title: Rare Variants in the Complement Factor H-Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy.
abstract: A recent genome-wide association study of IgA nephropathy (IgAN) identified 1q32, which contains multiple complement regulatory genes, including the complement factor H (CFH) gene and the complement factor H-related (CFHRs) genes, as an IgAN susceptibility locus. Abnormal complement activation caused by a mutation in CFHR5 was shown to cause CFHR5 nephropathy, which shares many characteristics with IgAN. To explore the genetic effect of variants in CFHR5 on IgAN susceptibility, we recruited 500 patients with IgAN and 576 healthy controls for genetic analysis. We sequenced all exons and their intronic flanking regions as well as the untranslated regions of CFHR5 and compared the frequencies of identified variants using the sequence kernel association test. We identified 32 variants in CFHR5, including 28 rare and four common variants. The distribution of rare variants in CFHR5 in patients with IgAN differed significantly from that in controls (P=0.002). Among the rare variants, in silico programs predicted nine as potential functional variants, which we then assessed in functional assays. Compared with wild-type CFHR5, three recombinant CFHR5 proteins, CFHR5-M (c.508G>A/p.Val170Met), CFHR5-S (c.533A>G/p.Asn178Ser), and CFHR5-D (c.822A>T/p.Glu274Asp), showed significantly higher C3b binding capacity (CFHR5-M: 109.67%±3.54%; P=0.02; CFHR5-S: 174.27%±9.78%; P<0.001; CFHR5-D: 127.25%±1.75%; P<0.001), whereas another recombinant CFHR5 (c.776T>A/p.Leu259Termination) showed less C3b binding (56.89%±0.57%; P<0.001). Our study found that rare variants in CFHR5 may contribute to the genetic susceptibility to IgAN, which suggests that CFHR5 is an IgAN susceptibility gene.
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; and 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; and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
authors.forename: Si-Jun
authors.initials: SJ
authors.lastname: Meng
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; and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China funnyzhuli@bjmu.edu.cn.
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; and 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; and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
authors.forename: Su-Xia
authors.initials: SX
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; and 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; and 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; and 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; and 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: 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; and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000328:Adult; D003165:Complement System Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D006801:Humans; D008297:Male
chemical_list: C432223:CFHR5 protein, human; D003165:Complement System Proteins
keywords: CFHR5; IgA nephropathy; genetic analysis
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