RT Journal Article
SR Electronic
T1 Variants in Complement Factor H and Complement Factor H-Related Protein Genes, <em>CFHR3</em> and <em>CFHR1</em>, Affect Complement Activation in IgA Nephropathy
JF Journal of the American Society of Nephrology
JO J. Am. Soc. Nephrol.
FD American Society of Nephrology
SP 1195
OP 1204
DO 10.1681/ASN.2014010096
VO 26
IS 5
A1 Zhu, Li
A1 Zhai, Ya-Ling
A1 Wang, Feng-Mei
A1 Hou, Ping
A1 Lv, Ji-Cheng
A1 Xu, Da-Min
A1 Shi, Su-Fang
A1 Liu, Li-Jun
A1 Yu, Feng
A1 Zhao, Ming-Hui
A1 Novak, Jan
A1 Gharavi, Ali G.
A1 Zhang, Hong
YR 2015
UL http://jasn.asnjournals.org/content/26/5/1195.abstract
AB 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.