α-防御素基因低拷贝数导致IgA肾病进展和肾脏存活率差的风险增加

艾珍; 李明; 刘文婷; Jia-Nee Foo; Omniah Mansouri; 尹沛然; 周倩; 唐雪晴; 董秀清; 冯少珍; 许日聪; 钟忠; 陈建; 万建新; 娄探奇; 余建文; 周琴; 范瑾瑾; 毛海萍; Daniel GalUCL; Jonathan Barratt; John AL Armour; 刘建军; 余学清

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Low alpha-defensin gene copy number increases the risk for IgA nephropathy development and poor renal survival

首发时间：2017-05-03

Zhen Ai ¹
Zhen Ai
Ming Li ¹ Wenting Liu ¹ Jia-Nee Foo ² Omniah Mansouri ³ Peiran Yin ¹ Qian Zhou ¹ Xueqing Tang ¹ Xiuqing Dong ¹ Shaozhen Feng ¹ Ricong Xu ¹ Zhong Zhong ¹ Jian Chen ⁴ Jianxin Wan ⁵ Tanqi Lou ⁶ Jianwen Yu ¹ Qin Zhou ¹ Jinjin Fan ¹ Haiping Mao ¹ Daniel GalUCL ⁷ Jonathan Barratt ⁸ John AL Armour ⁹ Jianjun Liu ²
Jianjun Liu
Xueqing Yu ¹
余学清（出生年1964-），男，主任医师，博士生导师，肾病研究所所长，主要研究方向：CKD 的早期预警和综合防治

1、Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
2、Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore. 4School of Life Sciences, University Jia-Nee Foo Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore
3、 School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK
4、 Department of Nephrology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian 350025, China
5、 Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
6、Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
7、Centre for Nephrology, Royal Free Hospital, London, NW3 2PF, UK
8、Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, UK.
9、School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK

Abstract： IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although being a major source of genetic variation, copy number variations (CNVs) are poorly studied for their involvement in disease development. Here we performed association analysis of DEFA1A3 CNV locus in two independent IgAN cohorts of Southern Chinese Han (total 1189 cases and 1187 healthy controls). We discovered three independent copy number associations within the locus: DEFA1A3 (P=3.99×10-9, 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 increased risk for IgAN (P=9.56×10-20), low total copy numbers of the three variants also showed significant association with poor long-term renal survival of IgAN (P=0.03, HR=3.69, after controlling the effects of known prognostic factors) as well as the high serum IgA1 level (P=0.02) and high proportion of galactose-deficient IgA1 (P=0.03). As 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 198controls) and found 211bp variant to be extremely rare in Caucasians. Interestingly, we also observed an association of 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 risk variance (the strongest genetic susceptibility locus so far) and influencing the renal progression of IgAN, the DEFA1A3 CNV locus is a potential candidate of novel therapeutic target and prognostic biomarker.

keywords： IgA nephropathy DEFA genome-wide association studies

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α-防御素基因低拷贝数导致IgA肾病进展和肾脏存活率差的风险增加

艾珍 ¹
Zhen Ai
李明 ¹ 刘文婷 ¹ Jia-Nee Foo ² Omniah Mansouri ³ 尹沛然 ¹ 周倩 ¹ 唐雪晴 ¹ 董秀清 ¹ 冯少珍 ¹ 许日聪 ¹ 钟忠 ¹ 陈建 ⁴ 万建新 ⁵ 娄探奇 ⁶ 余建文 ¹ 周琴 ¹ 范瑾瑾 ¹ 毛海萍 ¹ Daniel GalUCL ⁷ Jonathan Barratt ⁸ John AL Armour ⁹ 刘建军 ²
Jianjun Liu
余学清 ¹
余学清（出生年1964-），男，主任医师，博士生导师，肾病研究所所长，主要研究方向：CKD 的早期预警和综合防治

1、中山大学附属第一医院肾内科
2、Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore. 4School of Life Sciences, University Jia-Nee Foo Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore
3、 School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK
4、南京军区福州总医院肾脏科
5、福建医科大学第一附属医院
6、中山大学附属第三医院肾内科
7、Centre for Nephrology, Royal Free Hospital, London, NW3 2PF, UK
8、Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, UK.
9、School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK

摘要：目的探讨α-防御素基因拷贝数与IgA肾病发展的关系。方法对南方汉族人群中的两个独立IgAN组的α-防御素基因拷贝数（DEFA1A3 CNV）进行了关联分析（共1189例病例和1187例健康对照）。结果发现了在这个位点上三个独立的拷贝数与疾病关联：DEFA1A3（P = 3.99×10-9，OR = 0.88），DEFA3（P = 6.55×10-5，OR = 0.82）和非编码缺失变异（211bp）（P = 3.50×10-16，OR = 0.75）（OR每个拷贝数，固定效应meta分析）。三种变异体的低拷贝数不仅与IgAN风险增加密切相关（P = 9.56×10-20），同时与IgAN的长期肾脏存活率差（P = 0.03，HR = 3.69，控制已知预后因素的影响）以及高血清IgA1水平（P = 0.02）和高比例的半乳糖缺乏型IgA1（P = 0.03）密切相关。作为验证，我们证实了在白种人群组中，DEFA1A3（P = 4.42×10-4，OR = 0.82）和DEFA3拷贝数（P = 4.30×10-3，OR = 0.74）与IgA肾病的关联（531例和198对照），发现211bp变体在白种人中极为罕见。有趣的是，我们还观察到211bp拷贝变异与膜性肾病的关联（P = 1.11×10-7，493例中国病例和500匹配对照组OR = 0.74），但与糖尿病肾病无关联（806例中国病例和786例对照）。结论 α-防御素基因拷贝数变异可以解释4.96％的风险变异（迄今为止最强的遗传易感性位点），影响IgAN的肾脏进展，因此成为潜在的新型治疗靶点和预后生物标志物。。

关键词： IgA肾病 α-防御素基因关联分析

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Zhen Ai,Ming Li,Wenting Liu,et al. Low alpha-defensin gene copy number increases the risk for IgA nephropathy development and poor renal survival[EB/OL]. Beijing:Sciencepaper Online[2017-05-03]. https://www.paper.edu.cn/releasepaper/content/201705-232.

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论文编号	201705-232
论文题目	α-防御素基因低拷贝数导致IgA肾病进展和肾脏存活率差的风险增加
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