Control of fetal hemoglobin: new insights emerging from genomics and clinical implications
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The review traces the story of HbF quantitative genetics that uncannily mirrors the changing focus in genetic methodology, from candidate genes through positional cloning, to genome-wide association, that have expedited the dissection of the genetic architecture underlying HfF variability.Abstract:
Increased levels of fetal hemoglobin (HbF, alpha(2)gamma(2)) are of no consequence in healthy adults, but confer major clinical benefits in patients with sickle cell anemia (SCA) and beta thalassemia, diseases that represent major public health problems. Inter-individual HbF variation is largely genetically controlled, with one extreme caused by mutations involving the beta globin gene (HBB) complex, historically referred to as pancellular hereditary persistence of fetal hemoglobin (HPFH). These Mendelian forms of HPFH are rare and do not explain the common form of heterocellular HPFH which represents the upper tail of normal HbF variation, and is clearly inherited as a quantitative genetic trait. Genetic studies have identified three major quantitative trait loci (QTLs) (Xmn1-HBG2, HBS1L-MYB intergenic region on chromosome 6q23, and BCL11A on chromosome 2p16) that account for 20-50% of the common variation in HbF levels in patients with SCA and beta thalassemia, and in healthy adults. Two of the major QTLs include oncogenes, emphasizing the importance of cell proliferation and differentiation as an important contribution to the HbF phenotype. The review traces the story of HbF quantitative genetics that uncannily mirrors the changing focus in genetic methodology, from candidate genes through positional cloning, to genome-wide association, that have expedited the dissection of the genetic architecture underlying HbF variability. These genetic results have already provided remarkable insights into molecular mechanisms that underlie the hemoglobin 'switch'.read more
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Journal ArticleDOI
Fetal hemoglobin in sickle cell anemia
Idowu Akinsheye,Abdulrahman Alsultan,Nadia Solovieff,Duyen A. Ngo,Clinton T. Baldwin,Paola Sebastiani,David H.K. Chui,Martin H. Steinberg +7 more
TL;DR: New efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of Hbf inducers are spurred on.
Journal ArticleDOI
Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
Joseph Borg,Petros Papadopoulos,Marianthi Georgitsi,Laura Gutierrez,Godfrey Grech,Godfrey Grech,Pavlos Fanis,Marios Phylactides,Annemieke J.M.H. Verkerk,Peter J. van der Spek,Christian Scerri,Christian Scerri,Wilhelmina Cassar,Wilhelmina Cassar,Ruth Galdies,Ruth Galdies,Wilfred F. J. van IJcken,Zeliha Ozgur,Nynke Gillemans,Jun Hou,Marisa Bugeja,Marisa Bugeja,Frank Grosveld,Marieke von Lindern,Alex E. Felice,Alex E. Felice,George P. Patrinos,Sjaak Philipsen +27 more
TL;DR: Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression.
Journal ArticleDOI
Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6
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References
More filters
Journal ArticleDOI
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Paul Burton,David Clayton,Lon R. Cardon,Nicholas John Craddock,Panos Deloukas,Audrey Duncanson,Dominic P. Kwiatkowski,Mark I. McCarthy,Willem H. Ouwehand,Nilesh J. Samani,John A. Todd,Peter Donnelly,Jeffrey C. Barrett,Dan Davison,Doug Easton,David M. Evans,H. T. Leung,Jonathan Marchini,Andrew P. Morris,Chris C. A. Spencer,Martin D. Tobin,Antony P. Attwood,James P. Boorman,Barbara Cant,Ursula Everson,Judith M. Hussey,Jennifer Jolley,Alexandra S. Knight,Kerstin Koch,Elizabeth Meech,Sarah Nutland,Christopher Prowse,Helen Stevens,Niall C. Taylor,Graham R. Walters,Neil Walker,Nicholas A. Watkins,Thilo Winzer,Richard Jones,Wendy L. McArdle,Susan M. Ring,David P. Strachan,Marcus Pembrey,Gerome Breen,David St Clair,Sian Caesar,Katherine Gordon-Smith,Lisa Jones,Christine Fraser,Elaine K. Green,Detelina Grozeva,Marian L. Hamshere,Peter Holmans,Ian Jones,George Kirov,Valentina Moskvina,Ivan Nikolov,Michael Conlon O'Donovan,Michael John Owen,David A. Collier,Amanda Elkin,Anne Farmer,Richard Williamson,Peter McGuffin,Allan H. Young,I. Nicol Ferrier,Stephen G. Ball,Anthony J. Balmforth,Jennifer H. Barrett,D. Timothy Bishop,Mark M. Iles,Azhar Maqbool,Nadira Yuldasheva,Alistair