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1. Assembly and analysis of 100 full MHC haplotypes from the Danish population

Author

Jensen, Jacob M., Villesen, Palle, Friborg, Rune M., Mailund, Thomas, Besenbacher, Søren, Sørensen, Lasse Maretty, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Skov, Laurits, Belling, Kirstine G, Have, Christian Theil, Izarzugaza, Jose M. G., Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, Beusekom, Johan V., Espeseth, Thomas, Flindt, Esben, Halager, Anders E., Hellard, Stephanie Le, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Matey-Hernandez, Maria Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick, Syed, Ali, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Bolund, Lars, Krogh, Anders, Sørensen, Thorkild I. A., Pedersen, Oluf Borbye, Gupta, Ramneek, Rasmussen, Simon, Børglum, Anders D., Wang, Jun, Eiberg, Hans Rudolf Lytchoff, Kristiansen, Karsten, Brunak, Søren, and Schierup, Mikkel Heide

Subjects
Resource, 0301 basic medicine, Linkage disequilibrium, Denmark, Human leukocyte antigen, Biology, Balancing selection, Major histocompatibility complex, Polymorphism, Single Nucleotide, Genome, Linkage Disequilibrium, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Genetics, Humans, Alleles, Genetics (clinical), Haplotype, Chromosome Mapping, Genetic Variation, Genetics, Population, 030104 developmental biology, Haplotypes, Evolutionary biology, biology.protein, 030217 neurology & neurosurgery, Imputation (genetics), Reference genome
Abstract

Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

Published
2017
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2. Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios

Author

Matey-Hernandez, Maria Luisa, Brunak, Søren, Izarzugaza, Jose M.G., Sørensen, Lasse Maretty, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Belling, Kirstine G, Have, Christian Theil, Bork-Jensen, Jette, Sun, Jihua, Hansen, Torben, Krogh, Anders, Sørensen, Thorkild I.A., Pedersen, Oluf Borbye, Wang, Jun, Eiberg, Hans Rudolf Lytchoff, Kristiansen, Karsten, Matey-Hernandez, Maria Luisa, Brunak, Søren, Izarzugaza, Jose M.G., Sørensen, Lasse Maretty, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Belling, Kirstine G, Have, Christian Theil, Bork-Jensen, Jette, Sun, Jihua, Hansen, Torben, Krogh, Anders, Sørensen, Thorkild I.A., Pedersen, Oluf Borbye, Wang, Jun, Eiberg, Hans Rudolf Lytchoff, and Kristiansen, Karsten

Abstract

BACKGROUND: The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in next-generation sequencing (NGS) methodologies, have increased the need for precise computational typing methods.RESULTS: We tested two widespread HLA typing methods using high quality full genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles.CONCLUSIONS: Although current computational methods for HLA typing generally provide satisfactory results, our benchmark - using data with ultra-high sequencing depth - demonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.

Published
2018

3. Gastroschise og Omphalocele i Grønland 1989-2015

Author

Bugge, Merete, Drachmann, Gitte, Kern, Peder, Budtz-Jørgensen, Esben, Eiberg, Hans Rudolf Lytchoff, Olsen, Britta, Tommerup, Niels, Nielsen, Inge-Merete, Bugge, Merete, Drachmann, Gitte, Kern, Peder, Budtz-Jørgensen, Esben, Eiberg, Hans Rudolf Lytchoff, Olsen, Britta, Tommerup, Niels, and Nielsen, Inge-Merete

