Publications by authors named "Hans Knoblauch"

14 Publications

  • Page 1 of 1

[How intelligence is itself--abolition according to Thilo Sarrazin opposed--on the concept of inheritability].

Psychiatr Prax 2010 Nov 5;37(8):408-9. Epub 2010 Nov 5.

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http://dx.doi.org/10.1055/s-0030-1268363DOI Listing
November 2010

Mutability of Y-chromosomal microsatellites: rates, characteristics, molecular bases, and forensic implications.

Am J Hum Genet 2010 Sep;87(3):341-53

Department of Forensic Molecular Biology, Erasmus University Medical Center Rotterdam, The Netherlands.

Nonrecombining Y-chromosomal microsatellites (Y-STRs) are widely used to infer population histories, discover genealogical relationships, and identify males for criminal justice purposes. Although a key requirement for their application is reliable mutability knowledge, empirical data are only available for a small number of Y-STRs thus far. To rectify this, we analyzed a large number of 186 Y-STR markers in nearly 2000 DNA-confirmed father-son pairs, covering an overall number of 352,999 meiotic transfers. Following confirmation by DNA sequence analysis, the retrieved mutation data were modeled via a Bayesian approach, resulting in mutation rates from 3.78 × 10(-4) (95% credible interval [CI], 1.38 × 10(-5) - 2.02 × 10(-3)) to 7.44 × 10(-2) (95% CI, 6.51 × 10(-2) - 9.09 × 10(-2)) per marker per generation. With the 924 mutations at 120 Y-STR markers, a nonsignificant excess of repeat losses versus gains (1.16:1), as well as a strong and significant excess of single-repeat versus multirepeat changes (25.23:1), was observed. Although the total repeat number influenced Y-STR locus mutability most strongly, repeat complexity, the length in base pairs of the repeated motif, and the father's age also contributed to Y-STR mutability. To exemplify how to practically utilize this knowledge, we analyzed the 13 most mutable Y-STRs in an independent sample set and empirically proved their suitability for distinguishing close and distantly related males. This finding is expected to revolutionize Y-chromosomal applications in forensic biology, from previous male lineage differentiation toward future male individual identification.
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http://dx.doi.org/10.1016/j.ajhg.2010.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933352PMC
September 2010

Another side to statin-related side effects.

Ann Intern Med 2010 Apr;152(7):478-9

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http://dx.doi.org/10.7326/0003-4819-152-7-201004060-00025DOI Listing
April 2010

Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation.

Ann Neurol 2010 Jan;67(1):136-40

Muscle Research Unit, Experimental and Clinical Research Center, Charité University Medicine Berlin, Germany.

We investigated a large German family (n = 37) with male members who had contractures, rigid spine syndrome, and hypertrophic cardiomyopathy. Muscle weakness or atrophy was not prominent in affected individuals. Muscle biopsy disclosed a myopathic pattern with cytoplasmic bodies. We used microsatellite markers and found linkage to a locus at Xq26-28, a region harboring the FHL1 gene. We sequenced FHL1 and identified a new missense mutation within the third LIM domain that replaces a highly conserved cysteine by an arginine (c.625T>C; p.C209R). Our finding expands the phenotypic spectrum of the recently identified FHL1-associated myopathies and widens the differential diagnosis of Emery-Dreifuss-like syndromes.
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http://dx.doi.org/10.1002/ana.21839DOI Listing
January 2010

Improving global and regional resolution of male lineage differentiation by simple single-copy Y-chromosomal short tandem repeat polymorphisms.

Forensic Sci Int Genet 2009 Sep 23;3(4):205-13. Epub 2009 Feb 23.

Department of Forensic Molecular Biology, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.

We analyzed 67 short tandem repeat polymorphisms from the non-recombining part of the Y-chromosome (Y-STRs), including 49 rarely studied simple single-copy (ss)Y-STRs and 18 widely used Y-STRs, in 590 males from 51 populations belonging to 8 worldwide regions (HGDP-CEPH panel). Although autosomal DNA profiling provided no evidence for close relationship, we found 18 Y-STR haplotypes (defined by 67 Y-STRs) that were shared by two to five men in 13 worldwide populations, revealing high and widespread levels of cryptic male relatedness. Maximal (95.9%) haplotype resolution was achieved with the best 25 out of 67 Y-STRs in the global dataset, and with the best 3-16 markers in regional datasets (89.6-100% resolution). From the 49 rarely studied ssY-STRs, the 25 most informative markers were sufficient to reach the highest possible male lineage differentiation in the global (92.2% resolution), and 3-15 markers in the regional datasets (85.4-100%). Considerably lower haplotype resolutions were obtained with the three commonly used Y-STR sets (Minimal Haplotype, PowerPlex Y, and AmpFlSTR Yfiler. Six ssY-STRs (DYS481, DYS533, DYS549, DYS570, DYS576 and DYS643) were most informative to supplement the existing Y-STR kits for increasing haplotype resolution, or - together with additional ssY-STRs - as a new set for maximizing male lineage differentiation. Mutation rates of the 49 ssY-STRs were estimated from 403 meiotic transfers in deep-rooted pedigrees, and ranged from approximately 4.8 x 10(-4) for 31 ssY-STRs with no mutations observed to 1.3 x 10(-2) and 1.5 x 10(-2) for DYS570 and DYS576, respectively, the latter representing the highest mutation rates reported for human Y-STRs so far. Our findings thus demonstrate that ssY-STRs are useful for maximizing global and regional resolution of male lineages, either as a new set, or when added to commonly used Y-STR sets, and support their application to forensic, genealogical and anthropological studies.
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http://dx.doi.org/10.1016/j.fsigen.2009.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312386PMC
September 2009

