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Andreas Ziegler

Publications and source records attributed to Andreas Ziegler.

At least 19 recordsLinked to original sources
PubMed2007

Analysis of the base excision repair genes MTH1, OGG1 and MUTYH in patients with squamous oral carcinomas.

A number of environmental factors, such as tobacco and alcohol, have been implicated, through oxidative DNA damage, in the development of squamous cell carcinomas of the head and neck (SCCHN). Several pathways are involved in the repair of DNA lesions caused by oxidative stress, such as the base excision repair system (BER), which repairs mutation involving 8-oxoguanine and comprises the MUTYH, OGG1 and MTH1 genes. We analysed 29 patients, assessing germline polymorphisms or mutations in these genes by complete genomic sequencing of exons and adjacent intronic regions. Thirty healthy blood donors served as controls. No pathogenic germline mutations were identified. We found common and rare new variants in the coding and adjacent intronic regions. In summary, our data do not support a major role for MUTYH, OGG1 and MTH1 variants in the etiology of sporadic squamous oral/oropharyngeal carcinomas. This does not exclude the involvement of the three BER genes in the tumorigenesis of SCCHN through other mechanisms such as promotor hypermethylation, genomic rearrangements or mutations involving regulatory sequences.

Adult↗
PubMed2006

Variations of the melanocortin-1 receptor and the glutathione-S transferase T1 and M1 genes in cutaneous malignant melanoma.

Variations in the melanocortin-1 receptor (MC1R) and in the glutathione-S transferase genes mu1 (GSTM1) and theta 1 (GSTT1) have been reported to influence UV sensitivity and melanoma risk. MC1R is one of the major genes that determine skin pigmentation because the melanocortin-1 receptor regulates eumelanin synthesis. GSTT1 and GSTM1 are enzymes expressed in the skin that detoxify products of oxidative stress reactions caused by UV irradiation. In this study variations in the MC1R, GSTM1 and T1 genes were analyzed in 347 healthy subjects and 322 patients with cutaneous malignant melanoma by direct cycle sequencing, RFLP and multiplex PCR. Important phenotypic characteristics of the study participants were obtained to assess whether genetic associations occurred independently of phenotypic risk factors for melanoma. We found an association of the MC1R D84E and R151C polymorphisms with melanoma (odds ratios for carriage of the rare allele 4.96, 95% CI [1.06-23.13], P = 0.032, and 1.69, 95% CI [1.12-2.55], P = 0.013, respectively). Melanoma risk increased with the number of variant MC1R alleles carried by an individual (P = 0.003). In a multivariate model, however, only the D84E polymorphism influenced melanoma risk independently of the risk factors fair skin type, high nevus count and high age (P = 0.047). There was no effect of homozygous GST M1 or T1 deletions on melanoma risk. In contrast to previous data, there was no evidence that GSTM1 deficiency influences melanoma risk in the subgroup of individuals with red or blond hair.

Adult↗
PubMed2006

SNP-based analysis of genetic substructure in the German population.

OBJECTIVE: To evaluate the relevance and necessity to account for the effects of population substructure on association studies under a case-control design in central Europe, we analysed three samples drawn from different geographic areas of Germany. Two of the three samples, POPGEN (n = 720) and SHIP (n = 709), are from north and north-east Germany, respectively, and one sample, KORA (n = 730), is from southern Germany. METHODS: Population genetic differentiation was measured by classical F-statistics for different marker sets, either consisting of genome-wide selected coding SNPs located in functional genes, or consisting of selectively neutral SNPs from 'genomic deserts'. Quantitative estimates of the degree of stratification were performed comparing the genomic control approach [Devlin B, Roeder K: Biometrics 1999;55:997-1004], structured association [Pritchard JK, Stephens M, Donnelly P: Genetics 2000;155:945-959] and sophisticated methods like random forests [Breiman L: Machine Learning 2001;45:5-32]. RESULTS: F-statistics showed that there exists a low genetic differentiation between the samples along a north-south gradient within Germany (F(ST)(KORA/POPGEN): 1.7 . 10(-4); F(ST)(KORA/SHIP): 5.4 . 10(-4); F(ST)(POPGEN/SHIP): -1.3 . 10(-5)). CONCLUSION: Although the F(ST )-values are very small, indicating a minor degree of population structure, and are too low to be detectable from methods without using prior information of subpopulation membership, such as STRUCTURE [Pritchard JK, Stephens M, Donnelly P: Genetics 2000;155:945-959], they may be a possible source for confounding due to population stratification.

