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

Ai, Zhen; Li, Ming; Liu, Wenting; Foo, Jia-Nee; Mansouri, Omniah; Yin, Peiran; Zhou, Qian; Tang, Xueqing; Dong, Xiuqing; Feng, Shaozhen; Xu, Ricong; Zhong, Zhong; Chen, Jian; Wan, Jianxin; Lou, Tanqi; Yu, Jianwen; Zhou, Qin; Fan, Jinjin; Mao, Haiping; Gale, Daniel; Barratt, Jonathan; Armour, John A.L.; Liu, Jianjun; Yu, Xueqing


Zhen Ai

Ming Li

Wenting Liu

Jia-Nee Foo

Omniah Mansouri

Peiran Yin

Qian Zhou

Xueqing Tang

Xiuqing Dong

Shaozhen Feng

Ricong Xu

Zhong Zhong

Jian Chen

Jianxin Wan

Tanqi Lou

Jianwen Yu

Qin Zhou

Jinjin Fan

Haiping Mao

Daniel Gale

Jonathan Barratt

Professor of Human Genetics

Jianjun Liu

Xueqing Yu


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.


Ai, Z., Li, M., Liu, W., Foo, J., Mansouri, O., Yin, P., …Yu, X. (2016). Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction. Science Translational Medicine, 8(345),

Journal Article Type Article
Acceptance Date Jun 10, 2016
Online Publication Date Jun 29, 2016
Publication Date Jun 29, 2016
Deposit Date Jun 30, 2016
Publicly Available Date Jun 30, 2016
Journal Science Translational Medicine
Print ISSN 1946-6234
Electronic ISSN 1946-6242
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 8
Issue 345
Article Number 345ra88
Public URL
Publisher URL
Copyright Statement Copyright information regarding this work can be found at the following address:
Additional Information This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in
Science Translational Medicine on vol. 8, no. 345, 29 June 2016, DOI:10.1126/scitranslmed.aaf2106.


Author accepted manuscript-Zhen Ai et al 2016.pdf (2.1 Mb)

Copyright Statement
Copyright information regarding this work can be found at the following address:

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