Biomedical subjects

Jakob C Mueller

Publications and source records attributed to Jakob C Mueller.

16 recordsLinked to original sources

PubMed2006

Osteopontin is elevated in Parkinson's disease and its absence leads to reduced neurodegeneration in the MPTP model.

In the pathogenesis of Parkinson's disease (PD), oxidative and nitrosative stress, apoptosis, mitochondrial dysfunction, and excitotoxicity are involved, i.e., processes in which osteopontin (OPN) may also play a role. We have studied in PD patients serum and cerebrospinal fluid (CSF) concentrations of OPN, its immunohistochemical presence in substantia nigra (SN) and tested in OPN-null mice the impact of this protein on MPTP-induced neurodegeneration. PD was accompanied by increased OPN levels in the body fluids. Higher serum levels were associated with more severe motor symptoms. CSF levels were positively associated with concomitant dementia and negatively associated with dopaminergic treatment. In human SN, OPN was expressed in neurons, in their Lewy bodies and in microglia. Loss of tyrosine-hydroxylase-positive cells in the SN and of dopaminergic fibers in the striatum was reduced 3 weeks after MPTP intoxication in OPN-null mice. These data suggest that OPN is involved in PD-associated neurodegeneration.

Aged↗

PubMed2006

Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians.

PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS. By means of MALDI-TOF MS technique, we genotyped an expanded single nucleotide polymorphism panel, including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared with GG. As expected, the 22-genotype of the ins/del-19 variant, which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the additionally tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1,224 controls) also showed significant association only with ins/del-19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, P=0.0057). In contrast, the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, P=0.0011). By investigating a broad panel of CAPN10 variants, our results pointed to an allele dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.

Adult↗

PubMed2006

A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease.

A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-q22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Abeta) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N=679; Bonn N=282; Brescia (Italy) N=219; Perth (Australia) N=557 and one discordant sib-pair sample (Munich N=622). In brain tissue samples of neuropathologically confirmed cases with AD (N=33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P=0.02; Bonn, P=0.005; Brescia (Italy), P=0.001; Perth (Australia), P=0.03) and the discordant sib-pair sample (P=0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N=6; 60.3+/-16.9) compared with non-carriers (N=9; 26.3+/-8.8; P=0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Abeta proteins.

Age of Onset↗

PubMed2006

Weak independent association signals between IDE polymorphisms, Alzheimer's disease and cognitive measures.

Functional and genetic studies suggest that insulin-degrading enzyme (IDE) may be a strong functional and positional candidate. As there is a lack of consensus in regards to the level and location of IDE association signals we aimed to clarify these discrepancies through genotyping 28 SNPs in a large case-control collective together with quantitative measures of cognitive ability (MMSE). Four SNPs (rs11187007, rs2149632_ide12, rs11187033, rs11187040) were found to be associated with AD (nominal p<0.01). Tests with MMSE scores adjusted for disease duration identified associations, with the most significant result for rs1999763 (nominal p=0.008). Similarly, different reconstructed IDE haplotypes were associated with AD and higher MMSE scores. The association signals are only borderline significant after adjustment for multiple testing, but add further evidence to previous published results on the association between IDE and AD or MMSE. A subgroup analysis indicated more prominent associations with AD in younger, and with MMSE in older patients. There may be two independent effects mediated by IDE variants, risk for AD and modification of disease progression.

Aged↗

PubMed2006

Association of transforming growth factor-beta1 gene polymorphisms with myocardial infarction in patients with angiographically proven coronary heart disease.

