Journal
GENES AND IMMUNITY
Volume 16, Issue 3, Pages 231-237Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2015.1
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Funding
- National Natural Science Foundation of China [81200524]
- Foundation of Ministry of Education of China [20120001120008]
- Major State Basic Research Development Program of China (973 program) [2012CB517700]
- Research Fund of Beijing Municipal Science and Technology for the Outstanding PhD Program [20121000110]
- Natural Science Fund of China [81321064]
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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 x 10(-5), odds ratio (OR) = 0.76, 95% confidence interval (CI) 0.66-0.87 and rs9644778, P = 4.78 x 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.
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