Aberrant IgA1 Glycosylation Is Inherited in Familial and Sporadic IgA Nephropathy

Abstract

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 (Ն95th 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 ϭ 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.

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

“…This finding is consistent with a multi-hit hypothesis for the disease mechanism of IgAN, wherein an increased serum level of autoantigen alone is not sufficient to induce renal injury [25][26][27] ; it must combine with autoantibodies either in the circulation to form immune complexes that deposit in the glomerular mesangium or in situ with Gd-IgA1 already in the mesangium. Based on the physical and biologic characteristics of the immune complexes, such as composition and size, 17,28 mesangial cells may be activated to proliferate and overproduce components of mesangial matrix, chemokines, and cytokines.…”

“…25 However, most of these relatives do not manifest renal disease, even after extended periods of observation. The level of circulating autoantibodies (IgG or IgA) specific for Gd-IgA1 has not been examined in that setting.…”

Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

“…Although the serum level of Gd-IgA1 is considered a disease marker for IgAN, its unique role in inducing renal pathology or disease progression has been questioned. Notably, levels of Gd-IgA1 are commonly elevated in healthy first-degree relatives without clinical evidence of renal injury (13). In patients with IgAN, the specific degree of Gal deficiency of O-glycans on serum IgA1 remains constant over long intervals (2).…”

IgA1 Glycosylation Is Heritable in Healthy Twins

“…23,24,25 Studies of familial IgAN have provided heritability estimates for gd-IgA1 between 54% and 76%. [25][26][27] One difficulty of these studies is that at-risk relatives tend to show increased gd-IgA1 levels, biasing the heritability estimates which have been suggested to strongly depend on the gd-IgA1 levels of the index IgAN case. 26 In order to understand the genetic contribution to gd-IgA1 levels in IgAN patients, it is first necessary to understand the genetic contribution to gd-IgA1 levels in healthy individuals.…”