Case-Control Studies↗
PubMed2006

Calcium translocations during the moulting cycle of the semiterrestrial isopod Ligia hawaiiensis (Oniscidea, Crustacea).

Terrestrial isopods moult first the posterior and then the anterior half of the body. During the moulting cycle they retain a significant fraction of cuticular calcium partly by storing it in sternal CaCO(3) deposits. We analysed the calcium content in whole Ligia hawaiiensis and the calcium distribution between the posterior, the anterior ventral, and the anterior dorsal cuticle during four stages of the moulting cycle. The results indicate that: (1) overall, about 80% of the calcium is retained and 20% is lost with the exuviae, (2) in premoult 68% of the calcium in the posterior cuticle is resorbed (23% moved to the anterior ventral cuticle, 17% to the anterior dorsal cuticle, and the remaining 28% to internal tissues), (3) after the posterior moult 83% of the calcium in the anterior cuticle is shifted to the posterior cuticle and possibly to internal storage sites, (4) following the anterior moult up to 54% of the calcium in the posterior cuticle is resorbed and used to mineralise the new anterior cuticle. (45)Ca-uptake experiments suggest that up to 80% of calcium lost with the anterior exuviae may be regained after its ingestion. Whole body calcium of Ligia hawaiiensis is only 0.7 times that of the fully terrestrial isopods. These terrestrial species can retain only 48% of whole body calcium, suggesting that the amount of calcium that can be retained by shifting it between the anterior and posterior integument is limited. We propose that fully terrestrial Oniscidea rely to a larger degree on other calcium sources like internal stores and uptake from the ingested exuviae.

Animals↗
PubMed2006

Differential expression of major histocompatibility complex class I molecules in the brain of a New World monkey, the common marmoset (Callithrix jacchus).

It has been supposed that central nervous neurons do not express MHC class I molecules. However, recent studies clearly demonstrated functional MHC class I expression in the rodent brain. In the present study, we have extended these studies and investigated the presence of MHC class I transcripts and proteins in the brain of a non-human primate species, the common marmoset monkey (Callithrix jacchus). Using in-situ hybridization, we found strong expression of MHC class I transcripts in neocortex, hippocampal formation, substantia nigra and nucleus ruber. In-situ hybridization with emulsion autoradiography demonstrated MHC class I mRNA in distinct pyramidal neurons of cortex and hippocampus, in granule neurons of the dentate gyrus, in dopaminergic neurons of substantia nigra and in motor neurons of nucleus ruber. Immunocytochemistry confirmed MHC class I protein expression in these neurons. Two monoclonal antibodies, MRC-Ox18 and HB115, reacted differentially with MHC class I proteins on neuronal and non-neuronal cells, respectively. Interestingly, in marmoset monkeys that were immunosuppressed with FK506 (tacrolimus), expression of neuronal MHC class I proteins, which could be detected with MRC-Ox18, was either very low (neocortex, nucleus ruber, substantia nigra) or absent (hippocampus). In contrast, class I expression in endothelial cells, which was detected by HB115, was not affected by immunosuppression. Our data show that selected neurons in the brain of a non-human primate express MHC class I molecules and that this expression can be modulated by immunosuppression.

Animals↗
PubMed2006

Variations in the peroxisome proliferator-activated receptor-gamma gene and melanoma risk.

There is strong evidence to suggest that the peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear receptor family of transcriptional regulators, mediates tumor suppressive activities in a variety of human cancers. Recently, PPARgamma agonists were found to inhibit growth of melanoma cell lines. Here, we tested the possibility that variations in the gene encoding PPARgamma (PPARG) influence melanoma risk. Two variations of PPARG (P12A[rs1801282] and C161T [rs3856806]) were investigated in two independent case-control studies with a total of 832 melanoma patients and 790 control individuals. In the first study, homozygous carriers of the rare *T allele of the C161T polymorphism in exon 6 of PPARG were significantly more common among patients with melanoma than among healthy subjects (6.0 vs. 2.0%; P=0.0096) and this association was independent of clinical risk factors such as skin type and nevus count (odds ratio 5.18; 95% confidence interval 1.68-15.96; P=0.0041). This finding, however, could not be replicated in the second case-control study. We therefore conclude that the investigated PPARG polymorphisms are not likely to constitute a significant risk factor for the development of melanoma among German Caucasians.

