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Both these disorders display a remarkable diversity in their clinical severity. A major ameliorating factor is the innate ability to produce fetal haemoglobin (HbF). Using classical twin studies, we have shown that HbF levels are predominantly genetically controlled and that almost 60 per cent of the trait variance is accounted for by genetic factors outside the globin locus. Through linkage analyses and association studies we have discovered two of the three major quantitative trait loci (QTLs) for HbF variability known to date. Loci identified by us are on chromosomes 6q and 2p (BCL11A) and are involved in the control of haematopoiesis as well as of HbF production in adults. Several other loci are currently being validated.
The 6q QTL itself consists of single nucleotide polymorphisms (SNPs) distributed in three linkage disequilibrium (LD) blocks in an intergenic region, between genes MYB and HBS1L. Our expression profiling studies have shown that quantitative differences in MYB are key to the control of HbF levels. The transcriptional control of MYB is poorly understood, despite it being an important transcription factor involved in oncogenesis and hematopoiesis. Our studies have shown that the HBS1L-MYB interval contains regulatory sequences. We have begun characterisation of the intergenic QTL to determine how it regulates expression of the flanking genes; this will enable us to determine a functional basis for the genetic association with raised HbF levels.
Our investigation of BCL11a (the 2p QTL) is now also underway. Early investigations reveal a complex pattern of splice forms and intronic polymorphisms, which may explain the role of this gene in erythroid development and thus HbF levels.
Eventually we hope to delineate the genetic architecture of fetal haemoglobin control in adults and identify the loci and sequence variants that explain most of the trait variance in adults. The identification of these HbF QTLs will have implications for novel therapeutic options, more accurately informed genetic counselling, and improving predictive accuracy of disease severity in these haemoglobinopathies, and ultimately, improving patient management. Our work on dissection of the genetic architecture of HbF inheritance has contributed significantly towards understanding of genetic modifiers for monogenic disorders and complex traits in general.
The 2 major QTLs, HMIP on 6q and BCL11A on 2p, together with a SNP in the β globin cluster accounts for about 50% of the variability in HbF levels in adults, allowing us to make a prediction on an individual’s ability to produce HbF based on this genetic information.
Our work on dissecting genotype/phenotype relationship in the thalassaemias has also contributed significantly to DNA diagnostics in the haemoglobinopathies and unravelling the molecular basis of the unusual beta thalassaemias.
There is also an ongoing programme of clinical trials in sickle cell disease, including assessment of novel therapeutic agents and interventions. The role of environmental factors in determining the phenotype of sickle cell disease is also studied, together with the identification of useful biomarkers.
Molecular Haematology
DESCRIPTION
Our research centres on the pathophysiology of the haemoglobin disorders – the thalassaemias and sickle cell disease – diseases that have a major global impact on public health.Both these disorders display a remarkable diversity in their clinical severity. A major ameliorating factor is the innate ability to produce fetal haemoglobin (HbF). Using classical twin studies, we have shown that HbF levels are predominantly genetically controlled and that almost 60 per cent of the trait variance is accounted for by genetic factors outside the globin locus. Through linkage analyses and association studies we have discovered two of the three major quantitative trait loci (QTLs) for HbF variability known to date. Loci identified by us are on chromosomes 6q and 2p (BCL11A) and are involved in the control of haematopoiesis as well as of HbF production in adults. Several other loci are currently being validated.
The 6q QTL itself consists of single nucleotide polymorphisms (SNPs) distributed in three linkage disequilibrium (LD) blocks in an intergenic region, between genes MYB and HBS1L. Our expression profiling studies have shown that quantitative differences in MYB are key to the control of HbF levels. The transcriptional control of MYB is poorly understood, despite it being an important transcription factor involved in oncogenesis and hematopoiesis. Our studies have shown that the HBS1L-MYB interval contains regulatory sequences. We have begun characterisation of the intergenic QTL to determine how it regulates expression of the flanking genes; this will enable us to determine a functional basis for the genetic association with raised HbF levels.
Our investigation of BCL11a (the 2p QTL) is now also underway. Early investigations reveal a complex pattern of splice forms and intronic polymorphisms, which may explain the role of this gene in erythroid development and thus HbF levels.