Published
2018

5. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference

Author

Sørensen, Lasse Maretty, Jensen, Jacob Malte, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Villesen, Palle, Skov, Laurits, Belling, Kirstine G, Have, Christian Theil, Izarzugaza, Jose M. G., Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, van Beusekom, Johan, Espeseth, Thomas, Flindt, Esben, Friborg, Rune M., Halager, Anders E., Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Mailund, Thomas, Matey-Hernandez, Maria Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick, Syed, Ali, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Sørensen, Thorkild I. A., Pedersen, Oluf Borbye, Gupta, Ramneek, Rasmussen, Simon, Besenbacher, Søren, Børglum, Anders D., Wang, Jun, Eiberg, Hans Rudolf Lytchoff, Kristiansen, Karsten, Brunak, Søren, Schierup, Mikkel Heide, Sørensen, Lasse Maretty, Jensen, Jacob Malte, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Villesen, Palle, Skov, Laurits, Belling, Kirstine G, Have, Christian Theil, Izarzugaza, Jose M. G., Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, van Beusekom, Johan, Espeseth, Thomas, Flindt, Esben, Friborg, Rune M., Halager, Anders E., Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Mailund, Thomas, Matey-Hernandez, Maria Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick, Syed, Ali, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Sørensen, Thorkild I. A., Pedersen, Oluf Borbye, Gupta, Ramneek, Rasmussen, Simon, Besenbacher, Søren, Børglum, Anders D., Wang, Jun, Eiberg, Hans Rudolf Lytchoff, Kristiansen, Karsten, Brunak, Søren, and Schierup, Mikkel Heide

Abstract

Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits1, 2, 3, 4. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly2, 5, 6, 7. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology4, 8, 9, 10, 11, 12, 13. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.

Published
2017

6. Heterogeneity in glucose response curves during an oral glucose tolerance test and associated cardiometabolic risk

Author

Hulman, Adam, Simmons, Rebecca Kate, Vistisen, Dorte, Tabák, Adam G, Dekker, Jacqueline M, Alssema, Marjan, Rutters, Femke, Koopman, Anitra D M, Solomon, Thomas P J, Kirwan, John P, Hansen, Torben, Jonsson, Anna Elisabet, Gjesing, Anette Marianne Prior, Eiberg, Hans Rudolf Lytchoff, Astrup, Arne, Pedersen, Oluf Borbye, Sørensen, Thorkild I.A., Witte, Daniel, Færch, Kristine, Hulman, Adam, Simmons, Rebecca Kate, Vistisen, Dorte, Tabák, Adam G, Dekker, Jacqueline M, Alssema, Marjan, Rutters, Femke, Koopman, Anitra D M, Solomon, Thomas P J, Kirwan, John P, Hansen, Torben, Jonsson, Anna Elisabet, Gjesing, Anette Marianne Prior, Eiberg, Hans Rudolf Lytchoff, Astrup, Arne, Pedersen, Oluf Borbye, Sørensen, Thorkild I.A., Witte, Daniel, and Færch, Kristine

Abstract

We aimed to examine heterogeneity in glucose response curves during an oral glucose tolerance test with multiple measurements and to compare cardiometabolic risk profiles between identified glucose response curve groups. We analyzed data from 1,267 individuals without diabetes from five studies in Denmark, the Netherlands and the USA. Each study included between 5 and 11 measurements at different time points during a 2-h oral glucose tolerance test, resulting in 9,602 plasma glucose measurements. Latent class trajectories with a cubic specification for time were fitted to identify different patterns of plasma glucose change during the oral glucose tolerance test. Cardiometabolic risk factor profiles were compared between the identified groups. Using latent class trajectory analysis, five glucose response curves were identified. Despite similar fasting and 2-h values, glucose peaks and peak times varied greatly between groups, ranging from 7–12 mmol/L, and 35–70 min. The group with the lowest and earliest plasma glucose peak had the lowest estimated cardiovascular risk, while the group with the most delayed plasma glucose peak and the highest 2-h value had the highest estimated risk. One group, with normal fasting and 2-h values, exhibited an unusual profile, with the highest glucose peak and the highest proportion of smokers and men. The heterogeneity in glucose response curves and the distinct cardiometabolic risk profiles may reflect different underlying physiologies. Our results warrant more detailed studies to identify the source of the heterogeneity across the different phenotypes and whether these differences play a role in the development of type 2 diabetes and cardiovascular disease.

