title: Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy.
abstract: Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1∆) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1∆ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Zhai
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Feng-Mei
authors.initials: FM
authors.lastname: Wang
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Ji-Cheng
authors.initials: JC
authors.lastname: Lv
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Da-Min
authors.initials: DM
authors.lastname: Xu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Su-Fang
authors.initials: SF
authors.lastname: Shi
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Liu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China;
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China; hongzh@bjmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000483:Alleles; D001798:Blood Proteins / Q000235:genetics*; D016022:Case-Control Studies; D003167:Complement Activation; D015926:Complement C3a / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005260:Female; D005920:Glomerular Mesangium / Q000378:metabolism; D005922:Glomerulonephritis, IGA / Q000097:blood* / Q000235:genetics; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D007070:Immunoglobulin A; D015926:Complement C3a; D017242:Complement Factor H
keywords: IgA nephropathy; complement activation; complement factor H; complement factor H receptor 3-1Δ deletion