Eventually we hope to delineate the genetic architecture of fetal haemoglobin control in adults and identify the loci and sequence variants that explain most of the trait variance in adults. The identification of these HbF QTLs will have implications for novel therapeutic options, more accurately informed genetic counselling, and improving predictive accuracy of disease severity in these haemoglobinopathies, and ultimately, improving patient management. Our work on dissection of the genetic architecture of HbF inheritance has contributed significantly towards understanding of genetic modifiers for monogenic disorders and complex traits in general.
The 2 major QTLs, HMIP on 6q and BCL11A on 2p, together with a SNP in the β globin cluster accounts for about 50% of the variability in HbF levels in adults, allowing us to make a prediction on an individual’s ability to produce HbF based on this genetic information.
Our work on dissecting genotype/phenotype relationship in the thalassaemias has also contributed significantly to DNA diagnostics in the haemoglobinopathies and unravelling the molecular basis of the unusual beta thalassaemias.
There is also an ongoing programme of clinical trials in sickle cell disease, including assessment of novel therapeutic agents and interventions. The role of environmental factors in determining the phenotype of sickle cell disease is also studied, together with the identification of useful biomarkers.
Associated research programmes
Associated staff research interests
Interests:
Clinical and molecular characterisation of red cell disorders; sickle cell disease and haemoglobinopathies.
Tel:
0203 299 3242
Email:
Website:
Interests:
Genetic mapping of measurable (quantitative) traits in humans; disease and trait inheritance in families, population-genetic basis of ethnic trait differences.
Email:
Website:
Interests:
Our research centres on the pathophysiology of the beta haemoglobin disorders - the beta thalassaemias and sickle cell disease - diseases that have a major global impact on public health. Both these disorders display a remarkable diversity in their clinical severity, a major ameliorating factor is the innate ability to produce fetal haemoglobin (HbF, alpha2y2). Using classical twin studies, we showed that HbF levels are predominantly genetically controlled, and that almost 60 percent of the trait variance is accounted for by genetic factors outside the beta globin locus. We are at the forefront of identifying the genetic loci controlling fetal haemoglobin. Through linkage analyses and association studies we have identified 2 quantitative trait loci (QTLs) on chromosomes 6q and 8q, involved in the control of fetal haemoglobin production in adults, with several others currently being validated. Recently, our expression profiling studies have shown that quantitative difference in the cMYB transcription factor is key to the control of (HbF) levels. The cMYB gene lies within our 6q QTL candidate interval. We have identified single nucleotide polymorphisms (SNPs) in three linkage disequilibrium (LD) blocks within the intergenic interval between HBS1 L and cMYB on 6q that are highly associated with high F cells. Eventually we hope to delineate the genetic architecture of fetal haemoglobin control in adults and identify the loci and sequence variants that explain most of the trait variance in adults. The identification of these HbF QTLs will have implications for novel therapeutic options, more accurately informed genetic counselling, and improving predictive accuracy of disease severity in these beta haemoglobinopathies, and ultimately, improving patient management. Our work on dissection of the genetic architecture of HbF inheritance has contributed significantly towards understanding of genetic modifiers for other monogenic disorders and complex traits. Beta thalassaemia is typically inherited as haploinsufficient Mendelian recessives but atypical forms, in which inheritance of a single copy of Beta thalassaemia allele resulting in moderately severe anaemia, have been described. The molecular mechanisms underlying these so-called 'dominantly inherited Beta thalassaemias' have puzzled many for a long time. We could demonstrate that such dominantly inherited forms of Beta thalassaemia were due to hyper-instability of the Beta chain variants. We could also demonstrate that some of these autosomal dominant Beta thalassaemias are caused by failure of the surveillance mechanism of the nonsense mediated decay (NMD) pathway due to position effects of the mutations in relation to the gene sequence. Our work on dissecting genotype / phenotype relationship in the Beta thalassaemias has also contributed significantly to DNA diagnostics in the haemoglobinopathies. There is also an ongoing programme of clinical trials in sickle cell disease, involving the assessment of novel therapeutic agents and interventions. The role of environmental factors in determining the phenotype of sickle cell disease is also being studied, together with the identification of useful biomarkers.
Tel:
020 7848 5443; 020 3299 1679
Fax:
020 7346 5178
Email:
Website:
CONTACTS FOR FURTHER INFORMATION
Professor Swee Lay Thein (Head of Department), Dr. David Rees (Senior Lecturer), Dr. Steve Best (Lecturer), Dr. Stefan Menzel (Senior Lecturer), Rebecca Trumble (Research Administrator)
Email
Website