title: Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese.
abstract: An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r2=0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; P=8.5 × 10-8versus OR, 0.61; 95% CI, 0.50 to 0.75; P=1.6 × 10-6for rs6677604-A). Moreover, CFHR3,1Δ explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (P=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of CFHR3,1Δ with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate CFHR3,1Δ as the functional allele at this locus.
authors.affiliation: Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York; and.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York; and.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kiryluk
authors.affiliation: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York; and.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York; and.
authors.forename: Nikol
authors.initials: N
authors.lastname: Mladkova
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.affiliation: Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Wang
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York; and ag2239@columbia.edu.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D003180:Complement C3b Inactivator Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins
keywords: IgA nephropathy; complement; genetic renal disease; human genetics