Molecular Immunology 46 (2009) 1405–1408 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Is complement factor H a susceptibility factor for IgA nephropathy? Matthew Edey a , Lisa Strain b , Roy Ward c , Saeed Ahmed d , Trevor Thomas e , Timothy H.J. Goodship a,∗ a Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK b Northern Molecular Genetics Service, Newcastle upon Tyne, UK c Department of Immunology the Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK d Department of Nephrology, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UK e Department of Endocrinology, Diabetes and Metabolism, Cardiff University School of Medicine, Cardiff, UK article info Article history: Received 4 December 2008 Accepted 8 December 2008 Available online 21 January 2009 Keywords: Complement IgA nephropathy Genetics abstract There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogen- esis of IgA nephropathy. Mesangial C3 deposition is seen in ∼90% of patients and polymeric IgA has been shown to activate the alternative and lectin pathways. In addition there have been reports of deficiency and mutations in the serum complement regulator factor H (CFH) in association with IgA nephropathy. In this study we have examined the hypothesis that CFH is a susceptibility factor for IgA nephropathy. In 46 IgA nephropathy patients we undertook genotyping of three CFH SNPS (rs3753394, rs3753396 and rs1065489). There was no significant difference in the allele frequency of these 3 SNPs between the patients and normal controls. In the same group of patients we undertook mutation screening of CFH exons 18–23 using direct sequencing and found no abnormalities. All the patients had a normal serum factor H concentration. In this small cohort of IgA nephropathy patients we have not found evidence to support the hypothesis that factor H is a major susceptibility factor for the disease. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction There is substantial evidence to suggest that complement plays a pivotal role in the pathogenesis of IgA nephropathy (reviewed in Oortwijn et al. (2008)). Glomerular deposition of a variety of complement components including C3, properdin, the membrane attack complex, factor H, C4 binding protein and mannan-binding lectin is seen in 60–90% of patients (Bene and Faure, 1987; D’Amico et al., 1985; Endo et al., 1998, 2001; Ibels and Gyory, 1994; Lhotta et al., 1999; Matsuda et al., 1998; Miyazaki et al., 1984; Rauterberg et al., 1987). It has been shown that human polymeric IgA acti- vates the alternative pathway (Hiemstra et al., 1987; Zwirner et al., 1997) and lectin pathways (Roos et al., 2001, 2006) but not the classical (Lucisano Valim and Lachmann, 1991). There is also evi- dence of in situ activation of the alternative pathway (Tomino et al., 1981) with up-regulation of local C3 production (Abe et al., 2001). Whilst serum levels of complement proteins have been reported to be normal in the majority of IgA nephropathy patients there are anecdotal reports of deficiencies in individuals and families (Wyatt et al., 1981). In 1982, Wyatt et al. reported two families with partial factor H deficiency associated with glomerulonephritis (Wyatt et al., 1982). In one of these families five members over three gener- ∗ Corresponding author at: Institute of Human Genetics, Central Parkway, New- castle upon Tyne NE1 3BZ, UK. E-mail address: t.h.j.goodship@ncl.ac.uk (T.H.J. Goodship). ations had low levels of complement factor H. Two of the factor H-deficient individuals, a brother and sister, had biopsy-proven IgA nephropathy. In 2004 we reported the case of a female infant with atypical haemolytic uraemic syndrome (Filler et al., 2004). There was a strong family history of renal disease. The paternal grandfather had end-stage renal failure and a renal biopsy 2 years previously had shown membranoproliferative glomerulonephritis. His younger brother had died in his twenties of ‘Bright’s disease’ and another brother had hypertension, diabetes and progressive renal failure. His daughter (a paternal aunt of the index patient) had been found to have hypertension, renal impairment and urinary abnormalities whilst being worked-up as a potential kidney donor. A renal biopsy showed membranoproliferative glomerulonephri- tis, but with glomerular IgA deposition on immunofluorescence. Mutation screening of the gene encoding factor H (CFH) in this fam- ily showed a novel mutation (c.3546 3581dup36) in CFH exon 23. This mutation leads to the insertion of 12 additional amino acids after codon 1176. The serum factor H level in all individuals found to carry this mutation was normal. The mutation was found in the index case, the paternal grandfather and the paternal aunt with IgA deposition. In 1999 a Japanese group reported a case of atypical HUS in a 35-year-old man (Morita et al., 1999). Renal biopsy showed changes consistent with HUS but also mesangial IgA deposition on immunofluorescence in association with mesangial proliferation on light microscopy. C3 levels were at the lower end of the nor- mal range. Neither factor H levels or CFH mutation screening results were available. 0161-5890/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molimm.2008.12.002