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6. People get ready! A new generation of Alzheimer's therapies may require new ways to deliver and pay for healthcare.

Author

Wahlberg, Karin, Winblad, Bengt, Cole, Amanda, Herring, William L., Ramsberg, Joakim, Torontali, Ilona, Visser, Pieter‐Jelle, Wimo, Anders, Wollaert, Lieve, and Jönsson, Linus

Abstract

The development of disease‐modifying therapies (DMTs) for Alzheimer's disease (AD) has progressed over the last decade, and the first‐ever therapies with potential to slow the progression of disease are approved in the United States. AD DMTs could provide life‐changing opportunities for people living with this disease, as well as for their caregivers. They could also ease some of the immense societal and economic burden of dementia. However, AD DMTs also come with major challenges due to the large unmet medical need, high prevalence of AD, new costs related to diagnosis, treatment and monitoring, and uncertainty in the therapies' actual clinical value. This perspective article discusses, from the broad perspective of various health systems and stakeholders, how we can overcome these challenges and improve society's readiness for AD DMTs. We propose that innovative payment models such as performance‐based payments, in combination with learning healthcare systems, could be the way forward to enable timely patient access to treatments, improve accuracy of cost‐effectiveness evaluations and overcome budgetary barriers. Other important considerations include the need for identification of key drivers of patient value, the relevance of different economic perspectives (i.e. healthcare vs. societal) and ethical questions in terms of treatment eligibility criteria. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Contribution of child ABC-transporter genetics to prenatal MeHg exposure and neurodevelopment

Author

Love, Tanzy M, Wahlberg, Karin, Pineda, Daniela, Watson, Gene E, Zareba, Grazyna, Thurston, Sally W, Davidson, Philip W, Shamlaye, Conrad F, Myers, Gary J, Rand, Matthew, van Wijngaarden, Edwin, and Broberg, Karin

Subjects
General Neuroscience, Infant, Newborn, Infant, Mercury, Methylmercury Compounds, Seychelles, Toxicology, Article, Cohort Studies, Child Development, Seafood, Maternal Exposure, Pregnancy, Prenatal Exposure Delayed Effects, Fish Products, Humans, ATP-Binding Cassette Transporters, Female
Abstract

BACKGROUND: There is emerging evidence that exposure to prenatal methylmercury (MeHg) from maternal fish consumption during pregnancy can differ between individuals due to genetic variation. In previous studies, we have reported that maternal polymorphisms in ABC-transporter genes were associated with maternal hair MeHg concentrations, and with children’s early neurodevelopmental tests. In this study, we add to these findings by evaluating the contribution of genetic variation in children’s ABC-transporter genes to prenatal MeHg exposure and early child neurodevelopmental tests. METHODS: We genotyped six polymorphisms (rs2032582, rs10276499 and rs1202169 in ABCB1; rs11075290 and rs215088 in ABCC1; rs717620 in ABCC2) in DNA from cord blood and maternal blood of the Seychelles Child Development Study Nutrition Cohort 2. We determined prenatal MeHg exposure by measuring total mercury (Hg) in cord blood by atomic fluorescence spectrometry. We assessed neurodevelopment in children at approximately 20 months using the Bayley Scales of Infant Development (BSID-II). We used linear regression models to analyze covariate-adjusted associations of child genotype with cord MeHg and BSID-II outcomes (Mental Developmental and Psychomotor Developmental Indexes). We also evaluated interactions between genotypes, cord MeHg, and neurodevelopmental outcomes. All models were run with and without adjustment for maternal genotype. RESULTS: Of the six evaluated polymorphisms, only ABCC1 rs11075290 was associated with cord blood MeHg; children homozygous for the T-allele had on average 29.99 μg/L MeHg in cord blood while those homozygous for the C-allele had on average 38.06 μg/L MeHg in cord blood (p

Published
2022
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13. Filaggrin Polymorphisms and the Uptake of Chemicals through the Skin--A Human Experimental Study

