Space–time clustering of elevated thyroid stimulating hormone levels

International audiencePrevious studies of congenital hypothyroidism (CHT) have reported an increasing incidence which may suggest that environmental factors play an aetiological role. If so, then cases may exhibit space-time clustering, where cases occur at similar times and close proximities to other cases. In this study we investigated whether space-time clustering of elevated thyroid stimulating hormone (TSH) in newborns exists. All infants born in the Northern Region of England are screened by measuring levels of circulating TSH using a blood spot assay. Data on 207 cases of elevated TSH values, as a proxy for CHT, in newborns born from 1994 to 2006 inclusive were available and analysed using rigorous space-time clustering statistical methods. Analysis showed statistically significant evidence of space-time clustering. The strength of clustering was most marked for cases born within 0.1-0.7 year (1-8 months) of one another. This is the first study to find significant space-time clustering of cases of elevated TSH levels in newborns, a surrogate for space-time clustering of CHT. Whilst the reasons for the clustering are unclear, it would appear from this analysis that transient environmental exposures are likely to be involved, although environmental determinants of genetic mutations and epigenetic factors cannot be ruled out. Further research is required to a) validate these results in other populations and b) to assess in more detail the potential environmental determinants of increased CHT risk

Therapeutic levels of fetal hemoglobin in erythroid progeny of β-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer

β-Thalassemia major results from severely reduced or absent expression of the β-chain of adult hemoglobin (α2β2;HbA). Increased levels of fetal hemoglobin (α2γ2;HbF), such as occurs with hereditary persistence of HbF, ameliorate the severity of β-thalassemia, raising the potential for genetic therapy directed at enhancing HbF. We used an in vitro model of human erythropoiesis to assay for enhanced production of HbF after gene delivery into CD34+ cells obtained from mobilized peripheral blood of normal adults or steady-state bone marrow from patients with β-thalassemia major. Lentiviral vectors encoding (1) a human γ-globin gene with or without an insulator, (2) a synthetic zinc-finger transcription factor designed to interact with the γ-globin gene promoters, or (3) a short-hairpin RNA targeting the γ-globin gene repressor, BCL11A, were tested. Erythroid progeny of normal CD34+ cells demonstrated levels of HbF up to 21% per vector copy. For β-thalassemic CD34+ cells, similar gene transfer efficiencies achieved HbF production ranging from 45% to 60%, resulting in up to a 3-fold increase in the total cellular Hb content. These observations suggest that both lentiviral-mediated γ-globin gene addition and genetic reactivation of endogenous γ-globin genes have potential to provide therapeutic HbF levels to patients with β-globin deficiency