Research ArticleNephropathy

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

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Science Translational Medicine  29 Jun 2016:
Vol. 8, Issue 345, pp. 345ra88
DOI: 10.1126/scitranslmed.aaf2106

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In defense of the kidney

Copy number variations play an important role in human disease development. In a new study, Ai et al. have investigated copy number variations of the α-defensin gene in Chinese patients with IgA nephropathy (IgAN) and healthy controls. They show that low copy number of the α-defensin gene increased the risk for IgAN development and renal degeneration. They replicated the risk association in a Caucasian cohort of IgAN patients. In addition, they demonstrated that α-defensin copy number variants showed negative correlations with serum IgA1 and galactose-deficient IgA1. By explaining 4.96% of disease risk and influencing renal dysfunction, α-defensin may be a potential therapeutic target in IgAN.


Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of southern Chinese Han (total of 1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 [P = 3.99 × 10−9; odds ratio (OR), 0.88], DEFA3 (P = 6.55 × 10−5; OR, 0.82), and a noncoding deletion variant (211bp) (P = 3.50 × 10−16; OR, 0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with an increased risk for IgAN (P = 9.56 × 10−20), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P = 0.03; hazards ratio, 3.69; after controlling for the effects of known prognostic factors) and also with increased serum IgA1 (P = 0.02) and galactose-deficient IgA1 (P = 0.03). For replication, we confirmed the associations of DEFA1A3 (P = 4.42 × 10−4; OR, 0.82) and DEFA3 copy numbers (P = 4.30 × 10−3; OR, 0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. We also observed an association of the 211bp copy number with membranous nephropathy (P = 1.11 × 10−7; OR, 0.74; in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing renal dysfunction in patients with IgAN, the DEFA1A3 CNV locus may be a potential therapeutic target for developing treatments for this disease.

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