Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

Abstract

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

“…We manually curated a list of SNPs that both passed genome-wide significance and were associated with kidney disease traits (Table S7). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To acquire independent loci, we removed any SNPs having r 2 R 0.2. In total, we analyzed 110 leading SNPs and 2,357 tagging SNPs with r 2 R 0.8 (Table S7).…”

IgA1 Glycosylation Is Heritable in Healthy Twins

“…Interestingly, most of these loci are shared with other immune-related diseases. [12][13][14][15][16][17] One associated singlenucleotide polymorphism has been located within the ST6GAL1 gene. 16 ST6GAL1 encodes ST6 b-galactosamide a-2,6-sialyltranferase 1, a glycosyltransferase.…”

The role of the alternative pathway of complement activation in glomerular diseases

“…As an example, SNP rs6677604 located in an intronic region of CFH gene has no functional consequence. However, it tags a common copy number polymorphism CFHR3-1Δ, which confers protection for IgAN, has been shown to be a risk factor for SLE [65,[69][70][71][72]. Also, several rare mutations of the AP components have been described in GN patients.…”

“…Conversely, both 41 patients and 28 healthy controls with rs6677604-GG genotype carried two copies of CFHR1 and CFHR3 genes, and 90% of rs6677604-AG heterozygotes (39 patients and 49 controls) were also heterozygous for CFHR3-1Δ [70]. It has been estimated that the deletion of one CFHR3-1 allele reduced the disease risk by 26%, while the absence of two alleles decreased the disease risk by 45% [72]. However, the rs6677604-A allele was not associated with clinical outcomes, but with a reduced mesangial C3 deposition, high serum CFH, and low complement C3a levels [70].…”