siegmund
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[hide abstract]
ABSTRACT: Macrolide antibiotics penetrate in the lung against steep concentration gradients into the epithelial lining fluid (ELF) and broncho-alveolar cells (BAC). Since they interact with ABCB1, ABCC2, and organic anion transporting proteins (OATPs), which are localized to lung tissue, pulmonary concentration may be influenced by rifampicin (RIF), an inducer and modulator of efflux and uptake transporters. We measured concentrations of tulathromycin (TM) in plasma, ELF and BAC in 21 warm-blooded foals 24 and 192 h after first and last intramuscular injection of 2.5 mg/kg TM once weekly for 6 weeks. In 11 foals, TM was combined with RIF (10 mg/kg twice daily), and mRNA expression of ABCB1 and ABCC2 in BAC was assessed before and after RIF. Affinity of TM to ABCB1 and ABCC2 was measured by transport assays using cell monolayers and membrane vesicles of MDCKII and 2008 cells transfected with ABCB1 and ABCC2, respectively. At steady state, TM concentrated manifold in ELF and BAC. Comedication of RIF significantly decreased the AUC of TM (18.5 +/- 4.0 versus 24.4 +/- 3.7 microg x h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 +/- 0.05 versus 0.24 +/- 0.05 microg/ml; 192 h, 0.05 +/- 0.01 versus 0.06 +/- 0.01 microg/ml) and BAC (24 h, 0.84 +/- 0.36 versus 1.56 +/- 1.02 microg/ml; 192 h, 0.60 +/- 0.23 versus 1.23 +/- 0.90 microg/ml, all p < 0.05). Treatment with rifampicin did not markedly induce ABCB1 and ABCC2 expression. TM had no affinity to ABCB1 and ABCC2 in vitro. Concentration of TM in the lung of foals was significantly lowered by comedication of rifampicin most likely caused by extrapulmonary mechanisms leading to lower plasma concentrations.
Archiv für Experimentelle Pathologie und Pharmakologie 12/2009; 381(2):161-9. · 2.65 Impact Factor
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Iris M Heid,
Cornelia Huth,
Ruth J F Loos,
Florian Kronenberg,
Vera Adamkova,
Sonia S Anand,
Kristin Ardlie,
Heike Biebermann,
Peter Bjerregaard,
Heiner Boeing, [......],
Karani S Vimaleswaran,
Nicholas J Wareham,
Dawn Waterworth,
Salim Yusuf,
Cecilia Lindgren,
Mark I McCarthy,
Christoph Lange,
Joel N Hirschhorn,
Nan Laird,
H-Erich Wichmann
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ABSTRACT: The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.
PLoS Genetics 10/2009; 5(10):e1000694. · 8.69 Impact Factor
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Michael Lucht,
Agnieszka Samochowiec,
Jerzy Samochowiec,
Andrzej Jasiewicz,
Hans Joergen Grabe,
Ingrid Geissler,
Christian Rimmbach, Dieter Rosskopf,
Anna Grzywacz,
Justyna Pełka Wysiecka,
Piotr Tybura,
Bogusław Brzuchalski,
Przemysław Bieńkowski
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ABSTRACT: D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail.
Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12.
Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects.
This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2009; 34(1):45-9. · 3.25 Impact Factor
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ABSTRACT: Heterotrimeric G proteins are key mediators of signals from membrane receptors-including the thyroid-stimulating hormone (TSH) receptor-to cellular effectors. Gain-of-function mutations in the TSH receptor and the Galpha(S) subunit occur frequently in hyperfunctioning thyroid nodules and differentiated thyroid carcinomas, whereby the T allele of a common polymorphism (825C>T, rs5443) in the G protein beta3 subunit gene (GNB3) is associated with increased G protein-mediated signal transduction and a complex phenotype. The aim of this study was to investigate whether this common polymorphism affects key parameters of thyroid function and morphology and influences the pathogenesis of thyroid diseases in the general population.
The population-based cross-sectional Study of Health in Pomerania is a general health survey with focus on thyroid diseases in northeast Germany, a formerly iodine-deficient area. Data from 3428 subjects (1800 men and 1628 women) were analyzed for an association of the GNB3 genotype with TSH, free triiodothyronine and thyroxine levels, urine iodine and thiocyanate excretion, and thyroid ultrasound morphology including thyroid volume, presence of goiter, and thyroid nodules.
There was no association between GNB3 genotype status and the functional or morphological thyroid parameters investigated, neither in crude analyses nor upon multivariable analyses including known confounders of thyroid disorders.
Based on the data from this large population-based survey, we conclude that the GNB3 825C>T polymorphism does not affect key parameters of thyroid function and morphology in the general population of a formerly iodine-deficient area.
Thyroid: official journal of the American Thyroid Association 09/2009; 19(10):1115-9. · 2.60 Impact Factor
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ABSTRACT: The aim of this analysis was to assess the prospective association of serum testosterone and dehydroepiandrosterone sulfate (DHEAS) levels with incident metabolic syndrome (MetS) in men.
Data were obtained from the Study of Health in Pomerania (SHIP), a population-based prospective cohort of adults aged 20-79 years. Analyses were conducted in 1,004 men without baseline MetS defined by National Cholesterol Education Program Adult Treatment Panel III guidelines. Testosterone and DHEAS were categorized by age-specific quartiles and Poisson regression models with relative risks (RRs) and 95% CIs were estimated.
After a median follow-up time of 5.0 years, 480 men (47.8%) developed MetS. Testosterone levels decreased with increasing number of MetS components. Testosterone in the lowest quartile predicted MetS (RR 1.38 [95% CI 1.13-1.69]), particularly among men aged 20-39 years (2.06 [1.29-3.29]), even after adjustment for age, smoking, alcohol consumption, physical activity, waist circumference, self-related health, and time of blood sampling. DHEAS levels were not related to incident MetS (0.99 [0.83-1.19]).
Low testosterone but not DHEAS predicts development of MetS in a population-based cohort of 1,004 men aged 20-79 years. Especially in young men aged 20-39 years, results suggest low testosterone as a strong predictor for incident MetS. Assessment of testosterone in young and middle-age men may allow early interventions in the general population.
Diabetes 08/2009; 58(9):2027-31. · 8.29 Impact Factor
