There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the beta-globin gene cluster associated with the geographical origin of the sickle 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 is 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 these genetic markers and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdeletions in one or two of the four alpha-globin genes (alpha-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact alpha-globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and beta-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with alpha-globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular 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%, respectively, P<0.05). There were no such hematologic differences between CAR and non-CAR beta-globin haplotypes. There were no differences in duration of disease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenase levels between those with and without glomerulopathy, but the mean arterial pressure was higher (87+/-1 mm Hg) in patients with intact alpha gene locus versus those with microdeletions (80+/-2 mm Hg, P<0.05). It is concluded that the coinheritance of microdeletions in the alpha-globin gene locus in SSA patients confers "renoprotection" by mechanisms not related to the degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concentration.