title: Increased frequency of complement C4B deficiency in rheumatoid arthritis.
abstract: OBJECTIVE
  To assess the copy number variation of complement C4A and C4B genes in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  DNA samples were obtained from 299 patients and controls and analyzed for copy number variation of total complement C4, C4A, and C4B genes. The results were compared by chi-square analysis, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
  
  
  RESULTS
  Chi-square analysis revealed similar distribution patterns of total C4 alleles in RA patients (n = 160), non-RA patients (n = 88), and healthy controls (n = 51). There was no trend toward C4A deficiency as in lupus. Significant differences in C4B distribution were observed in RA patients, in whom an ∼2-fold increase in the frequency of homozygous and/or heterozygous C4B deficiency (0 or 1 allele) (40%) was present relative to non-RA patients or healthy controls (both 21.6%). C4B deficiency was more frequent in seropositive RA patients than in seronegative RA patients (44% versus 31%). The odds of C4B deficiency were 2.99 (95% CI 1.58-5.65) (P = 0.0006) in seropositive RA patients relative to non-RA controls. These findings were confirmed in a larger healthy control cohort, yielding an OR of 1.83 (95% CI 1.21-2.76) (P = 0.0056). The association of the shared epitope with C4B deficiency was significantly greater in seropositive RA patients than in non-seropositive RA controls (96% versus 54.5%) (P < 0.0001), suggesting that C4B deficiency interacts with the shared epitope in the development of seropositive RA.
  
  
  CONCLUSIONS
  Our findings indicate a relationship between C4B copy number variation and RA that approximates that seen between C4A copy number variation and lupus. The concurrence of C4B deficiency and the shared epitope in seropositive RA may have broad implications for our understanding of RA pathogenesis.
authors.affiliation: Dartmouth Medical School at Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA. william.rigby@dartmouth.edu
authors.forename: William F C
authors.initials: WF
authors.lastname: Rigby
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Moe
authors.initials: M
authors.lastname: Zan
authors.forename: Bi
authors.initials: B
authors.lastname: Zhou
authors.forename: Sanna
authors.initials: S
authors.lastname: Rosengren
authors.forename: Cheryl
authors.initials: C
authors.lastname: Carlson
authors.forename: Whitney
authors.initials: W
authors.lastname: Hilton
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D015934:Complement C4a / Q000235:genetics; D015935:Complement C4b / Q000172:deficiency / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007155:Immunologic Factors / Q000172:deficiency / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D015934:Complement C4a; D015935:Complement C4b
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