Author

Liljedahl, Emelie Rietz, Johanson, Gunnar, Paula, Helena Korres de, Faniband, Moosa, Assarsson, Eva, Littorin, Margareta, Engfeldt, Malin, Liden, Carola, Julander, Anneli, Wahlberg, Karin, Lindh, Christian, and Broberg, Karin

Subjects
Cytoskeletal proteins -- Health aspects, Genetic polymorphisms -- Health aspects, Environmental issues, Health
Abstract

Background: The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals. Objective: The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype. Method: We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects' urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis. Results: Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20-22 repeats) and high FLG CNV (23-24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve [(AUC.sub.(0-40hj)]) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by [AUC.sub.(0-40hj)]) for pyrimethanil than wt carriers with low and high CNV, respectively. Conclusion: We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310, Introduction Exposure to chemicals on the skin can cause skin diseases, such as irritant and allergic contact dermatitis, urticaria, and skin cancer (Anderson and Meade 2014). Dermal exposure is also [...]

Published
2021
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14. Maternal and child fatty acid desaturase genotype as determinants of cord blood long-chain PUFA (LCPUFA) concentrations in the Seychelles Child Development Study

Author

Conway, Marie C., primary, McSorley, Emeir M., additional, Mulhern, Maria S., additional, Spence, Toni, additional, Weslowska, Maria, additional, Strain, J. J., additional, van Wijngaarden, Edwin, additional, Davidson, Phil W., additional, Myers, Gary J., additional, Wahlberg, Karin E., additional, Shamlaye, Conrad F., additional, Cobice, Diego F., additional, Hyland, Barry W., additional, Pineda, Daniela, additional, Broberg, Karin, additional, and Yeates, Alison J., additional

Published
2021
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15. Filaggrin Polymorphisms and the Uptake of Chemicals through the Skin—A Human Experimental Study

Author

Rietz Liljedahl, Emelie, primary, Johanson, Gunnar, additional, Korres de Paula, Helena, additional, Faniband, Moosa, additional, Assarsson, Eva, additional, Littorin, Margareta, additional, Engfeldt, Malin, additional, Lidén, Carola, additional, Julander, Anneli, additional, Wahlberg, Karin, additional, Lindh, Christian, additional, and Broberg, Karin, additional

Published
2021
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16. Metal Exposure and SNCA rs356219 Polymorphism Associated With Parkinson Disease and Parkinsonism

Author

Lucchini, Roberto G., primary, Guazzetti, Stefano, additional, Renzetti, Stefano, additional, Broberg, Karin, additional, Caci, Margherita, additional, Covolo, Loredana, additional, Crippa, Patrizia, additional, Gelatti, Umberto, additional, Hashim, Dana, additional, Oppini, Manuela, additional, Pepe, Fulvio, additional, Pilotto, Andrea, additional, Passeri, Chiara, additional, Placidi, Donatella, additional, Rizzetti, Maira Cristina, additional, Turla, Marinella, additional, Wahlberg, Karin, additional, and Padovani, Alessandro, additional

Published
2020
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19. The influence of fish consumption on serum n-3 polyunsaturated fatty acid (PUFA) concentrations in women of childbearing age: a randomised controlled trial (the iFish Study)

Author

Conway, Marie C., primary, McSorley, Emeir M., additional, Mulhern, Maria S., additional, Spence, Toni, additional, Wijngaarden, Edwin van, additional, Watson, Gene E., additional, Wahlberg, Karin, additional, Pineda, Daniela, additional, Broberg, Karin, additional, Hyland, Barry W., additional, Cobice, Diego F., additional, Strain, J. J., additional, and Yeates, Alison J., additional

Published
2020
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20. Maternal Long-Chain Polyunsaturated Fatty Acid Status, Methylmercury Exposure, and Birth Outcomes in a High-Fish-Eating Mother–Child Cohort

