Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans

There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in th e beta-globin gene cluster associated with the geographical origin of the s ickle mutation. as well as microdeletions in the alpha-globin genes, could provide an epigenetic influence on the heterogeneous outcome in SSA. It has been determined that the cause of progressive renal insufficiency in SSA i s a glomerulopathy, clinically detected by the presence of macroalbuminuria (albumin excretion rate >300 mg/g creatinine). To investigate the role of the alpha-globin gene microdeletion and beta-globin gene cluster haplotypes on the degree of glomerular involvement, 76 adult SSA patients (hemoglobin SS) were studied to determine the relationship between those genetic marke rs and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdel etions in one or two of the four alpha-globin genes (alpha-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patien ts with intact alpha-globin genes (40%, P = 0.01), By contrast, there was n o association between albumin-uria and beta-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with alpha-glo bin gene microdeletions had lower mean corpuscular volumes and mean corpusc ular hemoglobin concentration than patients with all four alpha genes (86 /- 2 versus 99 +/- 3 fl, and 33.9 +/- 0.2 versus 34.9 +/- 0.2%, respectivel y, P < 0.05). There were no such hematologic differences between CAR and no n-CAR beta-globin haplotypes. There were, no differences in duration of dis ease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenas e levels between those with and without glomerulopathy. hut the mean arteri al pressure was higher (87 +/- 1 mmHg) in patients with intact alpha gene l ocus versus those with microdeletions (80 +/- 2 mmHg, P < 0.05), It is conc luded that the coinheritance of microdeletions in the alpha-globin gene loc us in SSA patients confers "renoprotection" by mechanisms not related to th e degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concen tration.