title: Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus.
abstract: BACKGROUND
  Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS).
  
  
  METHODS
  The exons of complement inhibitor genes CD46 and CFH (factor H) were fully sequenced using the Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and in healthy controls (n = 523).
  
  
  RESULTS
  We found nonsynonymous, heterozygous mutations in CFH in 6.1% patients with nephritis, in comparison with 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two nonsynonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients versus 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in noncoding regions of CD46, which were previously implicated in aHUS.
  
  
  CONCLUSIONS
  SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
authors.affiliation: Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Kioskgatan 3, SE-221 85 Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.forename: Sara C
authors.initials: SC
authors.lastname: Nilsson
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Karin G
authors.initials: KG
authors.lastname: Eriksson
authors.forename: Anders
authors.initials: A
authors.lastname: Bengtsson
authors.forename: Agneta
authors.initials: A
authors.lastname: Zickert
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics*; D015999:Multivariate Analysis; D009154:Mutation; D009393:Nephritis / Q000453:epidemiology / Q000235:genetics; D011110:Polymorphism, Genetic; D013548:Sweden / Q000453:epidemiology; D055815:Young Adult
chemical_list: D051916:Membrane Cofactor Protein; D017242:Complement Factor H