Published
2017

7. Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology

Author

Schnurr, Theresia Maria, Gjesing, Anette Marianne Prior, Sandholt, Camilla Helene, Jonsson, Anna Elisabet, Mahendran, Yuvaraj, Have, Christian Theil, Ekstrøm, Claus Thorn, Bjerregaard, Anne-Louise, Brage, Søren, Witte, Daniel, Jørgensen, Marit Eika, Aadahl, Mette, Thuesen, Betina Heinsbæk, Linneberg, Allan René, Eiberg, Hans Rudolf Lytchoff, Pedersen, Oluf Borbye, Grarup, Niels, Oskari Kilpeläinen, Tuomas, Hansen, Torben, Schnurr, Theresia Maria, Gjesing, Anette Marianne Prior, Sandholt, Camilla Helene, Jonsson, Anna Elisabet, Mahendran, Yuvaraj, Have, Christian Theil, Ekstrøm, Claus Thorn, Bjerregaard, Anne-Louise, Brage, Søren, Witte, Daniel, Jørgensen, Marit Eika, Aadahl, Mette, Thuesen, Betina Heinsbæk, Linneberg, Allan René, Eiberg, Hans Rudolf Lytchoff, Pedersen, Oluf Borbye, Grarup, Niels, Oskari Kilpeläinen, Tuomas, and Hansen, Torben

Abstract

Objectives: It has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus associates with CRF. Methods: Genetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (ntotal = 3206). The body fat% GRS was created by summing the alleles of twelve independent risk variants known to associate with body fat%. We assessed CRF as maximal oxygen uptake expressed in millilitres of oxygen uptake per kg of body mass (VO2max), per kg fat-free mass (VO2maxFFM), or per kg fat mass (VO2maxFM). All analyses were adjusted for age and sex, and when relevant, for body composition. Results: We found a significant negative genetic correlation between VO2max and body fat% (ρG = -0.72 (SE ±0.13)). The body fat% GRS associated with decreased VO2max (β = -0.15 mL/kg/min per allele, p = 0.0034, age and sex adjusted). The body fat%-increasing FTO allele was associated with a 0.42 mL/kg/min unit decrease in VO2max per allele (p = 0.0092, age and sex adjusted). Both associations were abolished after additional adjustment for body fat%. The fat% increasing GRS and FTO risk allele were associated with decreased VO2maxFM but not with VO2maxFFM. Conclusions: Our findings suggest a shared genetic etiology between whole body fat% and CRF.

Published
2016

9. The influence of parental history of diabetes and offspring birthweight on offspring glucose metabolism in adulthood

Author

Lauenborg, Jeannet, Jørgensen, Mie K W, Damm, Peter, Major-Pedersen, Atheline, Eiberg, Hans Rudolf Lytchoff, Urhammer, Søren, Pedersen, Oluf, and Hansen, Torben

Subjects
stomatognathic diseases, reproductive and urinary physiology
Abstract

Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood.

Published
2011
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10. Risk of cancer in relatives of patients with myotonic dystrophy:a population-based cohort study

Author

Lund, M, Diaz, L J, Gørtz, S, Feenstra, B, Duno, Morten, Juncker, I, Eiberg, Hans Rudolf Lytchoff, Vissing, John, Wohlfahrt, J, Melbye, Mads, Lund, M, Diaz, L J, Gørtz, S, Feenstra, B, Duno, Morten, Juncker, I, Eiberg, Hans Rudolf Lytchoff, Vissing, John, Wohlfahrt, J, and Melbye, Mads

