title: Immunogenetics of complement in mixed cryoglobulinaemia.
abstract: OBJECTIVE
  A low C4 level is one of the hallmarks of mixed cryoglobulinaemia (MC). However, several reports suggest that other factors may be involved in C4 depletion. The C4 gene is located in a multiallelic CNV locus in the human MHC region. We studied the C4 gene copy number (GCN) and both C4A and C4B isotypes, as well as the presence of the hypofunctional C4A6 allotype (rs41315824) and C4A0 allotype (rs367709216) in 41 MC patients, 16 SLE patients and 78 healthy controls.
  
  
  METHODS
  GCN of the C4 gene were evaluated by real time PCR. C4A6 allotype (p.Arg458Trp) and ins 2-bp mutation in exon 29 were screened by primer extension. Correlation with clinical signs of the disease (cutaneous ulcers, peripheral neuropathy, GN, purpura, hepatitis) have been performed by cluster analysis, (K-means algorithm).
  
  
  RESULTS
  C4 GCN analysis showed that fewer MC patients had more than 2 copies of the C4A gene as well as a lower C4A gene-copy index (1.90 ± 0.54 vs. 2.21 ± 0.78) as compared to healthy controls. SNP rs41315824 analysis showed a significant increase in the frequency of the p.Arg458Trp (C4A6) variant in cryoglobulinaemic patients. Lastly, cluster analysis allowed us to identify two separate clusters of patients. The cluster that included patients with three or less C4 gene copies was found to have a greater prevalence of the most severe complications such as glomerulonephritis, neuropathy and severe cutaneous ulcers.
  
  
  CONCLUSIONS
  These data suggest there may be a relationship between polymorphisms of the C4 gene and clinical presentation.
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy. elisa.menegatti@unito.it.
authors: Elisa
authors: E
authors: Menegatti
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Margherita
authors: M
authors: Messina
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Valentina
authors: V
authors: Oddone
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Elena
authors: E
authors: Rubini
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Savino
authors: S
authors: Sciascia
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Carla
authors: C
authors: Naretto
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Simone
authors: S
authors: Baldovino
authors: Department of Clinical and Biological Sciences, Center of Research on Immunopathology and Rare Diseases (CMID) and Clinical Pathology Unit, University of Turin, Italy.
authors: Dario
authors: D
authors: Roccatello
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003181:Complement C4 / Q000235:genetics*; D003449:Cryoglobulinemia / Q000235:genetics / Q000276:immunology*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D003181:Complement C4