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Aberrant IgA1 Glycosylation Is Inherited in Familial and Sporadic IgA Nephropathy

Ali G. Gharavi^*, Zina Moldoveanu, Robert J. Wyatt, Catherine V. Barker, Susan Y. Woodford, Richard P. Lifton^||, Jiri Mestecky, Jan Novak and Bruce A. Julian^,

^* Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, Departments of Microbiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama, Children's Hospital Research Foundation at the Le Bonheur Children's Medical Center and the University of Tennessee Health Sciences Center, Memphis, Tennessee, and ^|| Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

Correspondence: Ali G. Gharavi, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 W 168th Street, P&S 10-445 New York, NY 10032. Phone: 212-851-5556; Fax: 212-305-3986; E-mail: ag2239{at}columbia.edu or Bruce A. Julian, Division of Nephrology, University of Alabama at Birmingham, 1530 Third Avenue South THT 643, Birmingham, AL 35294. Phone: 205-934-9045; Fax: 205-934-7742; E-mail: bjulian{at}uab.edu

Received for publication September 27, 2007. Accepted for publication November 8, 2007.

IgA nephropathy (IgAN) is a complex trait determined by genetic and environmental factors. Most IgAN patients exhibit a characteristic undergalactosylation of the O-glycans of the IgA1 hinge region, which promotes formation and glomerular deposition of immune complexes. It is not known whether this aberrant glycosylation is the result of an acquired or inherited defect, or whether the presence of aberrant IgA1 glycoforms alone can produce IgAN. A newly validated lectin enzyme-linked immunosorbent assay (ELISA) was used to determine the serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 of their relatives. High Gd-IgA1 levels (95th percentile for controls) were observed in all 5 available patients with familial IgAN, in 21 of 45 (47%) of their at-risk relatives (assuming autosomal dominant inheritance), and in only 1 of 19 (5%) of unrelated individuals who married into the family. This provides evidence that abnormal IgA1 glycosylation is an inherited rather than acquired trait. Similarly, Gd-IgA1 levels were high in 65 of 84 (78%) patients with sporadic IgAN and in 50 of 202 (25%) blood relatives. Heritability of Gd-IgA1 was estimated at 0.54 (P = 0.0001), and segregation analysis suggested the presence of a major dominant gene on a polygenic background. Because most relatives with abnormal IgA1 glycoforms were asymptomatic, additional cofactors must be required for IgAN to develop. The fact that abnormal IgA1 glycosylation clusters in most but not all families suggests that measuring Gd-IgA1 may help distinguish patients with different pathogenic mechanisms of disease.

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