Relating two deep-rooted pedigrees from Central Germany by high-resolution Y-STR haplotyping.

Forensic Sci Int Genet 2007 Jun 13;1(2):125-8. Epub 2007 Mar 13.

Department of Forensic Molecular Biology, Erasmus MC-University Medical Center Rotterdam, The Netherlands.

Y-STR haplotyping is a powerful forensic and anthropological tool for identifying male lineages. We used high-resolution Y-STR haplotyping to evaluate the possibility of a blood relationship between two deep-rooted paternal genealogies with the same surname and originating from the same geographical region in Central Germany. One pedigree comprised 13 generations covering >450 years, the other comprised nine generations covering >300 years. Of the 68 loci tested, 64 (94%) consistently had the same allele in all males in the two pedigrees (except for some unambiguously sporadic mutations within pedigrees). Only four Y-STRs had a consistent allelic difference of exactly one repeat between the two pedigrees. These findings suggested that the two pedigrees were paternally related, and a conservative assessment taking average mutation rates and the available local haplotype frequencies for nine loci into account yielded a likelihood ratio of 8.2:1 in favour of this hypothesis. Our study thus highlights the power of Y-STR haplotyping to identify male lineages. It also shows that families can be linked to common ancestors on the basis of Y-STR data, even if these individuals lived several hundred years ago. However, the potential of Y-STR haplotyping could still not be fully exploited in our case due to a lack of appropriate population frequency data for all analysed Y-STR loci. This shortcoming makes a strong case for more comprehensive haplotype databases, including more samples and larger numbers of loci.
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http://dx.doi.org/10.1016/j.fsigen.2007.02.004DOI Listing
June 2007

Monozygotic twins concordant for female-to-male transsexualism: a case report.

Arch Sex Behav 2007 Apr;36(2):135-7

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http://dx.doi.org/10.1007/s10508-006-9156-xDOI Listing
April 2007

Concordant association of lipid gene variation with a combined HDL/LDL-cholesterol phenotype in two European populations.

Hum Hered 2006 12;61(3):123-31. Epub 2006 Jun 12.

Department of Bioinformatics, Max Delbruck Center for Molecular Medicine, Berlin, Germany.

Objective: SNP/phenotype associations are difficult to validate. This comparative study demonstrates significant contribution of candidate genes to the variation of a complex cholesterol phenotype, measured in two general populations by a gene-based approach.

Methods: Independent samples of normolipidemic subjects from two Caucasian populations (371 Swiss and 157 Germans) were selected for a case-control-study (high LDL/low HDL versus low LDL/high HDL) with SNP genotypes as independent factors. We examined locus-specific common SNPs that densely cover the genomic regions of 10 lipid genes.

Results: Genotype effects were concordant in both ethnic samples, showing that APOE, ABCA1, CETP, and to a lesser degree LDLR, LIPC, and PLTP explained a substantial part of the genetic variation, whereas LPL was associated in only one sample. APOA1, LCAT, and SRB1 exerted no measurable influence.

Conclusion: This comparison showed that sets of common SNPs representing candidate regions reproducibly validate significant linkage disequilibrium association with a complex metabolic trait.
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http://dx.doi.org/10.1159/000093773DOI Listing
October 2006

Insulin resistance in healthy prepubertal twins.

J Pediatr 2004 May;144(5):608-13

Liggins Institute, Health Research Council Biostatistics Unit, Department of Community Health, University of Auckland, Auckland, New Zealand.

Objectives: To evaluate insulin sensitivity (S(I)) in prepubertal twins and to examine the relation to reduced birth weight, prematurity, and peroxisome proliferator-activated receptor-gamma (PPAR gamma) polymorphism.