Adolescent↗
PubMed2006

The leukocyte receptor complex in chicken is characterized by massive expansion and diversification of immunoglobulin-like Loci.

The innate and adaptive immune systems of vertebrates possess complementary, but intertwined functions within immune responses. Receptors of the mammalian innate immune system play an essential role in the detection of infected or transformed cells and are vital for the initiation and regulation of a full adaptive immune response. The genes for several of these receptors are clustered within the leukocyte receptor complex (LRC). The purpose of this study was to carry out a detailed analysis of the chicken (Gallus gallus domesticus) LRC. Bacterial artificial chromosomes containing genes related to mammalian leukocyte immunoglobulin-like receptors were identified in a chicken genomic library and shown to map to a single microchromosome. Sequencing revealed 103 chicken immunoglobulin-like receptor (CHIR) loci (22 inhibitory, 25 activating, 15 bifunctional, and 41 pseudogenes). A very complex splicing pattern was found using transcript analyses and seven hypervariable regions were detected in the external CHIR domains. Phylogenetic and genomic analysis showed that CHIR genes evolved mainly by block duplications from an ancestral inhibitory receptor locus, with transformation into activating receptors occurring more than once. Evolutionary selection pressure has led not only to an exceptional expansion of the CHIR cluster but also to a dramatic diversification of CHIR loci and haplotypes. This indicates that CHIRs have the potential to complement the adaptive immune system in fighting pathogens.

Alternative Splicing↗
PubMed2006

Detection of divergent genes in microbial aCGH experiments.

BACKGROUND: Array-based comparative genome hybridization (aCGH) is a tool for rapid comparison of genomes from different bacterial strains. The purpose of such analysis is to detect highly divergent or absent genes in a sample strain compared to an index strain. Development of methods for analyzing aCGH data has primarily focused on copy number abberations in cancer research. In microbial aCGH analyses, genes are typically ranked by log-ratios, and classification into divergent or present is done by choosing a cutoff log-ratio, either manually or by statistics calculated from the log-ratio distribution. As experimental settings vary considerably, it is not possible to develop a classical discriminant or statistical learning approach. METHODS: We introduce a more efficient method for analyzing microbial aCGH data using a finite mixture model and a data rotation scheme. Using the average posterior probabilities from the model fitted to log-ratios before and after rotation, we get a score for each gene, and demonstrate its advantages for ranking and detecting divergent genes with enlarged specificity and sensitivity. RESULTS: The procedure is tested and compared to other approaches on simulated data sets, as well as on four experimental validation data sets for aCGH analysis on fully sequenced strains of Staphylococcus aureus and Streptococcus pneumoniae. CONCLUSION: When tested on simulated data as well as on four different experimental validation data sets from experiments with only fully sequenced strains, our procedure out-competes the standard procedures of using a simple log-ratio cutoff for classification into present and divergent genes.

Computational Biology↗
PubMed2006

Brain-derived neurotrophic factor: a genetic risk factor for obsessive-compulsive disorder and Tourette syndrome?

A strong association of the G196A polymorphism of the brain-derived neurotrophic factor (BDNF) gene with obsessive-compulsive disorder (OCD) has been reported. Patients with Gilles de la Tourette's syndrome (GTS) often develop OCD as well, suggesting a shared genetic susceptibility for OCD and GTS. We investigated whether BNDF is associated not only with OCD but also with GTS. The G196A polymorphism of the BNDF gene was genotyped in 88 GTS trios. The extended transmission/disequilibrium test was applied. The transmission rates for both alleles did not differ from the expected transmission rates. This finding suggests that GTS and OCD may have distinct genetic risk factors.

Adolescent↗
PubMed2006

Anterior chamber angle measurement with optical coherence tomography: intraobserver and interobserver variability.

