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 a

lso 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.