title: Lack of association between polymorphisms in C4b-binding protein and atypical haemolytic uraemic syndrome in the Spanish population.
abstract: Dysregulation of the alternative pathway of complement activation, caused by mutations or polymorphisms in the genes encoding factor H, membrane co-factor protein, factor I or factor B, is associated strongly with predisposition to atypical haemolytic uraemic syndrome (aHUS). C4b-binding protein (C4BP), a major regulator of the classical pathway of complement activation, also has capacity to regulate the alternative pathway. Interestingly, the C4BP polymorphism p.Arg240His has been associated recently with predisposition to aHUS and the risk allele His240 showed decreased capacity to regulate the alternative pathway. Identification of novel aHUS predisposition factors has important implications for diagnosis and treatment in a significant number of aHUS patients; thus, we sought to replicate these association studies in an independent cohort of aHUS patients. In this study we show that the C4BP His240 allele corresponds to the C4BP*2 allele identified previously by isoelectric focusing in heterozygosis in 1.9-3.7% of unrelated Caucasians. Crucially, we found no differences between 102 unrelated Spanish aHUS patients and 128 healthy age-matched Spanish controls for the frequency of carriers of the His240 C4BP allele. This did not support an association between the p.Arg240His C4BP polymorphism and predisposition to aHUS in the Spanish population. In a similar study, we also failed to sustain an association between C4BP polymorphisms and predisposition to age-related macular degeneration, another disorder which is associated strongly with polymorphisms in factor H, and is thought to involve alternative pathway dysregulation.
authors.affiliation: Departmento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas and Ciber de Enfermedades Raras, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Martínez-Barricarte
authors.forename: E
authors.initials: E
authors.lastname: Goicoechea de Jorge
authors.forename: T
authors.initials: T
authors.lastname: Montes
authors.forename: A G
authors.initials: AG
authors.lastname: Layana
authors.forename: S
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D050716:Complement C4b-Binding Protein / Q000235:genetics* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008268:Macular Degeneration / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D013030:Spain
chemical_list: D050716:Complement C4b-Binding Protein