OBJECTIVE: Transforming growth factor (TGF)-beta1 (TGF-beta1) is a multifunctional cytokine that exhibits vasculoprotective properties. Production and plasma levels of TGF-beta1 are influenced by polymorphisms in the TGF-beta1 gene (TGFB1). We investigated whether the -509C/T (rs1800469), 868T/C (rs1982073), 913G/C (rs1800471), and 11929C/T (rs1800472) polymorphisms of TGFB1 are associated with myocardial infarction. METHODS AND RESULTS: The study population consisted of 3657 patients with myocardial infarction (885 women and 2772 men) and 1211 control individuals (598 women and 613 men) with angiographically normal coronary arteries and without signs or symptoms of myocardial infarction. Polymorphism-related genotypes were determined with TaqMan assays and haplotypes were estimated from the genotype data. The -509C/T polymorphism and -509C/868T/913G/11929C (CTGC) haplotype were associated with myocardial infarction in men, independently from the potentially confounding factors age, arterial hypertension, hypercholesterolemia, cigarette smoking, and diabetes mellitus. Lower risks of myocardial infarction were observed among the carriers of the -509CC genotype (adjusted odds ratio [OR], 0.49; 95% confidence interval [CI], 0.27 to 0.87; P=0.014) and homozygous carriers of the CTGC haplotype (adjusted OR, 0.61; 95% CI, 0.38 to 0.98; P=0.042) than among the noncarriers of this genotype or haplotype. None of the genotypes (P> or =0.37) or haplotypes (P> or =0.35) was associated with myocardial infarction in women. CONCLUSIONS: Positive association findings in this study suggest that TGFB1 is a susceptibility locus for myocardial infarction.

Adult↗

PubMed2006

Genetic architecture of the APM1 gene and its influence on adiponectin plasma levels and parameters of the metabolic syndrome in 1,727 healthy Caucasians.

The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease.

Adiponectin↗

PubMed2005

No replication of association between estrogen receptor alpha gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent.

BACKGROUND: The effects of estrogen on blood vessels are partly due to changes in vascular cell gene expression and protein synthesis that are mediated by estrogen receptors. In previous association studies, the -397T/C (rs2234693) and -351A/G (rs9340799) single nucleotide polymorphisms in the estrogen receptor alpha gene (ESR1) have been implicated in the risk of coronary atherosclerosis and myocardial infarction. To test these findings, we examined the relationship of the polymorphisms to myocardial infarction in a large sample of white patients and control individuals of predominantly European descent. METHODS AND RESULTS: The case group included 3657 patients with myocardial infarction, and the control group comprised 1211 individuals with angiographically normal coronary arteries and without signs or symptoms of myocardial infarction. TaqMan assays were used for the determination of genotypes. Genotype distributions of the -397T/C and -351A/G polymorphisms were not significantly different between the control and patient groups (P> or =0.85). The frequencies of haplotypes defined by the -397T/C and -351A/G polymorphisms were similar in the control group and the patient group (P=0.42). In addition, the distributions of haplotype-defined genotypes (diplotypes) were not significantly different between the control group and the patient group (P=0.81). Separate analyses in women and men did not reveal sex-related associations of specific genotypes or haplotypes of the polymorphisms with myocardial infarction (P> or =0.25). CONCLUSIONS: The results indicate that the -397T/C and -351A/G polymorphisms of ESR1 or haplotypes based on these polymorphisms are not associated with myocardial infarction in a white population.

Aged↗

PubMed2005

Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study.

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

Adult↗

PubMed2005

ALOX5AP gene and the PDE4D gene in a central European population of stroke patients.

BACKGROUND AND PURPOSE: Recent evidence has implicated the genes for 5-lipoxygenase activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) as susceptibility genes for stroke in the Icelandic population. The aim of the present study was to explore the role of these genes in a central European population of stroke patients. METHODS: A total of 639 consecutive stroke patients and 736 unrelated population-based controls that had been matched for age and sex were examined using a case-control design. Twenty-two single-nucleotide polymorphisms (SNPs) covering ALOX5AP were genotyped. For PDE4D, microsatellite AC008818-1 and 12 SNPs, which tag all common haplotypes in previously identified linkage disequilibrium (LD) blocks, were analyzed. RESULTS: A nominally significant association with stroke was observed with several SNPs from ALOX5AP, including SNP SG13S114, which had been part of the Icelandic at-risk haplotype. Associations were stronger in males than in females, with SG13S114 (odds ratio, 1.24; 95% CI, 1.04 to 1.55; P=0.017) and SG13S100 (odds ratio, 1.26; 95% CI 1.03 to 1.54; P=0.024) showing the strongest associations. No significant associations were detected with single markers and haplotypes in PDE4D. The frequencies of single-marker alleles and haplotypes differed largely from those in the Icelandic population. CONCLUSIONS: The present study suggests that sequence variants in the ALOX5AP gene are significantly associated with stroke, particularly in males. Variants in the PDE4D gene are not a major risk factor for stroke in individuals from central Europe. Population differences in allele and haplotype frequencies as well as LD structure may contribute to the observed differences between populations.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

Linkage disequilibrium patterns and tagSNP transferability among European populations.

