Abstract: FR-PO835
Genome-Wide Association Study for Serum Galactose-Deficient IgA1 in IgA Nephropathy
Session Information
- Glomerular Diseases: Immunology, Inflammation - I
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Wang, Yanna, Peking University First Hospital, Beijing, China
- Zhou, Xujie, Peking University First Hospital, Beijing, China
- Zhang, Hong, Peking University First Hospital, Beijing, China
Background
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgAN. Although the heritability of serum Gd-IgA1 levels is high (ranging from 54% to 80%), the genetic association between Gd-IgA1 and IgAN has not yet been clearly determined. To further identify novel susceptibility loci, we carried out a genome wide association study (GWAS) for serum Gd-IgA1 levels in IgAN patients.
Methods
We performed a quantitative trait GWAS for serum Gd-IgA1 levels, with discovery and follow-up in 1,127 IgAN patients in a Chinese population. Gd-IgA1 levels were measured using a Helix aspersa lectin–based ELISA method. The mRNA levels of susceptibility genes in peripheral blood mononuclear cells (PBMCs) were evaluated by mRNA microarrays (Affymetrix PrimeView Human Gene Expression Array and Illumina HT-12 v4 Expression BeadChip).
Results
We identified two loci passing genome-wide significance, including GALNT12 (P = 1.67 × 10-8, Beta = 0.68) and C1GALT1 (P = 3.10 × 10-8, Beta = 0.24). Additionally, we confirmed reported association of C1GALT1 with serum Gd-IgA1 levels, including rs1008897 (P = 9.75 × 10-3) and rs13226913 (P = 3.89 × 10-2), which are common variants in Europeans but rare in East Asians (MAF 34% vs. 5% and 58% vs. 7%). C1GALT1 variant associated in our study is in partial linkage disequilibrium with rs1008897 (D' = 0.92, r2 = 0.07) and rs13226913 (D' = 0.44, r2 = 0.02). Compared with healthy controls (n = 61), GALNT12 and C1GALT1 showed lower mRNA expression in PBMCs from IgAN patients (n = 94) (0.86-fold change, P = 1.00 × 10-6 and 0.90-fold change, P = 1.92 × 10-4, respectively). Sub-phenotype analysis showed that the risk allele of GALNT12 variant was associated with decreased serum C3 levels (P = 0.02, Beta = - 0.05).
Conclusion
Our study identifies two loci, which encode two enzymes (GALNT12 and C1GALT1) involved in O-linked glycosylation, are associated with serum levels of Gd-IgA1 in IgAN. Down-regulation of these two enzymes may contribute to the generation of aberrantly glycosylated IgA1 in IgAN.