S. Hall,Peter S. Braund,Richard J. Dixon,Massimo Mangino,Suzanne Stevens,John R. Thompson,Francesca Bredin,Mark Tremelling,Miles Parkes,Hazel E. Drummond,Charlie W. Lees,Elaine R. Nimmo,Jack Satsangi,Sheila A. Fisher,Alastair Forbes,Cathryn M. Lewis,Clive M. Onnie,Natalie J. Prescott,Jeremy D. Sanderson,Christopher G. Mathew,Jamie Barbour,M. Khalid Mohiuddin,Catherine E. Todhunter,John C. Mansfield,Tariq Ahmad,Fraser Cummings,Derek P. Jewell,John Webster,Morris J. Brown,G. Mark Lathrop,John M. C. Connell,Anna F. Dominiczak,Carolina A. Braga Marcano,Beverley Burke,Richard Dobson,Johannie Gungadoo,Kate L. Lee,Patricia B. Munroe,Stephen Newhouse,Abiodun Onipinla,Chris Wallace,Mingzhan Xue,Mark J. Caulfield,Martin Farrall,Anne Barton,Ian N. Bruce,Hannah Donovan,Steve Eyre,Paul D. Gilbert,Samantha L. Hider,Anne Hinks,Sally John,Catherine Potter,Alan J. Silman,Deborah P M Symmons,Wendy Thomson,Jane Worthington,David B. Dunger,Barry Widmer,Timothy M. Frayling,Rachel M. Freathy,Hana Lango,John R. B. Perry,Beverley M. Shields,Michael N. Weedon,Andrew T. Hattersley,Graham A. Hitman,Mark Walker,Kate S. Elliott,Christopher J. Groves,Cecilia M. Lindgren,Nigel W. Rayner,Nicholas J. Timpson,Eleftheria Zeggini,Melanie J. Newport,Giorgio Sirugo,Emily J. Lyons,Fredrik O. Vannberg,Adrian V. S. Hill,Linda A. Bradbury,C Farrar,J J Pointon,Paul Wordsworth,Matthew A. Brown,Jayne A. Franklyn,Joanne M. Heward,Matthew J. Simmonds,Stephen C. L. Gough,Sheila Seal,Michael R. Stratton,Nazneen Rahman,Maria Ban,An Goris,Stephen Sawcer,Alastair Compston,David J. Conway,Muminatou Jallow,Kirk A. Rockett,Suzannah Bumpstead,Amy Chaney,Kate Downes,Mohammed J. R. Ghori,Rhian Gwilliam,Sarah E. Hunt,Michael Inouye,Andrew Keniry,Emma King,Ralph McGinnis,Simon C. Potter,Rathi Ravindrarajah,Pamela Whittaker,Claire Widden,David Withers,Niall Cardin,Teresa Ferreira,Joanne Pereira-Gale,Ingileif B. Hallgrímsdóttir,Bryan Howie,Zhan Su,Yik Ying Teo,Damjan Vukcevic,David Bentley,A Compston +195 more
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Journal ArticleDOI
Genome-wide association studies for complex traits: consensus, uncertainty and challenges
Mark I. McCarthy,Mark I. McCarthy,Gonçalo R. Abecasis,Lon R. Cardon,Lon R. Cardon,David Goldstein,Julian Little,John P. A. Ioannidis,John P. A. Ioannidis,Joel N. Hirschhorn,Joel N. Hirschhorn,Joel N. Hirschhorn +11 more
TL;DR: This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
Journal ArticleDOI
The Wellcome Trust Case Control Consortium, U.K.
TL;DR: This article reports that the magazine's award for Research Leader of the Year was given to the Wellcome Trust Case Control Consortium which conducted a huge genetic study to look at the genetic causes for various diseases.
Journal ArticleDOI
Genetic Mapping in Human Disease
TL;DR: The intellectual foundations of genetic mapping of Mendelian and complex traits in humans are discussed, lessons emerging from linkage analysis of MendELian diseases and genome-wide association studies of common diseases are examined, and questions and challenges that lie ahead are discussed.
Journal ArticleDOI
Common variants at 30 loci contribute to polygenic dyslipidemia.
Sekar Kathiresan,Sekar Kathiresan,Sekar Kathiresan,Cristen J. Willer,Gina M. Peloso,Serkalem Demissie,Kiran Musunuru,Eric E. Schadt,Lee M. Kaplan,Derrick A Bennett,Yun Li,Toshiko Tanaka,Benjamin F. Voight,Benjamin F. Voight,Lori L. Bonnycastle,Anne U. Jackson,Gabriel Crawford,Aarti Surti,Candace Guiducci,Noël P. Burtt,Sarah Parish,Robert Clarke,Diana Zelenika,Kari Kubalanza,Mario A. Morken,Laura J. Scott,Heather M. Stringham,Pilar Galan,Amy J. Swift,Johanna Kuusisto,Richard N. Bergman,Jouko Sundvall,Markku Laakso,Luigi Ferrucci,Paul Scheet,Serena Sanna,Manuela Uda,Qiong Yang,Kathryn L. Lunetta,Josée Dupuis,Paul I.W. de Bakker,Christopher J. O'Donnell,Christopher J. O'Donnell,John C. Chambers,Jaspal S. Kooner,Serge Hercberg,Pierre Meneton,Edward G. Lakatta,Angelo Scuteri,David Schlessinger,Jaakko Tuomilehto,Francis S. Collins,Leif Groop,Leif Groop,David Altshuler,David Altshuler,Rory Collins,G. Mark Lathrop,Olle Melander,Veikko Salomaa,Leena Peltonen,Leena Peltonen,Leena Peltonen,Marju Orho-Melander,Jose M. Ordovas,Michael Boehnke,Gonçalo R. Abecasis,Karen L. Mohlke,L. Adrienne Cupples +68 more
TL;DR: The results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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