Abstract

BACKGROUND AND PURPOSE: Myotonic dystrophies (DM) are autosomal dominantly inherited neuromuscular disorders caused by unstable nucleotide repeat expansions. DM and cancer have been associated, but the pathogenesis behind the association remains unclear. It could relate to derived effects of the DM genotype in which case non-DM relatives of DM patients would not be expected to be at increased risk of cancer. To elucidate this, a population-based cohort study investigating risk of cancer in relatives of DM patients was conducted.METHODS: DM was identified using the National Danish Patient Registry and results of genetic testing. Information on cancer was obtained from the Danish Cancer Registry. A population-based cohort of 5 757 565 individuals with at least one relative was established using the Danish Family Relations Database based on kinship links in the Danish Civil Registration System. Familial aggregation of cancer was evaluated by (incidence) rate ratios (RRs) comparing the rate of cancer amongst relatives of patients with DM from 1977 to 2010 (exposed) with the rate of cancer amongst persons with a relative of the same type but without DM (non-exposed).RESULTS: In first-degree relatives of individuals with DM the adjusted RR of cancer was 0.89 (95% confidence interval 0.71-1.12) overall, and in stratified analyses 0.68 (0.37-1.12) before age 50 and 0.96 (0.74-1.23) at age 50 or older.CONCLUSIONS: The present study does not support an increased risk of cancer in non-DM relatives of DM patients suggesting that cancer and DM are associated through derived effects of the DM genotype.

Published
2014

13. Fasting and oral glucose-stimulated levels of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are highly familial traits

Author

Gjesing, Anette Marianne Prior, Ekstrøm, Claus Thorn, Eiberg, Hans Rudolf Lytchoff, Urhammer, S.A., Holst, Jens Juul, Pedersen, Oluf, Hansen, Teis, Gjesing, Anette Marianne Prior, Ekstrøm, Claus Thorn, Eiberg, Hans Rudolf Lytchoff, Urhammer, S.A., Holst, Jens Juul, Pedersen, Oluf, and Hansen, Teis

Abstract

Heritability estimates have shown a varying degree of genetic contribution to traits related to type 2 diabetes. Therefore, the objective of this study was to investigate the familiality of fasting and stimulated measures of plasma glucose, serum insulin, serum C-peptide, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) among non-diabetic relatives of Danish type 2 diabetic patients.

Published
2012

14. Family and population-based studies of variation within the ghrelin receptor locus in relation to measures of obesity

Author

Gjesing, Anette P., Larsen, Lesli Hingstrup, Torekov, Signe Sørensen, Hainerová, Irena Aldhoon, Kapur, Rahul, Johansen, Anders, Albrechtsen, Anders, Boj, Sylvia, Holst, Birgitte, Harper, Angela, Urhammer, Søren A., Borch-Johnsen, Knut, Pisinger, Charlotta Holm, Echwald, Søren M, Eiberg, Hans Rudolf Lytchoff, Astrup, Arne, Lebl, Jan, Ferrer, Jorge, Schwartz, Thue W., Hansen, Torben, Pedersen, Oluf, Gjesing, Anette P., Larsen, Lesli Hingstrup, Torekov, Signe Sørensen, Hainerová, Irena Aldhoon, Kapur, Rahul, Johansen, Anders, Albrechtsen, Anders, Boj, Sylvia, Holst, Birgitte, Harper, Angela, Urhammer, Søren A., Borch-Johnsen, Knut, Pisinger, Charlotta Holm, Echwald, Søren M, Eiberg, Hans Rudolf Lytchoff, Astrup, Arne, Lebl, Jan, Ferrer, Jorge, Schwartz, Thue W., Hansen, Torben, and Pedersen, Oluf

Abstract

BACKGROUND: The growth hormone secretagogue receptor (GHSR) is mediating hunger sensation when stimulated by its natural ligand ghrelin. In the present study, we tested the hypothesis that common and rare variation in the GHSR locus are related to increased prevalence of obesity and overweight among Whites. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based study sample of 15,854 unrelated, middle-aged Danes, seven variants were genotyped to capture common variation in an 11 kbp region including GHSR. These were investigated for their individual and haplotypic association with obesity. None of these analyses revealed consistent association with measures of obesity. A -151C/T promoter mutation in the GHSR was found in two unrelated obese patients. One family presented with complete co-segregation, but the other with incomplete co-segregation. The mutation resulted in an increased transcriptional activity (p<0.02) and introduction of a specific binding for Sp-1-like nuclear extracts relative to the wild type. The -151C/T mutation was genotyped in the 15,854 Danes with a minor allele frequency of 0.01%. No association with obesity in carriers (mean BMI: 27+/-4 kg/m(2)) versus non-carriers (mean BMI: 28+/-5 kg/m(2)) (p>0.05) could be shown. CONCLUSIONS/SIGNIFICANCE: In a population-based study sample of 15,854 Danes no association between GHSR genotypes and measures of obesity and overweight was found. Also, analyses of GHSR haplotypes lack consistent associations with obesity related traits. A rare functional GHSR promoter mutation variant was identified, yet there was no consistent relationship with obesity in neither family- nor population-based studies.

