Ming Li1,2, Ling Wang3, Dian-Chun Shi4,2,5, Jia-Nee Foo3,6, Zhong Zhong4,2, Chiea-Chuen Khor3,7, Chiara Lanzani8, Lorena Citterio8, Erika Salvi9, Pei-Ran Yin4,2, Jin-Xin Bei10,11, Li Wang12, Yun-Hua Liao13, Jian Chen14, Qin-Kai Chen15, Gang Xu16, Geng-Ru Jiang17, Jian-Xin Wan18, Meng-Hua Chen19, Nan Chen20, Hong Zhang21, Yi-Xin Zeng10,11, Zhi-Hong Liu22, Jian-Jun Liu23,5,24, Xue-Qing Yu1,2,5,25. 1. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China yuxq@mail.sysu.edu.cn liuj3@gis.a-star.edu.sg. 2. National Health Commission Key Laboratory of Nephrology (Sun Yat-sen University), Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. 3. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. 4. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 5. Guangdong Provincial People's Hospital, Guangzhou, China. 6. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore. 7. Singapore Eye Research Institute, Singapore, Singapore. 8. Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. 9. Neurology Unit, IRCCS Neurology Institute "Carlo Besta," Milan, Italy. 10. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China. 11. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. 12. Department of Nephrology, Sichuan Provincial People's Hospital, Chengdu, China. 13. Department of Nephrology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China. 14. Department of Nephrology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, China. 15. Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, China. 16. Department of Nephrology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China yuxq@mail.sysu.edu.cn liuj3@gis.a-star.edu.sg. 17. Department of Nephrology, XinHua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 18. Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. 19. Department of Nephrology, General Hospital of Ningxia Medical University, Yinchuan, China. 20. Department of Nephrology, RuiJin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 21. Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Beijing, China. 22. National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China yuxq@mail.sysu.edu.cn liuj3@gis.a-star.edu.sg. 23. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore yuxq@mail.sysu.edu.cn liuj3@gis.a-star.edu.sg. 24. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 25. School of Medicine, South China University of Technology, Guangzhou, China.
Abstract
BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
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