PURPOSE: To assess intraobserver and interobserver variability of anterior segment optical coherence tomography (AS-OCT) as an objective diagnostic tool to quantify the anterior chamber angle and opening width. SETTING: University Eye Clinic, Lübeck, Germany. METHODS: The anterior chamber angle and opening width were assessed in 18 eyes of 9 healthy volunteers by 2 observers. Intraobserver reproducibility was evaluated by calculating an intraclass correlation coefficient (ICC) in a mixed model. Each observer had a separate model using information from 5 scans. Interobserver variability was determined by Bland-Altman analysis. The ICC was calculated in a mixed model using a residual maximum likelihood method. The results of 3 and 5 repeated scans were evaluated to indicate the change to 1 measurement application. RESULTS: The mean anterior chamber angle measurement was 35.9 degrees +/- 5.7 (SD) for observer A and 36.2 +/- 5.7 degrees for observer B. The ICC was 0.94 and 0.91, respectively. The mean opening width was 315 +/- 62 microm for observer A and 317 +/- 60 microm for observer B. The ICC was 0.97 and 0.93, respectively. Interobserver comparisons showed a mean difference between anterior chamber angle measurements of -0.27 +/- 1.6 degrees, a limit of agreement (LOA) interval from -3.52 to 2.98 degrees, and an ICC estimate of 0.96. The mean difference in opening width measurements was 2.40 +/- 12.40 microm, the LOA from -27.20 to 22.40 microm, and the estimated ICC 0.96. Using 1 instead of the mean of 5 measurements, the LOA range increased by 3.46 degrees for the anterior chamber angle and 30.0 microm for the opening width. CONCLUSION: Anterior chamber angle and opening width measurements by OCT showed low intraobserver and interobserver variability, indicating OCT is a valuable technique for quantitative assessment that provides reproducible measurements and objective documentation by different examiners.

Adult↗
PubMed2006

Association of a functional polymorphism in the CYP4A11 gene with systolic blood pressure in survivors of myocardial infarction.

OBJECTIVE: Survivors of myocardial infarction (MI) are known to have a high prevalence of arterial hypertension which, at the same time, imposes a major risk to such patients. Genetic variants of the arachidonic acid monooxygenase CYP4A11 may result in decreased synthesis of 20-hydroxyeicostatetraenoic acid (20-HETE), experimental hypertension and elevated blood pressure levels in humans. The present study aimed to investigate the impact of the functionally relevant T8590C polymorphism of this gene on blood pressure and the prevalence of hypertension in MI patients. METHODS: Survivors of MI from the MONICA Augsburg MI registry (n = 560) were studied after a mean of 5.6 years after the acute event. Participants were examined by standardized anthropometric and echocardiographic measurements, as well as genotyping for CYP4A11 T8590C allele status. RESULTS: Genotype frequencies in MI patients (TT = 71.8%, CT = 26.2%, CC = 2.0%) did not differ from those in population-based controls (n = 1363; TT = 75.4%, CT = 22.5% and CC = 2.1%, P = 0.22). MI survivors with the CC genotype displayed higher systolic blood pressure levels (CC: 143.4 +/- 4.9 mmHg versus CT: 134.5 +/- 1.3 mmHg and TT: 131.1 +/- 0.8 mmHg; P = 0.02) and a non-significant trend towards higher diastolic blood pressure levels (CC: 88.4 +/- 3.0 mmHg versus CT: 84.9 +/- 0.8 mmHg and TT: 83.9 +/- 0.5 mmHg; P = 0.17) in multivariate models. Accordingly, the C allele was related to elevated odds ratios for hypertension in a recessive [4.14; 95% confidence interval (CI) = 1.07-15.96, P = 0.04] and in a dominant model (1.50; 95% CI = 1.03-2.20, P = 0.04), respectively. No blood pressure-independent association of the T8590C polymorphism with echocardiographic parameters of left ventricular function and/or geometry was found. CONCLUSION: The data obtained in the present study strengthen the evidence of an association of the CYP4A11 T8590C polymorphism with blood pressure levels and hypertension prevalence. Particularly, the risk of arterial hypertension is substantially higher in MI patients homozygous for the CC allele. By contrast, no evidence was obtained for an association between this genotype and MI.

Case-Control Studies↗
PubMed2006

Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.

OBJECT: Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS. METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18). CONCLUSIONS: The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

Activin Receptors, Type II↗
PubMed2005

Haseman-Elston weighted by marker informativity.

In the Haseman-Elston approach the squared phenotypic difference is regressed on the proportion of alleles shared identical by descent (IBD) to map a quantitative trait to a genetic marker. In applications the IBD distribution is estimated and usually cannot be determined uniquely owing to incomplete marker information. At Genetic Analysis Workshop (GAW) 13, Jacobs et al. [BMC Genet 2003, 4(Suppl 1):S82] proposed to improve the power of the Haseman-Elston algorithm by weighting for information available from marker genotypes. The authors did not show, however, the validity of the employed asymptotic distribution. In this paper, we use the simulated data provided for GAW 14 and show that weighting Haseman-Elston by marker information results in increased type I error rates. Specifically, we demonstrate that the number of significant findings throughout the chromosome is significantly increased with weighting schemes. Furthermore, we show that the classical Haseman-Elston method keeps its nominal significance level when applied to the same data. We therefore recommend to use Haseman-Elston with marker informativity weights only in conjunction with empirical p-values. Whether this approach in fact yields an increase in power needs to be investigated further.

