title: Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction.
abstract: 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.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ai
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Liu
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Jia-Nee
authors.initials: JN
authors.lastname: Foo
authors.affiliation: School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Omniah
authors.initials: O
authors.lastname: Mansouri
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Peiran
authors.initials: P
authors.lastname: Yin
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Shaozhen
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Ricong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Department of Nephrology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian 350025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
authors.forename: Tanqi
authors.initials: T
authors.lastname: Lou
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Mao
authors.affiliation: University College London Centre for Nephrology, Royal Free Hospital, London NW3 2PF, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gale
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barratt
authors.affiliation: School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: John A L
authors.initials: JA
authors.lastname: Armour
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore. School of Biological Sciences, Anhui Medical University, Hefei, Anhui 230032, China. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore. yuxq@mail.sysu.edu.cn liuj3@gis.a-star.edu.sg.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China. yuxq@mail.sysu.edu.cn liuj3@gis.a-star.edu.sg.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
mesh_terms: D016022:Case-Control Studies; D018628:Gene Dosage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000097:blood; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics; D016017:Odds Ratio; D010456:Peptides, Cyclic / Q000235:genetics; D010641:Phenotype; D023084:alpha-Defensins / Q000235:genetics*
chemical_list: C429483:DEFA1A3 protein, human; D010456:Peptides, Cyclic; D023084:alpha-Defensins