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Evidence that Microdeletions in the Globin Gene Protect Against the Development of Sickle Cell Glomerulopathy in Humans

ANTONIO GUASCH^*, CARLOS F. ZAYAS^*, JAMES R. ECKMAN, KASINATHAN MURALIDHARAN, WEI ZHANG and LOUIS J. ELSAS

^* Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
Division of Medical Genetics, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
Georgia National Institutes of Health Sickle Cell Center, Emory University School of Medicine, Atlanta, Georgia.

Correspondence to Dr. Antonio Guasch, Renal Division, Room 338, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322. Phone: 404-727-2525; Fax: 404-727-3425; E-mail: aguasch{at}emory.edu

Abstract. There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the ß-globin gene cluster associated with the geographical origin of the sickle mutation, as well as microdeletions in the -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 -globin gene microdeletion and ß-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 -globin genes (-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact -globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and ß-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with -globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular hemoglobin concentration than patients with all four 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 ß-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 mmHg) in patients with intact gene locus versus those with microdeletions (80 ± 2 mmHg, P < 0.05). It is concluded that the coinheritance of microdeletions in the -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.

This article has been cited by other articles:

				A. Guasch, J. Navarrete, K. Nass, and C. F. Zayas Glomerular Involvement in Adults with Sickle Cell Hemoglobinopathies: Prevalence and Clinical Correlates of Progressive Renal Failure J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2228 - 2235. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673