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  • Review Article
  • Published:

The genetics of IgA nephropathy

Nature Clinical Practice Nephrology volume 3, pages 325–338 (2007)Cite this article

Abstract

IgA nephropathy is the most common form of primary glomerulonephritis. Variations in clinical manifestations indicate that a diagnosis of IgA nephropathy encompasses multiple disease subsets that cannot be distinguished on the basis of renal pathology or clinical variables alone. Familial forms of the disease have been reported throughout the world, but are probably under-recognized because associated urinary abnormalities are often intermittent in affected family members. IgA nephropathy has complex determination, with different genes probably causing disease in different patient subgroups. Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently implicated. Here, we present the evidence for genetic contributions to the disease, review clinical patterns of familial disease, and summarize some of the most promising genetic studies conducted to date. Linkage-based approaches to the study of familial forms of the disease have identified significant or suggestive loci on chromosomes 6q22-23, 2q36, 4q26-31, 17q12-22 and 3p24-23, but no causal gene has yet been identified. Many interesting, but poorly replicated, genetic association studies have also been reported. We discuss recent developments in analytic tools that should enable genetic studies of sporadic forms of disease by the genome-wide association approach.

Key Points

  • Up to 15% of cases of the common primary glomerulonephritis IgA nephropathy (IgAN) are classified as 'familial', indicating an underlying genetic component

  • Familial IgAN is probably underdiagnosed, as urinary abnormalities that cause clinical suspicion can occur intermittently

  • Analysis of extended kindreds has shown that some patients with 'sporadic' forms of IgAN share common ancestors

  • Families affected by IgAN are often affected by other glomerular diseases such as IgM nephropathy, Henoch-Schönlein purpura nephritis and focal segmental glomerulosclerosis

  • Autosomal dominant inheritance with incomplete penetrance is a likely form of transmission in families with IgAN

  • Linkage-based genetic studies have detected associations between IgAN and several chromosomal loci, but no specific disease-causing gene has been identified

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Figure 1: Human IgA1 and its hinge region amino acid sequence with the attached O-linked glycans and possible glycan variants of circulatory IgA1
Figure 2: Examples of familial IgA nephropathy

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Acknowledgements

We thank the patients and their family members for participating in our research studies. This work is supported by NIH grants DK61525, DK71802, DK78244 and DK64400, and by the General Clinical Research Centers of the University of Alabama at Birmingham M01 RR00032, and the University of Tennessee Health Sciences Center M01 RR00211. AG Gharavi is supported by the Emerald Foundation and the National Kidney Foundation Clinical Scientist Program. We thank www.carbonwood.com for assistance with preparation of figure 1.

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Authors and Affiliations

  1. I Beerman is a graduate student at Yale University School of Medicine, New Haven, CT.,

    Isabel Beerman

  2. J Novak is Associate Professor of Microbiology, and BA Julian is Professor of Medicine, at University of Alabama at Birmingham, Birmingham, AL.,

    Jan Novak & Bruce A Julian

  3. RJ Wyatt is Professor of Pediatrics at the University of Tennessee Center for Health Sciences, Memphis, TN.,

    Robert J Wyatt

  4. AG Gharavi is Assistant Professor of Medicine at the College of Physicians and Surgeons, Columbia University New York, NY, USA.,

    Ali G Gharavi

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  1. Isabel Beerman
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  2. Jan Novak
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  3. Robert J Wyatt
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  4. Bruce A Julian
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  5. Ali G Gharavi
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Corresponding author

Correspondence to Ali G Gharavi.

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The authors declare no competing financial interests.

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Beerman, I., Novak, J., Wyatt, R. et al. The genetics of IgA nephropathy. Nat Rev Nephrol 3, 325–338 (2007). https://doi.org/10.1038/ncpneph0492

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