Author

Yeates, Alison Jayne, primary, Zavez, Alexis, additional, Thurston, Sally W, additional, McSorley, Emeir M, additional, Mulhern, Maria S, additional, Alhamdow, Ayman, additional, Engström, Karin, additional, Wahlberg, Karin, additional, Strain, J J, additional, Watson, Gene E, additional, Myers, Gary J, additional, Davidson, Philip W, additional, Shamlaye, Conrad F, additional, Broberg, Karin, additional, and van Wijngaarden, Edwin, additional

Published
2020
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22. The influence of maternal and child FADS genotype on cord blood polyunsaturated fatty acid (PUFA) concentrations

Author

Conway, Marie C., primary, Mulhern, Maria S., additional, McSorley, Emeir M., additional, Strain, J.J., additional, van Wijngaarden, Edwin, additional, Davidson, Phil W., additional, Myers, Gary J., additional, Wahlberg, Karin, additional, Shamlaye, Conrad F., additional, Pineda, Daniela, additional, Broberg, Karin, additional, and Yeates, Alison J, additional

Published
2020
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24. Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children

Author

Broberg, Karin, primary, Taj, Tahir, additional, Guazzetti, Stefano, additional, Peli, Marco, additional, Cagna, Giuseppa, additional, Pineda, Daniela, additional, Placidi, Donatella, additional, Wright, Robert O., additional, Smith, Donald R., additional, Lucchini, Roberto G., additional, and Wahlberg, Karin, additional

Published
2019
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25. Associations of blood mercury and fatty acid concentrations with blood mitochondrial DNA copy number in the Seychelles Child Development Nutrition Study

Author

Xu, Yiyi, primary, Wahlberg, Karin, additional, Love, Tanzy M., additional, Watson, Gene E., additional, Yeates, Alison J., additional, Mulhern, Maria S., additional, McSorley, Emeir M., additional, Strain, J.J., additional, Davidson, Philip W., additional, Shamlaye, Conrad F., additional, Rand, Matthew D., additional, Myers, G.J., additional, van Wijngaarden, Edwin, additional, and Broberg, Karin, additional

Published
2019
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27. Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis

Author

Wahlberg, Karin E., primary, Guazzetti, Stefano, additional, Pineda, Daniela, additional, Larsson, Susanna C., additional, Fedrighi, Chiara, additional, Cagna, Giuseppa, additional, Zoni, Silvia, additional, Placidi, Donatella, additional, Wright, Robert O., additional, Smith, Donald R., additional, Lucchini, Roberto G., additional, and Broberg, Karin, additional

Published
2018
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28. Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis

Author

Wahlberg, Karin E, Guazzetti, Stefano, Pineda, Daniela, Larsson, Susanna C., Fedrighi, Chiara, Cagna, Giuseppa, Zoni, Silvia, Placidi, Donatella, Wright, Robert O, Smith, Donald R, Lucchini, Roberto G, Broberg, Karin, Wahlberg, Karin E, Guazzetti, Stefano, Pineda, Daniela, Larsson, Susanna C., Fedrighi, Chiara, Cagna, Giuseppa, Zoni, Silvia, Placidi, Donatella, Wright, Robert O, Smith, Donald R, Lucchini, Roberto G, and Broberg, Karin