Published
2010

17. Polymorphic drug metabolizing CYP-enzymes - a pathogenic factor in oral lichen planus?

Author

Kragelund, Camilla, Hansen, Claus, Reibel, Jesper, Nauntofte, Birgitte, Brøsen, Kim, Pedersen, Anne Marie Lynge, Smidt, Dorte, Eiberg, Hans Rudolf Lytchoff, Torpet, Lis Andersen, Kragelund, Camilla, Hansen, Claus, Reibel, Jesper, Nauntofte, Birgitte, Brøsen, Kim, Pedersen, Anne Marie Lynge, Smidt, Dorte, Eiberg, Hans Rudolf Lytchoff, and Torpet, Lis Andersen

Abstract

Udgivelsesdato: 2009

Published
2009

18. Non-disjunction of chromosome

Author

Bugge, Tove Merete, Collins, A., Hertz, J.M., Eiberg, Hans Rudolf Lytchoff, Lundsteen, C., Brandt, C.A., Hansen, C., deLozier, C.D., Lespinasse, J., Tranebjærg, Lisbeth, Hahnemann, J.M.D., Rasmussen, K., Bruun-Petersen, G., Duprez, L., Tommerup, Niels, Petersen, M.B., Bugge, Tove Merete, Collins, A., Hertz, J.M., Eiberg, Hans Rudolf Lytchoff, Lundsteen, C., Brandt, C.A., Hansen, C., deLozier, C.D., Lespinasse, J., Tranebjærg, Lisbeth, Hahnemann, J.M.D., Rasmussen, K., Bruun-Petersen, G., Duprez, L., Tommerup, Niels, and Petersen, M.B.

Abstract

Udgivelsesdato: 2007/8/15

Published
2007

19. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms

Author

Thiel, S., Steffensen, R., Christensen, Ib Jarle, Ip, W.K., Lau, Y.L., Reason, I.J.M., Eiberg, Hans Rudolf Lytchoff, Gadjeva, M., Ruseva, M., Jensenius, J.C., Thiel, S., Steffensen, R., Christensen, Ib Jarle, Ip, W.K., Lau, Y.L., Reason, I.J.M., Eiberg, Hans Rudolf Lytchoff, Gadjeva, M., Ruseva, M., and Jensenius, J.C.

Abstract

Udgivelsesdato: 2007/3

Published
2007

22. Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses

Author

Sanggaard, K.M., Rendtorff, Nanna Dahl, Kjær, K.W., Eiberg, Hans Rudolf Lytchoff, Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K.O., Lage, K., Tranebjærg, Lisbeth, Sanggaard, K.M., Rendtorff, Nanna Dahl, Kjær, K.W., Eiberg, Hans Rudolf Lytchoff, Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K.O., Lage, K., and Tranebjærg, Lisbeth

Abstract

Udgivelsesdato: 2007/11

Published
2007

25. Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Author

Bross, Peter, Li, Zhijie, Hansen, Jakob, Hansen, Jens Jacob, Nielsen, Marit Nyholm, Corydon, Thomas Juhl, Georgopoulos, Costa, Ang, Debbie, Lundemose, Jytte Banner, Niezen-Koning, Klary, Eiberg, Hans Rudolf Lytchoff, Yang, Huanming, Kølvraa, Steen, Bolund, Lars, Gregersen, Niels, Bross, Peter, Li, Zhijie, Hansen, Jakob, Hansen, Jens Jacob, Nielsen, Marit Nyholm, Corydon, Thomas Juhl, Georgopoulos, Costa, Ang, Debbie, Lundemose, Jytte Banner, Niezen-Koning, Klary, Eiberg, Hans Rudolf Lytchoff, Yang, Huanming, Kølvraa, Steen, Bolund, Lars, and Gregersen, Niels