Chromosomes, Human, Pair 4↗
PubMed2005

Haplotype-sharing analysis for alcohol dependence based on quantitative traits and the Mantel statistic.

Haplotype-based methods have become increasingly popular in the last decade because shared lengths in haplotypes can be used for disease localization. In this contribution, we propose a novel linkage-based haplotype-sharing approach for quantitative traits based on the class of Mantel statistics which is closely related to the weighted pair-wise correlation statistic. Because these statistics are known to be liberal, we propose a permutation test to evaluate significance. We applied the Mantel statistic to the autosomal data from the genome-wide scan of the Collaborative Study on the Genetics of Alcoholism with the Affymetrix Genotype 10 K array that was provided for the Genetic Analysis Workshop 14. Four regions on chromosome 4, 8, 16, and 20 showed p-values less than 0.005 with a minimum p-value of < 0.0001 on chromosome 16 (tsc0520638 at 72.8 cM). Three of these four regions located on chromosome 4, 16, and 20 have been reported previously in the Genetic Analysis Workshop 11.

Alcoholism↗
PubMed2005

X-ray diffraction analysis of crystals from the human major histocompatibility antigen HLA-B*2706 in complex with a viral peptide and with a self-peptide.

The human leukocyte antigen (HLA) alleles HLA-B*2704 and HLA-B*2706 show an ethnically restricted distribution and are differentially associated with ankylosing spondylitis, with HLA-B*2706 lacking association with this autoimmune disease. However, the products of the two alleles differ by only two amino acids, at heavy-chain residues 114 (His in HLA-B*2704; Asp in HLA-B*2706) and 116 (Asp in HLA-B*2704; Tyr in HLA-B*2706). Both residues could be involved in contacting amino acids of a bound peptide, suggesting that peptides presented by these subtypes play a role in disease pathogenesis. Two HLA-B*2706-peptide complexes were crystallized using the hanging-drop vapour-diffusion method with PEG as precipitant. Data sets were collected to resolutions of 2.70 A (viral peptide pLMP2, RRRWRRLTV; space group P2(1)2(1)2(1)) and 1.83 A (self-peptide pVIPR, RRKWRRWHL; space group P2(1)). Using HLA-B*2705 complexed with the pGR peptide (RRRWHRWRL) as a search model, unambiguous molecular-replacement solutions were found for both HLA-B*2706 complexes.

Crystallization↗
PubMed2005

Monodisperse oligofluorenes with keto defect as models to investigate the origin of green emission from polyfluorenes: synthesis, self-assembly, and photophysical properties.

Oligofluorenes (a trimer, pentamer, and heptamer) with one fluorenone unit in the center (OFnK: n=3, 5, or 7) were synthesized and used as models to understand the origin of the low-energy emission band in the photoluminescence and electroluminescence spectra of some polyfluorenes. All compounds form glasses with T(g) at 30 degrees C (OF3 K), 50 degrees C (OF5 K) and 57 degrees C (OF7 K). Oligomers OF5 K and OF7 K exhibit smectic liquid crystal phases that undergo transition to isotropic melts at 107 and 205 degrees C, respectively. Oligomer OF5 K could be obtained in form of single crystals. The X-ray structure analysis revealed the helical nature of the molecule and a helix reversal defect located at the central fluorenone unit. The packing pattern precludes formation of excimers. Electrochemical properties were investigated by cyclic voltammetry. The ionization potential (I(p)) and electron affinity (E(a)) were calculated from these data. Studies of the photophysical properties of OFnK in solution and thin film by steady-state and time-resolved fluorescence spectroscopic measurements suggest efficient funneling of excitation energy from the photoexcited fluorene segments to the low-energy fluorenone sites by both intra- and intermolecular hopping events whereby they give rise to green emission. Intermolecular energy transfer was investigated by using a model system composed of a highly defect free polyfluorene PF2/6 doped by OFnK. Förster-type energy transfer takes place from PF2/6 to OFnK. The energy-transfer efficiency increases predictably with increasing concentration of OFnK.

Journal Article↗