Abstract

Background: Manganese (Mn) is an essential element but at excessive levels, it is neurotoxic. Even a moderate increase in Mn has been suggested to interfere with neurodevelopment in children. Genetics influencing Mn concentrations and toxicity is unclear. Objective: We assessed, in a cross-sectional study, whether common single-nucleotide polymorphisms in the Mn transporters SLC39A8 (influx) and SLC30A10 (efflux) are associated with neurodevelopment in children. Design: We genotyped SLC39A8 (rs13107325 C/T) and SLC30A10 (rs1776029 G/A and rs12064812 T/C) in Italian children (n = 686, ages 11-14). We then used linear regression models to analyze associations between genotype, blood Mn concentrations, and neurodevelopmental outcomes including intelligence, behavior, motor function, and sway. Inferred causal relationships were evaluated using instrumental variables (IV) analysis. Results: For SLC30A10 rs1776029, the minor allele (A) was associated with increased average blood Mn of 41% (p < 0.001), whereas minor alleles for rs12064812 (C) and rs13107325 (T) were associated with reduced blood Mn of 7% (p = 0.002) and 15% (p < 0.001), respectively. For children carrying genotypes associated with high blood Mn, we observed lower performance for certain IQ subtests, increased sway, and increased scores for behavioral problems. High Mn genotypes showed odds ratios of 2-4 (p ≤ 0.01) for high scores in tests assessing ADHD-related behavior. IV analyses suggested that several of the associations were mediated by blood Mn. Conclusions: Our results suggest that common polymorphisms in SLC39A8 and SLC30A10 influence neurodevelopmental outcomes in children via differences in Mn homeostasis.

Published
2018
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29. Maternal polymorphisms in glutathione-related genes are associated with maternal mercury concentrations and early child neurodevelopment in a population with a fish-rich diet

Author

Wahlberg, Karin, primary, Love, Tanzy M., additional, Pineda, Daniela, additional, Engström, Karin, additional, Watson, Gene E., additional, Thurston, Sally W., additional, Yeates, Alison J., additional, Mulhern, Maria S., additional, McSorley, Emeir M., additional, Strain, J.J., additional, Smith, Tristram H., additional, Davidson, Philip W., additional, Shamlaye, Conrad F., additional, Myers, G.J., additional, Rand, Matthew D., additional, van Wijngaarden, Edwin, additional, and Broberg, Karin, additional

Published
2018
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30. AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes

Author

Palmgren, Michael, Engstrom, Karin, Hallström, Björn M., Wahlberg, Karin, Sondergaard, Dan Ariel, Sall, Torbjorn, Vahter, Marie, Broberg, Karin, Palmgren, Michael, Engstrom, Karin, Hallström, Björn M., Wahlberg, Karin, Sondergaard, Dan Ariel, Sall, Torbjorn, Vahter, Marie, and Broberg, Karin

Abstract

Organisms have evolved the ability to tolerate toxic substances in their environments, often by producing metabolic enzymes that efficiently detoxify the toxicant. Inorganic arsenic is one of the most toxic and carcinogenic substances in the environment, but many organisms, including humans, metabolise inorganic arsenic to less toxic metabolites. This multistep process produces mono-, di-, and trimethylated arsenic metabolites, which the organism excretes. In humans, arsenite methyltransferase (AS3MT) appears to be the main metabolic enzyme that methylates arsenic. In this study, we examined the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic during evolution. These findings are supported by the observation that genetic variation in AS3MT correlates with the capacity to methylate arsenic. Adaptation to arsenic thus serves as a model for how organisms evolve to survive under toxic conditions., QC 20170601

Published
2017
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31. AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes

Author

Palmgren, Michael Broberg, Engström, Karin, Hallström, Björn M, Wahlberg, Karin, Søndergaard, Dan Ariel, Säll, Torbjörn, Vahter, Marie, Broberg, Karin, Palmgren, Michael Broberg, Engström, Karin, Hallström, Björn M, Wahlberg, Karin, Søndergaard, Dan Ariel, Säll, Torbjörn, Vahter, Marie, and Broberg, Karin

Abstract

Organisms have evolved the ability to tolerate toxic substances in their environments, often by producing metabolic enzymes that efficiently detoxify the toxicant. Inorganic arsenic is one of the most toxic and carcinogenic substances in the environment, but many organisms, including humans, metabolise inorganic arsenic to less toxic metabolites. This multistep process produces mono-, di-, and trimethylated arsenic metabolites, which the organism excretes. In humans, arsenite methyltransferase (AS3MT) appears to be the main metabolic enzyme that methylates arsenic. In this study, we examined the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic during evolution. These findings are supported by the observation that genetic variation in AS3MT correlates with the capacity to methylate arsenic. Adaptation to arsenic thus serves as a model for how organisms evolve to survive under toxic conditions.

