title: Complement factor H, FHR-3 and FHR-1 variants associate in an extended haplotype conferring increased risk of atypical hemolytic uremic syndrome.
abstract: Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy affecting the renal microvasculature and is associated with complement dysregulation caused by mutations or autoantibodies. Disease penetrance and severity is modulated by inheritance of "risk" polymorphisms in the complement genes MCP, CFH and CFHR1. We describe the prevalence of mutations, the frequency of risk polymorphisms and the occurrence of anti-FH autoantibodies in a Spanish aHUS cohort (n=367). We also report the identification of a polymorphism in CFHR3 (c.721C>T; rs379370) that is associated with increased risk of aHUS (OR=1.78; CI 1.22-2.59; p=0.002), and is most frequently included in an extended risk haplotype spanning the CFH-CFHR3-CFHR1 genes. This extended haplotype integrates polymorphisms in the promoter region of CFH and CFHR3, and is associated with poorer evolution of renal function and decreased FH levels. The CFH-CFHR3-CFHR1 aHUS-risk haplotype seems to be the same as was previously associated with protection against meningococcal infections, suggesting that the genetic variability in this region is limited to a few extended haplotypes, each with opposite effects in various human diseases. These results suggest that the combination of quantitative and qualitative variations in the complement proteins encoded by CFH, CFHR3 and CFHR1 genes is key for the association of these haplotypes with disease.
authors.affiliation: Unidad de Investigación, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Bernabéu-Herrero
authors.affiliation: Unidad de Investigación, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Jiménez-Alcázar
authors.affiliation: Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Jaouad
authors.initials: J
authors.lastname: Anter
authors.affiliation: Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sánchez Chinchilla
authors.affiliation: Unidad de Inmunología, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Garrido
authors.affiliation: Unidad de Inmunología, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: López-Trascasa
authors.affiliation: Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
authors.affiliation: Unidad de Investigación, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; Ciber de Enfermedades Raras (CIBERER), Madrid, Spain. Electronic address: pilar.sanchezcorral@salud.madrid.org.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000276:immunology; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics*; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003180:Complement C3b Inactivator Proteins / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D059645:Mutation Rate; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D012307:Risk Factors; D013030:Spain; D055815:Young Adult
chemical_list: D000906:Antibodies; D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H
keywords: Atypical hemolytic uremic syndrome; Complement; Factor H; Factor H-related protein 1; Factor H-related protein 3; Haplotypes