DEFA gene variants associated with IgA nephropathy in a Chinese population

Abstract

IgA nephropathy (IgAN) is a complex syndrome with high genetic heterogeneity. More recently, a genome-wide association study (GWAS) from Southern Han population revealed that variants within 8p23.1, where the DEFA genes encoding a-defensins assembled, were associated with susceptibility to IgAN. To replicate the association and fine-map the genetic variants, a case-control genetic study from an independent Northern Han cohort was conducted. A total of 60 single-nucleotide polymorphisms in a region spanning 350 kb encompassing the DEFA genes cluster were analyzed in 2096 individuals. Copy number variations of DEFA1A3 within the loci were also checked for the independent association. Functional significance of the associated variants was further examined by the in silico method as well as by cis-acting expression quantitative trait loci analysis with mRNA. It showed that 17 out of 60 (28.3%) variants were associated with susceptibility to IgAN. Two independent signals with functional potentials were discovered (rs2738058, P=4.64 × 10(-5), odds ratio (OR)=0.76, 95% confidence interval (CI) 0.66-0.87 and rs9644778, P=4.78 × 10(-3), OR=1.21, 95% CI 1.06-1.39). Besides, marginally significant association of rs9644778 risk genotype with lower proportion of gross hematuria (CC+CA vs AA 35.2% vs 30.2%, P=0.073) was observed. In conclusion, DEFA gene polymorphisms have potentially pathogenic roles in IgAN, and the role of mucosal immunity in the pathogenesis of IgAN has to be emphasized.

Novel genes and variants associated with IgA nephropathy by co-segregating with the disease phenotypes in 10 IgAN families

“…Another recent genomewide association study also found a new positive signal (rs10086568) in the DEFA cluster on 8p23 (Kiryluk et al, 2014). Recently, a paper reported that SNPs (rs2738058 and rs9644778) in the DEFA gene were associated with IgAN in a Chinese population (Qi et al, 2015). Our study not only confirmed the association, but also identified three deleterious mutations in the coding region of the gene.…”

“…An association between DEFA4 and IgAN has been reported previously (Yu et al, 2012;Kiryluk et al, 2014;Xu et al, 2014;Qi et al, 2015). DEFA4 codes for α-defensins, which is an important mediator in mammalian innate immunity.…”

Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction

“…In addition, our study has also demonstrated that the newly reported susceptibility signal rs12716641(8)was independent ofDEFA1A3 CNVs. A previous study reported a positive correlation between DEFA1A3copy number and rs2738048, but did not evaluate the association of DEFA1A3 with IgAN (49). Recently, a newly published IgAN GWAS revealed another independent SNP rs10086568 within the GWAS locus on 8p23.1 in a Caucasian population(7).…”

Is immunoglobulin A nephropathy different in different ethnic populations?

“…The risk alleles that were common across these population groups were those involved in the regulation of adaptive immunity (major histocompatibility complex), complement activation (CFH, CFHR3‐1, ITGAM‐ITGAX), mucosal innate immunity (DEFA, CARD9, VAV3, ODF1‐KLF10, UBR5) and in the regulation of mucosal IgA production (TNFSF13, HORMAD2, ST6GAL1) . However, risk alleles demonstrating variants coding for MEGSIN, DEFENSINS and TNF SF13/APRIL have been demonstrated to be associated with IgAN susceptibility in Chinese cohorts but not Europeans . The observation that genetic susceptibility loci associated with IgAN have only been reported in Asian, but not only in Europeans, explains in part the differences in observed prevalence, but also calls into question if the pathogenic processes in the “disease” is indeed the same in different populations across different areas.…”