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

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          Abstract

          Low copy number of the α-defensin DEFA1A3 locus increases the risk for IgA nephropathy.

          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.

          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.

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          Most cited references52

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                Author and article information

                Journal
                Science Translational Medicine
                Sci. Transl. Med.
                American Association for the Advancement of Science (AAAS)
                1946-6234
                1946-6242
                June 29 2016
                June 29 2016
                : 8
                : 345
                Affiliations
                [1 ]Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
                [2 ]Key Laboratory of Nephrology, Ministry of Health and Guangdong Province, Guangzhou, Guangdong 510080, China.
                [3 ]Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
                [4 ]School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK.
                [5 ]Department of Nephrology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian 350025, China.
                [6 ]Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China.
                [7 ]Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
                [8 ]University College London Centre for Nephrology, Royal Free Hospital, London NW3 2PF, UK.
                [9 ]Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, UK.
                [10 ]School of Biological Sciences, Anhui Medical University, Hefei, Anhui 230032, China.
                [11 ]Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore.
                Article
                10.1126/scitranslmed.aaf2106
                27358498
                e3269a69-3280-43d5-b9d6-2281b1109616
                © 2016
                History

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