HDCN Abstract:  ASN Annual Meeting -- San Diego  

Kiryluk K, Karnib HH, Suzuki H, et al.

A Genome Wide Linkage Scan Identifies New QTL (s) Controlling Glycosylation of IgA1 in Familial IgA Nephropathy.

ASN Annual Meeting -- San Diego
J Am Soc Nephrol (Nov) 20:434A 2009

Background: We have previously demonstrated that increased serum level of galactose-deficient IgA1 (Gd-IgA1) is a highly heritable biomarker for IgA nephropathy (IgAN) and can be used as a quantitative endophenotype in genetic mapping studies.

Methods: We recruited a large consanguineous Lebanese pedigree with familial IgAN (42 individuals available) and 40 unrelated healthy controls from the same geographic area. Among family members, there were 9 affected individuals: 2 with biopsy-diagnosed IgAN, 3 with ESRD of unknown etiology, and 4 with hematuria and proteinuria on at least 3 visits; 7 additional family members had persistent isolated micorohematuria. Total serum IgA, IgA1, and Gd-IgA1 (HAA-lectin binding) were measured using ELISA. Family members were genotyped with 383 microsatellite markers spaced at 10 cM across the genome. Variance components linkage analyses were performed with LOKI and SOLAR programs.

Results: All affected individuals had high Gd -IgA1 levels compared to controls (p=0.003). Serum levels of total IgA and IgA1 were not different between IgAN cases and controls. The pattern of transmission of high Gd-IgA1 levels was consistent with AD inheritance and heritability was estimated at 0.80 (p=0.003 adjusted for age, sex, and bmi). In a genome-wide quantitative linkage scan we detected a major linkage peak for Gd-IgA1 on chromosome 6p12-21.1 (LOD=3.76, genome wide empiric p=0.028) and two suggestive peaks on chromosomes 4p14 (LOD=2.6) and 12q23 (LOD=2.5). Interestingly, there was no linkage of total serum IgA and IgA1 levels to these loci.

Conclusions: Our analysis identified new loci that specifically contribute to aberrant glycosylation of IgA1. Identification of genes that control Gd-IgA1 levels has a potential to define the molecular pathways involved in IgAN pathogenesis.

© Copyright 2009-2010 American Society of Nephrology.Reproduced with permission.
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