Abstract

Molecular chaperones assist protein folding, and variations in their encoding genes may be disease-causing in themselves or influence the phenotypic expression of disease-associated or susceptibility-conferring variations in many different genes. We have screened three candidate patient groups for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had a significant impact. Taken together, our data argue against the notion that the chaperonin genes play a major role in the investigated diseases. However, the described variations may represent genetic modifiers with subtle effects.

Published
2007

26. Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young

Author

Ellard, S., Thomas, K., Edghill, E.L., Owens, M., Ambye, L., Cropper, J., Little, J., Strachan, M., Stride, A., Ersoy, B., Pedersen, O., Shepherd, M.H., Hansen, T., Harries, L.W., Hattersley, A.T., Eiberg, Hans Rudolf Lytchoff, Ellard, S., Thomas, K., Edghill, E.L., Owens, M., Ambye, L., Cropper, J., Little, J., Strachan, M., Stride, A., Ersoy, B., Pedersen, O., Shepherd, M.H., Hansen, T., Harries, L.W., Hattersley, A.T., and Eiberg, Hans Rudolf Lytchoff

Abstract

Udgivelsesdato: 2007/11

Published
2007

30. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Author

Witt, H., Sahin-Toth, M., Landt, O., Chen, J.M., Kahne, T., Drenth, J.P.H., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.U., Marechal, C. Le, Akar, N., Ammann, R.W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., Cavestro, G.M., Cerny, M., Destro-Bisol, G., Spedini, G., Jansen, J.B.M.J., Koudova, M., Rausova, E., Macek, M., Malats, N., Real, F.X., Menzel, H.J., Moral, P., Galavotti, R., Pignatti, P.F., Rickards, O., Spicak, J., Zarnescu, N.O., Bock, W., Gress, T.M., Friess, H., Ockenga, J., Schmidt, H., Pfutzer, R., Lohr, M., Simon, P., Weiss, F.U., Lerch, M.M., Teich, N., Keim, V., Berg, T., Wiedenmann, B., Luck, W., Groneberg, D.A., Becker, M., Keil, T., Kage, A., Bernardova, J., Braun, M., Guldner, C., Halangk, J., Rosendahl, J., Witt, U., Treiber, M., Nickel, R., Ferec, C., Eiberg, Hans Rudolf Lytchoff, Witt, H., Sahin-Toth, M., Landt, O., Chen, J.M., Kahne, T., Drenth, J.P.H., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.U., Marechal, C. Le, Akar, N., Ammann, R.W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., Cavestro, G.M., Cerny, M., Destro-Bisol, G., Spedini, G., Jansen, J.B.M.J., Koudova, M., Rausova, E., Macek, M., Malats, N., Real, F.X., Menzel, H.J., Moral, P., Galavotti, R., Pignatti, P.F., Rickards, O., Spicak, J., Zarnescu, N.O., Bock, W., Gress, T.M., Friess, H., Ockenga, J., Schmidt, H., Pfutzer, R., Lohr, M., Simon, P., Weiss, F.U., Lerch, M.M., Teich, N., Keim, V., Berg, T., Wiedenmann, B., Luck, W., Groneberg, D.A., Becker, M., Keil, T., Kage, A., Bernardova, J., Braun, M., Guldner, C., Halangk, J., Rosendahl, J., Witt, U., Treiber, M., Nickel, R., Ferec, C., and Eiberg, Hans Rudolf Lytchoff

Abstract

Udgivelsesdato: 2006/6

Published
2006

31. Heat-shock protein 70 genes and human longevity: a view from Denmark

Author

Singh, R., Kolvraa, S., Bross, P., Christensen, K., Gregersen, N., Tan, Q., Jensen, U.B., Eiberg, Hans Rudolf Lytchoff, Rattan, S.I., Singh, R., Kolvraa, S., Bross, P., Christensen, K., Gregersen, N., Tan, Q., Jensen, U.B., Eiberg, Hans Rudolf Lytchoff, and Rattan, S.I.

