[Show abstract][Hide abstract] ABSTRACT: beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.
Proceedings of the National Academy of Sciences 02/2008; 105(5):1620-5. DOI:10.1073/pnas.0711566105 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholelithiasis has been reported with a variable incidence in homozygous beta-thalassaemia, the reasons for which have only partially been defined. Disease-associated factors or specific modifier genes may be implicated. We assessed the prevalence of cholelithiasis and the effect of co-inherited Gilbert's syndrome genotype on its development in 261 thalassaemia major (TM) and 35 thalassaemia intermedia (TI) patients. Cholelithiasis was found in 20.3% of TM and in 57.1% of TI patients. Its incidence was higher (P < 0.05) in patients homozygous for the (TA7) motif in the promoter of the UGT1-A1 gene, the genotype associated with Gilbert's syndrome, which seems to be a risk factor for the development of gallstones in TM and TI patients.
British Journal of Haematology 01/2002; 115(4):926-8. DOI:10.1046/j.1365-2141.2001.03200.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of neonatal hyperbilirubinemia has not yet been completely defined in normal and glucose-6-phosphate-dehydrogenase (G6PD)-deficient newborns. The recent identification of a variant promoter in the gene encoding for the bilirubin uridine-diphosphoglucuronosyl-transferase (UGT-1 A) associated with Gilbert's syndrome, allowed us to explore whether the presence of this variant promoter is a risk factor for the development of neonatal hyperbilirubinemia in normal newborns and in association with G6PD deficiency. We found that the variant (TA)7/(TA)7 promoter shows no statistically significant difference in normal or G6PD-deficient newborns developing severe hyperbilirubinemia and in control subjects from the same population. This finding indicates that the variant promoter of UGT-1 A does not contribute to the development of hyperbilirubinemia in the newborn.
European Journal of Pediatrics 12/1999; 158(11):914-6. DOI:10.1007/s004310051241 · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with thalassemia major and intermedia show a marked variability of serum indirect bilirubin levels. In this paper we tested the hypothesis related to the variability of the glucuronidation bilirubin rate which depends on the configuration of the A(TA)nTAA motif of the UGT1*1 glucuronosyltransferase gene promoter.
We studied the configuration of the A(TA)nTAA motif in 26 patients with thalassemia major and 34 with thalassemia intermedia.
In patients with thalassemia major and in those with thalassemia intermedia significantly higher bilirubin levels were found in patients with the (TA)7/(TA)7 genotype, than in those with the (TA)7/(TA)6 or (TA)6/(TA)6 genotype.
These results indicate that the (TA)7/(TA)7 genotype, the configuration found in patients with Gilbert's syndrome, is capable of modifying the clinical phenotype of homozygous beta-thalassemia. This is an example of the role played by co-inherited modifying gene(s) on the extent of clinical heterogeneity of monogenic disorders.