Study Design: Fifty twins (birth weight SDS, -0.7 +/- 0.2; gestation, 33.5 +/- 0.5 weeks; and body mass index SDS, -0.04 +/- 0.2) were studied at 8.2 +/- 0.3 years. S(I) was measured by Bergman's minimal model from a 90 minutes frequently sampled intravenous glucose test. Twenty control children (height SDS, -1.7 +/- 0.3; birth weight SDS, -0.3 +/- 0.2; and gestation of 39.2 +/- 0.7 weeks) were also evaluated at 7.0 +/- 0.4 years. The PPAR gamma T-variant polymorphism was evaluated in 41 twins. Values are expressed as mean +/- SEM, or 95% confidence intervals.

Results: S(I) was reduced in twins compared with control subjects, (12.7 [11-15] versus 23.0 [16.8-31.4] 10(-4) min(-1) microU/mL, respectively, P=.005). The reduction in S(I) was independent of prematurity and birth weight and zygosity (P<.0001). There was no difference in S(I), even in twin pairs with >20% difference in birth weight (P=.9). The PPAR gamma heterozygote T-variant polymorphism was present in 7 of 41, with a further reduction in S(I) (P=.03) and a later gestation (P=.03). These twins also had increased fat mass (P=.02) but with similar fat free mass (P=.14).

Conclusions: Twin children, independent of prematurity or birth weight, had a marked reduction in S(I). To use twins as a model to study the fetal origins of adult diseases for glucose homeostasis is not valid.
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http://dx.doi.org/10.1016/j.jpeds.2004.01.059DOI Listing
May 2004

Haplotypes and SNPs in 13 lipid-relevant genes explain most of the genetic variance in high-density lipoprotein and low-density lipoprotein cholesterol.

Hum Mol Genet 2004 May 25;13(10):993-1004. Epub 2004 Mar 25.

Medical Faculty of the Charité, Franz Volhard Clinic, Helios Klinikum, Berlin, Germany.

Single nucleotide polymorphisms (SNPs) and derived haplotypes within multiple genes may explain genetic variance in complex traits; however, this hypothesis has not been rigorously tested. In an earlier study we analyzed six genes and have now expanded this investigation to include 13. We studied 250 families including 1054 individuals and measured lipid phenotypes. We focused on low-density cholesterol (LDL), high-density cholesterol (HDL) and their ratio (LDL/HDL). A component analysis of the phenotypic variance relying on a standard genetic model' showed that the genetic variance on LDL explained 26%, on HDL explained 38% and on LDL/HDL explained 28% of the total variance, respectively. Genotyping of 93 SNPs in 13 lipid-relevant genes generated 230 haplotypes. The association of haplotypes in all the genes tested explained a major fraction of the genetic phenotypic variance component. For LDL, the association with haplotypes explained 67% and for HDL 58% of the genetic variance relative to the polygenic background. We conclude that these haplotypes explain most of the genetic variance in LDL, HDL and LDL/HDL in these representative German families. An analysis of the contribution to the genetic variance at each locus showed that APOE (50%), CETP (28%), LIPC (9%), APOB (8%) and LDLR (5%) influenced variation in LDL. LIPC (53%), CETP (25%), ABCA1 (10%), LPL (6%) and LDLR (6%) influenced the HDL variance. The LDL/HDL ratio was primarily influenced by APOE (36%), CETP (27%) and LIPC (31%). This expanded analysis substantially increases the explanation of genetic variance on these complex traits.
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http://dx.doi.org/10.1093/hmg/ddh119DOI Listing
May 2004

Two brothers with findings resembling congenital intrauterine infection-like syndrome (pseudo-TORCH syndrome).

Am J Med Genet A 2003 Jul;120A(2):261-5

Institut für Medizinische Genetik, Medizinische Fakultät Charité, Humboldt Universität zu Berlin, Germany.

Clinical, pathological, and X-ray findings of two brothers with features resembling congenital intrauterine infection-like syndrome are presented. Extensive screening for intrauterine infection was performed. Nevertheless all confirmatory tests were normal. Both brothers showed extensive intra- and extra-cranial calcifications, thrombocytopenia, a septum pellucidum cyst, one-sided paresis of the diaphragm, and metaphyseal changes on X-ray scans resembling intrauterine infection. Within the first days of life, they developed seizures and died from severe cerebral hemorrhage. The MRI scan of the brain showed cerebellar hypoplasia in one of the boys, while the cerebellum had normal size in the other. No indication of a metabolic disorder, especially in calcium metabolism, was identified. Due to the clinical overlap with Hoyeraal-Hreidarsson syndrome, mutations in the DKC1 gene (Xq28) and the hTR gene (RNA component of telomerase on chromosome 3q) have been excluded. The parents are non-consanguineous and further family history was unremarkable. The findings in these boys overlap with features described in congenital intrauterine infection-like syndrome (pseudo-TORCH syndrome).
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http://dx.doi.org/10.1002/ajmg.a.20138DOI Listing
July 2003

Single nucleotide polymorphism haplotypes in the cholesteryl-ester transfer protein (CETP) gene and lipid phenotypes.

