Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus.
OBJECTIVE
To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels.


METHODS
The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set.


RESULTS
We demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives.


CONCLUSIONS
Non-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.
Hunnangkul
Saowalak
S
London School of Hygiene and Tropical Medicine, London, UK.
Nitsch
Dorothea
D
Rhodes
Benjamin
B
Chadha
Sapna
S
Roberton
Cheri A
CA
Pessôa-Lopes
Pedro
P
Norsworthy
Peter J
PJ
Fernando
Michelle M A
MM
Charles
Peter
P
Mackworth-Young
Charles
C
Isenberg
David A
DA
Whittaker
John C
JC
Vyse
Timothy J
TJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D016000:Cluster Analysis; D015331:Cohort Studies; D015922:Complement C1q / Q000276:immunology*; D003176:Complement C3 / Q000032:analysis*; D003181:Complement C4 / Q000032:analysis* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D006113:United Kingdom
D001323:Autoantibodies; D003176:Complement C3; D003181:Complement C4; D015922:Complement C1q