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Abstract Number: 984

Association of Elevated C5a Levels, but Not the Presence of Anti-Cfh IgG Autoantibodies, with the Deletion of CFHR3 and CFHR1 in SLE

Jian Zhao1, Seema Kamble1, Yun Deng1, Magdangal Erika1, Daisuke Sakurai2, Rongqun Li2, Weiling Chen2, Jennifer M. Grossman3, Bevra H. Hahn4 and Betty P. Tsao5, 1Division of Rheumatology, Department of Medicine,, Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 2Division of Rheumatology, Department of Medicine, Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 3Div of Rheumatology, Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 4Rheumatology, UCLA David Geffen School of Medicine, Los Angeles, CA, 5Medicine/Rheumatology, Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Systemic lupus erythematosus (SLE)

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Session Information

Session Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose:

We previously reported association of the deletion of complement regulator factor H related CFHR3 and CFHR1 genes (CFHR3-1Δ), rather than CFH exonic SNPs, with SLE in 15,864 case-control subjects of multiple ancestries (P=2.9×10-7, OR=1.17). Both CFHR3 and CFHR1 suppress C5a generation, and CFHR3-1Δ has been associated with the presence of anti-CFH IgG autoantibodies that block CFH C-terminal binding in patients with atypical hemolytic uremic syndrome. To investigate possible functional consequences of CFHR3-1Δ in SLE, we tested its association with 1) the presence of anti-CFH IgG autoantibodies, and 2) elevated C5a levels.

Methods:

CFHR3-1Δ was either directly genotyped by multiplex ligation-dependent probe amplification or deduced by its tag SNP rs6677604 (r2=1).  Levels of plasma C5a and anti-CFH IgG autoantibodies were measured by ELISA. The presence of anti-CFH IgG autoantibodies (anti-CFH+) was defined as higher levels than the mean + 3 SD of those from healthy controls carrying no deletion. 

Results:

Plasma anti-CFH IgG autoantibodies levels showed no difference between SLE cases and controls (Mean±SEM: 5.46±0.074 RU/ml in 75 cases vs. 5.47±0.063 RU/ml in 45 controls, P=0.91), no difference between men and women (P=0.71 in cases [9 men and 66 women]; P=0.23 in controls [22 men and 23 women]) and no correlation with age (r2=0.00042 in cases [mean: 43 years old, range: 18-72], P=0.91; r2=0.0010 in controls, P=0.79 [mean: 39, range: 20-77]). Anti-CFH+ was only identified in 4 of the 75 studied SLE cases (7%): two of them carried two copies of CFHR3-1Δ and the other two had zero copies, showing no association of anti-CFH+ with CFHR3-1Δ (P=1.00). Although none of the 45 controls  was classified as anti-CFH+, the presence of anti-CFH was not significantly associated with SLE (P=0.30) at the current sample size.

Preliminary results of plasma C5a levels were significantly higher in 15 SLE cases carrying two copies of CFHR3-1Δ than in 84 cases carrying one or zero copy (Mean±SEM: 5.23±0.13 ng/ml vs. 4.86±0.06 ng/ml, P=0.018). We observed no significant difference in plasma C5a levels between 5 controls carrying two copies of CFHR3-1Δ and 57 controls carrying one or zero copy (Mean±SEM: 4.57±0.29 ng/ml vs. 4.76±0.09 ng/ml, P=0.55), which might be due to the small sample size.

Conclusion:

Our preliminary data showed that homozygous deletion of CFHR3-1Δ, which predisposes to SLE, was associated with elevated C5a levels in SLE cases, suggesting that this deletion might confer SLE risk by uninhibited production of C5a leading to neutrophil chemotaxis and inflammatory injuries. In contrast, the deletion was not associated with IgG antibodies to CFH. Further investigation of these association in additional samples is ongoing.


Disclosure:

J. Zhao,
None;

S. Kamble,
None;

Y. Deng,
None;

M. Erika,
None;

D. Sakurai,
None;

R. Li,
None;

W. Chen,
None;

J. M. Grossman,
None;

B. H. Hahn,
None;

B. P. Tsao,
None.

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