Published
2017

33. Polymorphisms in ATP-binding cassette transporters associated with maternal methylmercury disposition and infant neurodevelopment in mother-infant pairs in the Seychelles Child Development Study

Author

Engström, Karin, primary, Love, Tanzy M., additional, Watson, Gene E., additional, Zareba, Grazyna, additional, Yeates, Alison, additional, Wahlberg, Karin, additional, Alhamdow, Ayman, additional, Thurston, Sally W., additional, Mulhern, Maria, additional, McSorley, Emeir M., additional, Strain, J.J., additional, Davidson, Philip W., additional, Shamlaye, Conrad F., additional, Myers, G.J., additional, Rand, Matthew D., additional, van Wijngaarden, Edwin, additional, and Broberg, Karin, additional

Published
2016
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35. Genetic variation in FADS genes is associated with maternal long-chain PUFA status but not with cognitive development of infants in a high fish-eating observational study.

Author

Yeates, Alison J, Love, Tanzy M, Engström, Karin, Mulhern, Maria S, McSorley, Emeir M, Grzesik, Katherine, Alhamdow, Ayman, Wahlberg, Karin E, Thurston, Sally W, Davidson, Philip W, van Wijngaarden, Edwin, Watson, Gene E, Shamlaye, Conrad F, Myers, G J, Strain, J J, Broberg, Karin, Yeates, Alison J, Love, Tanzy M, Engström, Karin, Mulhern, Maria S, McSorley, Emeir M, Grzesik, Katherine, Alhamdow, Ayman, Wahlberg, Karin E, Thurston, Sally W, Davidson, Philip W, van Wijngaarden, Edwin, Watson, Gene E, Shamlaye, Conrad F, Myers, G J, Strain, J J, and Broberg, Karin

Abstract

Long-chain n-6 and n-3 PUFA (LC-PUFA), arachidonic acid (AA) (20:4n-6) and DHA (22:6n-3), are critical for optimal brain development. These fatty acids can be consumed directly from the diet, or synthesized endogenously from precursor PUFA by Δ-5 (encoded by FADS1) and Δ-6 desaturases (encoded by FADS2). The aim of this study was to determine the potential importance of maternal genetic variability in FADS1 and FADS2 genes to maternal LC-PUFA status and infant neurodevelopment in populations with high fish intakes. The Nutrition Cohorts 1 (NC1) and 2 (NC2) are longitudinal observational mother-child cohorts in the Republic of Seychelles. Maternal serum LC-PUFA was measured at 28 weeks gestation and genotyping for rs174537 (FADS1), rs174561 (FADS1), rs3834458 (FADS1-FADS2) and rs174575 (FADS2) was performed in both cohorts. The children completed the Bayley Scales of Infant Development II (BSID-II) at 30 months in NC1 and at 20 months in NC2. Complete data were available for 221 and 1310 mothers from NC1 and NC2 respectively. With increasing number of rs3834458 minor alleles, maternal concentrations of AA were significantly decreased (NC1 p=0.004; NC2 p<0.001) and precursor:product ratios for linoleic acid (LA) (18:2n-6)-to-AA (NC1 p<0.001; NC2 p<0.001) and α-linolenic acid (ALA) (18:3n-3)-to-DHA were increased (NC2 p=0.028). There were no significant associations between maternal FADS genotype and BSID-II scores in either cohort. A trend for improved PDI was found among infants born to mothers with the minor rs3834458 allele.In these high fish-eating cohorts, genetic variability in FADS genes was associated with maternal AA status measured in serum and a subtle association of the FADS genotype was found with neurodevelopment.

