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Pulmonary hypertension induced by drugs and toxins
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Kim Bouillon, Yola Moride, Lucien Abenhaim, Marc Humbert
Since only a minority of patients exposed to fenfluramines develop PAH, the need for other predisposing factors, such as genetic susceptibility, could be postulated, with anorexigens acting as a ‘second hit’ in those predisposed subjects. BMPR2 mutations have been described in more than 70 per cent of PAH familial cases and in 10–40 per cent of patients with idiopathic apparently sporadic PAH.38,39 BMPR2 mutations were found among 9 per cent40 and 18 per cent25 of patients with fenflu-ramine-associated PAH. Interestingly, the duration of exposure in patients with BMPR2 mutation was significantly lower than in patients without the mutation. This is in agreement with the ‘multiple hit’ concept, fenfluramine exposure being a trigger/risk factor in genetically predisposed individuals. Recently, in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine-associated PAH, an endoglin germline mutation has been observed.41 Endoglin and BMPR2 genes encode trans-membrane proteins which belong to the TGF-β receptor super-family which plays an important role in the maturation and development of pulmonary vessels. These data are in favour of a role of the TGF-β signalling pathway in anorexigen-induced PAH.41 Regarding the role of serotonin receptors in anorexigen-induced PAH, a mutation causing loss of function of the serotonin 5-HT2B receptor was found in 1 out of 10 patients with fenfluramine-induced PAH, whereas no mutations were found among 18 patients with idiopathic PAH.35 These findings stress the complexity of the pathophysiological mechanisms by which appetite suppressants may cause pulmonary hypertension.
Posthumanism: Creation of ‘New Men’ Through Technological Innovation
Published in The New Bioethics, 2021
A meta-analysis of 78,308 individuals identified 52 genes in 18 loci linked to intelligence, of which 40 were new; albeit their combined influence on intelligence is very small. Epigenetic states in which genetic inheritance is not altered but gene expression is, were calculated for 51 out of 52 implicated genes, and showed that 57% of genes were at least weakly transcribed in at least 50% of body tissues (Sniekers et al. 2017). Amongst the genes linked to intelligence, 35 were reported previously in association with at least one of 67 distinct traits. Nine genes were implicated with body mass index, seven with schizophrenia, and four with obesity. The strongest association of intelligence was with FOXO3 that encodes the Forkhead box 3 protein and its promoter region; this gene is part of the insulin/insulin-like growth factor 1 signalling pathway and is associated with longevity (Willcox et al. 2008). Pathway analysis demonstrated one associated gene-set of four genes of genome-wide significance; one of them, bone morphogenetic protein receptor 2 (BMPR2), is linked to embryogenesis and endochondral bone formation, and pulmonary arterial hypertension (Sniekers et al. 2017).