Abstract

Udgivelsesdato: 2006/5

Published
2006

45. Hereditary spastic paraplegia with cerebellar ataxia:a complex phenotype associated with a new SPG4 gene mutation.

Author

Nielsen, Jørgen Erik, Johnson, B, Koefoed, Pernille, Scheuer, K.H., Grønbech-Jensen, M., Law, I., Krabbe, K., Nørremølle, Anne, Eiberg, Hans Rudolf Lytchoff, Søndergård, H., Dam, M., Rehfeld, J.F., Krarup, C., Paulson, O.B., Hasholt, Lis Frydenreich, Sørensen, Sven Asger, Nielsen, Jørgen Erik, Johnson, B, Koefoed, Pernille, Scheuer, K.H., Grønbech-Jensen, M., Law, I., Krabbe, K., Nørremølle, Anne, Eiberg, Hans Rudolf Lytchoff, Søndergård, H., Dam, M., Rehfeld, J.F., Krarup, C., Paulson, O.B., Hasholt, Lis Frydenreich, and Sørensen, Sven Asger

Abstract

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations

Published
2004

46. No evidence of linkage between manic depressive illness and the dopa decarboxylase gene or nearby region on chromosome 7p

Author

Ewald, H, Mors, O, Eiberg, Hans Rudolf Lytchoff, Zacharov, Tracey Flint, and Kruse, T A

Subjects
Genetic Markers, Male, Bipolar Disorder, Models, Genetic, Genetic Linkage, Denmark, Chromosome Mapping, Genes, Recessive, Pedigree, Dopa Decarboxylase, Humans, Family, Female, Lod Score, Chromosomes, Human, Pair 7, Genes, Dominant
Abstract

Dopa decarboxylase (DDC) is involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. The present study investigated two Danish families for linkage between manic depressive illness, a marker at the DDC locus which has been mapped to 7p11-p13 and 10 microsatellite markers covering chromosome 7q11-p15. No evidence of linkage was found assuming a dominant or a recessive mode of inheritance. We have earlier reported evidence against linkage between manic depressive illness and tyrosine hydroxylase and dopamine beta-hydroxylase. Mutations of major importance in the genes encoding the three enzymes involved in the synthesis of dopamine and noradrenaline seem less likely in the families we have studied. Further investigations of genetic and other pathophysiological mechanisms in relation to the monoamine hypotheses for manic depressive illness are still of relevance. There is a need for further linkage and association studies as well as a search for possible mutations in the relevant genes involved in the monoaminergic pathways to clarify their possible role in the aetiology of manic depressive illness.

Published
1995

47. Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localised head to head on chromosome 2 seperated by a bidirectional promoter

Author

Hansen, Jens J., Broos, Peter, Westergaard, Majken, Nielsen, Marit Nyholm, Eiberg, Hans Rudolf Lytchoff, Børglum, Anders D., Mogensen, J., Kristiansen, Karsten, Bolund, Lars, Gregersen, Niels, Hansen, Jens J., Broos, Peter, Westergaard, Majken, Nielsen, Marit Nyholm, Eiberg, Hans Rudolf Lytchoff, Børglum, Anders D., Mogensen, J., Kristiansen, Karsten, Bolund, Lars, and Gregersen, Niels

Published
2003

48. Mutational analysis of the human FATE gene in 144 infertile men

Author

Olesen, C., Silber, J., Eiberg, Hans Rudolf Lytchoff, Ernst, E., Petersen, K, Lindenberg, S., Tommerup, Niels, Olesen, C., Silber, J., Eiberg, Hans Rudolf Lytchoff, Ernst, E., Petersen, K, Lindenberg, S., and Tommerup, Niels

Published
2003

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