Published
2015

36. Genetic variation in FADS genes is associated with maternal long-chain PUFA status but not with cognitive development of infants in a high fish-eating observational study

Author

Yeates, Alison J., primary, Love, Tanzy M., additional, Engström, Karin, additional, Mulhern, Maria S., additional, McSorley, Emeir M., additional, Grzesik, Katherine, additional, Alhamdow, Ayman, additional, Wahlberg, Karin, additional, Thurston, Sally W., additional, Davidson, Philip W., additional, van Wijngaarden, Edwin, additional, Watson, Gene E., additional, Shamlaye, Conrad F., additional, Myers, G.J., additional, Strain, J.J., additional, and Broberg, Karin, additional

Published
2015
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41. A major quantitative trait locus on chromosome 6q23 for HbF levels – An update

Author

Lay Thein, Swee, primary, Menzel, Stephan, additional, Peng, Xu, additional, Best, Steve, additional, Jiang, Jie, additional, Close, James, additional, Silver, Nicholas, additional, Gerovasilli, Ageliki, additional, Ping, Chen, additional, Yamaguchi, Masao, additional, Wahlberg, Karin, additional, Muller, Heike, additional, Spector, Tim D., additional, Garner, Chad, additional, Matsuda, Fumihiko, additional, Farrall, Martin, additional, and Lathrop, Mark, additional

Published
2007
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43. Intergenic Variants of HBS1L-MYB Are Responsible for a Major Quantitative Trait Locus on Chromosome 6q23 Influencing HbF Levels in Adults.

Author

Thein, Swee Lay, primary, Menzel, Stephan, primary, Peng, Xu, primary, Best, Steve, primary, Jiang, Jie, primary, Close, James, primary, Silver, Nicholas, primary, Gerovasilli, Ageliki, primary, Ping, Chen, primary, Yamaguchi, Masao, primary, Wahlberg, Karin, primary, Muller, Heike, primary, Spector, Tim D., primary, Garner, Chad, primary, Matsuda, Fumihiko, primary, Farrall, Martin, primary, and Lathrop, Mark, primary

Published
2006
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44. The HBS1L-MYBintergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells

Author

Wahlberg, Karin, Jiang, Jie, Rooks, Helen, Jawaid, Kiran, Matsuda, Fumihiko, Yamaguchi, Masao, Lathrop, Mark, Thein, Swee Lay, and Best, Steve

Abstract

HBS1L-MYBintergenic polymorphism (HMIP)on chromosome 6q23 is associated with elevated fetal hemoglobin levels and has pleiotropic effects on several hematologic parameters. To investigate potential regulatory activity in the region, we have measured sensitivity of the sequences to DNase I cleavage that identified 3 tissue-specific DNase I hypersensitive sites in the core intergenic interval. Chromatin immunoprecipitation with microarray (ChIP-chip) analysis showed strong histone acetylation in a defined interval of 65 kb corresponding to the core HBS1L-MYBintergenic region in primary human erythroid cells but not in non–MYB-expressing HeLa cells. ChIP-chip analysis also identified several potential cis-regulatory elements as strong GATA-1 signals that coincided with the DNase I hypersensitive sites present in MYB-expressing erythroid cells. We suggest that HMIPcontains regulatory sequences that could be important in hematopoiesis by controlling MYBexpression. This study provides the functional link between genetic association of HMIPwith control of fetal hemoglobin and other hematologic parameters. We also present a large-scale analysis of histone acetylation as well as RNA polymerase II and GATA-1 interactions on chromosome 6q, and α and β globin gene loci. The data suggest that GATA-1 regulates numerous genes of various functions on chromosome 6q.

Published
2009
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45. Att inte debattera är inte ett alternativ

Author

Karin Broberg, Ingrid Dunér, Kristofer Hansson, Mats Hansson, Johan Jakobsson, Marcus Järås, Ulf Kristoffersson, Hindrik Mulder, Ana Nordberg, Anna Tunlid, Niklas Vareman, and Wahlberg, Karin E.