Hum Hered 2002 ;54(4):166-73

Max Delbrück Center, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.

We studied the association between high (HDL) and low-density (LDL) cholesterol concentrations and family-derived haplotypes based on six common SNPs in the cholesteryl-ester transfer protein (CETP) gene. We based our analysis on 201 founders from families recruited throughout Germany. The analysis revealed one subhaplotype block with complete, pairwise, linkage disequilibrium between 5 SNPs located in the promoter and intron 1. The sixth SNP was the well known 1405V polymorphism in exon 14, close to the 3' end of the gene. Four haplotypes accounted for 86% of the entire sample. We found that haplotype associations with HDL, LDL, and the LDL/HDL ratio were more robust than associations with individual SNPs. Moreover, the associations were robust for men, but not for women. Our data suggest an interaction between gender and genetic variation within the CETP gene.
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http://dx.doi.org/10.1159/000070662DOI Listing
July 2003

DNA testing for familial hypercholesterolemia: improving disease recognition and patient care.

Am J Pharmacogenomics 2002 ;2(4):253-62

Max Delbruck Center for Molecular Medicine, University Hospital Charité, Humboldt University of Berlin, Berlin, Germany.

Cardiovascular disease is the leading cause of death worldwide and, like most chronic diseases, it has major genetic and environmental components. Among patients with coronary heart disease onset before the age of 55, about 5% of cases are attributable to heterozygous familial hypercholesterolemia (FH), a disease following autosomal dominant inheritance. About 50% of individuals with FH die before the age of 60 due to myocardial infarction. The frequency of FH is estimated to be 1 : 500. FH is related to mutations in the low-density lipoprotein (LDL)-cholesterol LDL-receptor gene and apolipoprotein B (apoB) gene. The identification of individuals with FH has been based on lipid levels and segregation of lipid levels within the family. However, phenotypes are overlapping and family history is not always informative. Therefore, a DNA-based genetic test for FH appears to offer the best alternative. The DNA test gives a simple yes/no answer. The FH test is a definitive tool for the identification of affected family members. The approach of targeted family genetic screening to find new patients is faster and more reliable compared with a biochemical form of screening. Early identification and efficient treatment of such patients is important and highly cost effective. There is evidence to suggest that the nature of the LDL-receptor (LDLR) mutation influences the degree of cholesterol lowering achieved by HMG-CoA reductase inhibitors (statins). The observed differences in the LDL-cholesterol (LDL-C) responses to these drugs among the various LDLR gene mutations are not yet completely understood. The relationships shown between LDLR mutation types and lipid levels, and the response of lipid levels to HMG-CoA reductase inhibitor treatment, will have to be investigated within the framework of pharmacogenetic studies. The variables, which are important in determining the overall atherosclerosis risk, are the result of combined activity in a dynamic network of numerous genes and environment. Candidate genes for atherosclerosis need to be further tested and validated. Future research should be directed at determining the significance of such targets, which patients with FH are at particularly high risk of premature cardiovascular disease, and which environmental factors are effective in modulating this risk. Genetics-based diagnostics will complement identification of FH while improving cardiovascular risk prediction, prevention of disease and treatment efficacy.
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http://dx.doi.org/10.2165/00129785-200202040-00005DOI Listing
May 2003

Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population.

Hum Mol Genet 2002 Jun;11(12):1477-85

Franz Volhard Clinic, HELIOS Kliniken, Berlin, Germany.

We studied the association between common haplotypes in six relevant lipid metabolism genes with plasma lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic triglyceride lipase (HL), low-density lipoprotein cholesterol receptor (LDLR), apolipoprotein E (ApoE) and lecithin-cholesterol acyltransferase (LCAT) genes, and studied 732 individuals from 184 German families. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) were similar to those reported in other European and American populations. Haplotypes derived from SNP combinations resulted in more significance and of a higher degree than did single SNPs in the genotype-phenotype association analysis. Reduction of the polygenic variance attributable to haplotypes was estimated using variance components analysis. Under the biometrical genetic model, allelic association of haplotypes was highly significant for HDL, LDL and the LDL/HDL ratio. The residual kinship correlation was reduced accordingly. The ApoE gene had a strong effect on trait variation; however, the other genes also contributed substantially. An epistatic interaction could not be demonstrated in this sample. The data are consistent with the notion that common genetic variants influence common traits.
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http://dx.doi.org/10.1093/hmg/11.12.1477DOI Listing
June 2002