GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway

Abstract

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10−11) and C1GALT1C1 (rs5910940, P = 2.7 x 10−8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy

“…Histopathologically, IgAN is characterized by mesangial cell proliferation with IgA-IC deposition in the glomerular mesangium, which is indistinguishable from pathologic findings of HSPN [2,12,14]. Regarding the pathogenesis of IgAN, several studies that investigated aberrant IgA1 O-glycosylation indicated that galactose-deficient IgA1 (Gd-IgA1) plays a pivotal role in the progression of IgAN [15][16][17][18][19][20][21][22][23]. According to these studies, patients with IgAN have aberrant IgA1 molecules with a Gal deficiency of O-linked glycans in the hinge region, which indicates that Gd-IgA1 consists of terminal N-acetyl-galactosamine (GalNAc) or sialylated GalNAc [20][21][22][23].…”

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy

“…Recent GWAS findings showed an association of IgAN with SNPs for critical glycosyltransferase and chaperone genes, C1GALT1 and COSMC. These data were validated with in vitro studies that revealed that 2 genome-wide significant loci, on chromosomes 7p21.3 and Xq24, influence Gd-IgA1 production [15,16]. Furthermore, environmental factors, such as mucosal infections, may further accentuate the aberrant O-glycosylation of IgA1.…”

“…These findings together suggested that elevated production of Gd-IgA1 in patients with IgAN was due to an abnormal biosynthesis in IgA1-secreting cells rather than galactose removal/degradation. This conclusion was further supported by 2 genome-wide association studies (GWAS) that implicated variants of C1GALT1 and COSMC in Gd-IgA1 serum levels [15,16].…”

Two distinct E3 ligases, SCFFBXL19and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively

“…It regulates the expression of thyroid-specific genes, including the NIS, TSHR, TG, and TPO. TTF1 usually plays an important role when it is biochemically and synergistically associated with Paired box gene 8 (46)(47)(48)(49)(50). Here, we revealed that TTF1 significantly up-regulates gene expression, cell proliferation, and migration in HTori3 cells, whereas these effects are attenuated by HECW1.…”