46. Vi måste ta ställning till den nya gentekniken

Author

Karin Broberg, Ingrid Dunér, Kristofer Hansson, Mats Hansson, Johan Jakobsson, Marcus Järås, Ulf Kristoffersson, Hindrik Mulder, Ana Nordberg, Anna Tunlid, Niklas Vareman, and Wahlberg, Karin E.

47. Functional Characterisation of a MYB-HBS1LIntergenic Region Controlling Fetal Hemoglobin Levels in Adults

Author

Wahlberg, Karin E, Jiang, Jie, Rooks, Helen, Best, Steve, and Thein, Swee Lay

Abstract

A major ameliorating factor in sickle cell disease and beta-thalassemia is the inherent ability to produce fetal hemoglobin (HbF, a2g2), a highly heritable trait. We have previously mapped a major quantitative trait locus (QTL) controlling HbF levels to an array of single nucleotide polymorphisms (SNPs) within a 79 kb block between the gene for HBS1L (a G-protein/elongation factor) and the MYBproto-oncogene in Northern European Caucasians. These variants in chromosome 6q23.3, are referred to as HBS1L-MYBintergenic polymorphism (HMIP) and exist in three linkage disequilibrium (LD) blocks, HMIP-1, -2and -3,of which HMIP-2shows the strongest association. Association of HMIPwith HbF has recently been replicated in two independent cohorts of patients with sickle cell disease, African-American and Brazilian, as well as in a cohort of Chinese patients with beta-thalassemia. Physiologically, MYBand HBS1Lexpression was simultaneously down-regulated in individuals with high HbF while over-expression of MYBinhibits gamma-globin expression. We also showed that HMIPinfluences erythrocyte, platelet and monocyte counts in humans. We hypothesised that the genetic variants in the MYB-HBS1Lintergenic region are situated in a regulatory region and affect HbF levels by altering the expression of MYBand/or HBS1L.

Published
2008
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48. Polymorphisms in Manganese Transporters SLC30A1 0 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis.

Author

Wahlberg KE, Guazzetti S, Pineda D, Larsson SC, Fedrighi C, Cagna G, Zoni S, Placidi D, Wright RO, Smith DR, Lucchini RG, and Broberg K

Abstract

Background: Manganese (Mn) is an essential element but at excessive levels, it is neurotoxic. Even a moderate increase in Mn has been suggested to interfere with neurodevelopment in children. Genetics influencing Mn concentrations and toxicity is unclear. Objective: We assessed, in a cross-sectional study, whether common single-nucleotide polymorphisms in the Mn transporters SLC39A8 (influx) and SLC30A10 (efflux) are associated with neurodevelopment in children. Design: We genotyped SLC39A8 (rs13107325 C/T) and SLC30A10 (rs1776029 G/A and rs12064812 T/C) in Italian children ( n = 686, ages 11-14). We then used linear regression models to analyze associations between genotype, blood Mn concentrations, and neurodevelopmental outcomes including intelligence, behavior, motor function, and sway. Inferred causal relationships were evaluated using instrumental variables (IV) analysis. Results: For SLC30A10 rs1776029, the minor allele (A) was associated with increased average blood Mn of 41% ( p < 0.001), whereas minor alleles for rs12064812 (C) and rs13107325 (T) were associated with reduced blood Mn of 7% ( p = 0.002) and 15% ( p < 0.001), respectively. For children carrying genotypes associated with high blood Mn, we observed lower performance for certain IQ subtests, increased sway, and increased scores for behavioral problems. High Mn genotypes showed odds ratios of 2-4 (p ≤ 0.01) for high scores in tests assessing ADHD-related behavior. IV analyses suggested that several of the associations were mediated by blood Mn. Conclusions: Our results suggest that common polymorphisms in SLC39A8 and SLC30A10 influence neurodevelopmental outcomes in children via differences in Mn homeostasis.

Published
2018
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