The pattern of linkage disequilibrium (LD) is critical for association studies, in which disease-causing variants are identified by allelic association with adjacent markers. The aim of this study is to compare the LD patterns in several distinct European populations. We analyzed four genomic regions (in total, 749 kb) containing candidate genes for complex traits. Individuals were genotyped for markers that are evenly distributed at an average spacing of approximately 2-4 kb in eight population-based samples from ongoing epidemiological studies across Europe. The Centre d'Etude du Polymorphisme Humain (CEPH) trios of the HapMap project were included and were used as a reference population. In general, we observed a conservation of the LD patterns across European samples. Nevertheless, shifts in the positions of the boundaries of high-LD regions can be demonstrated between populations, when assessed by a novel procedure based on bootstrapping. Transferability of LD information among populations was also tested. In two of the analyzed gene regions, sets of tagging single-nucleotide polymorphisms (tagSNPs) selected from the HapMap CEPH trios performed surprisingly well in all local European samples. However, significant variation in the other two gene regions predicts a restricted applicability of CEPH-derived tagging markers. Simulations based on our data set show the extent to which further gain in tagSNP efficiency and transferability can be achieved by increased SNP density.

Alleles↗

PubMed2005

Multiple regions of alpha-synuclein are associated with Parkinson's disease.

alpha-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of alpha-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the alpha-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case-control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the alpha-synuclein gene. Several markers within the 3'-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5'-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.

Age Factors↗

PubMed2005

Common variants of LRRK2 are not associated with sporadic Parkinson's disease.

Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk.

Age of Onset↗

PubMed2004

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Adult↗

PubMed2004

Plotting haplotype-specific linkage disequilibrium patterns by extended haplotype homozygosity.

UNLABELLED: Association studies may request more details of a specific haplotype. Haplotype-specific decay of linkage disequilibrium is such a crucial and versatile characteristic. It may be used, e.g. to search for signals of natural selection in a risk haplotype. Here, we present a web-based tool to explore the relationship between population frequency and extended linkage disequilibrium measured as haplotype homozygosity of observed haplotypes within a specified candidate region. AVAILABILITY: The web-tool is available at http://ihg.gsf.de/cgi-bin/mueller/webehh.pl

Algorithms↗

PubMed2004

Linkage disequilibrium for different scales and applications.

Assessing the patterns of linkage disequilibrium (LD) has become an important issue in both evolutionary biology and medical genetics since the rapid accumulation of densely spaced DNA sequence variation data in several organisms. LD deals with the correlation of genetic variation at two or more loci or sites in the genome within a given population. There are a variety of LD measures which range from traditional pairwise LD measures such as D' or r2 to entropy-based multi-locus measures or haplotype-specific approaches. Understanding the evolutionary forces (in particular recombination) that generate the observed variation of LD patterns across genomic regions is addressed by model-based LD analysis. Marker type and its allelic composition also influence the observed LD pattern, microsatellites having a greater power to detect LD in population isolates than SNPs. This review aims to explain basic LD measures and their application properties.

Algorithms↗

PubMedDate not supplied

Gene mapping and marker clustering using Shannon's mutual information.

Finding the causal genetic regions underlying complex traits is one of the main aims in human genetics. In the context of complex diseases, which are believed to be controlled by multiple contributing loci of largely unknown effect and position, it is especially important to develop general yet sensitive methods for gene mapping. We discuss the use of Shannon's information theory for population-based gene mapping of discrete and quantitative traits and for marker clustering. Various measures of mutual information were employed in order to develop a comprehensive framework for gene mapping analyses. An algorithm aimed at finding so-called relevance chains of causal markers is proposed. Moreover, entropy measures are used in conjunction with multidimensional scaling to visualize clusters of genetic markers. The relevance chain algorithm successfully detected the two causal regions in a simulated scenario. The approach has also been applied to a published clinical study on autoimmune (Graves') disease. Results were consistent with those of standard statistical methods, but identified an additional locus of interest in the promotor region of the associated gene CTLA4. The developed software is freely available at http://www.Int.ei.tum.de/download/InfoGeneMap/.

Algorithms↗