Background and Aims

Copy number variation in complement component 4 (C4) genes, C4A and C4B, has previously been associated with SLE. We asked if C4 copy number variation is connected to clinical features of SLE.

Methods

Copy numbers of C4A and C4B genes were determined for 913 SLE patients and 1,016 healthy controls using targeted sequencing (Fig. 1a). Coding variants in C4 genes were analysed, and HLA alleles called. Clinical data was retrieved from medical records.

Results

A low C4A copy number was more prevalent in SLE patients compared with controls (Fig. 1b; p_C4A=2x10^-24), while C4B copy number did not differ (p_C4B=0.09). C4A copy number was not related to any ACR criteria for SLE, but associated with presence of Ro/SSA and La/SSB autoantibodies. Stratifying SLE patients on anti-SSA/SSB autoantibody status showed a dose-response relationship (Fig. 1c), with a C4A copy number of 0 being strongly associated with SLE with autoantibodies against both SSA and SSB (OR=32.5, CI_95%: 15.9-69.7), while a weaker association was found for patients without anti-SSA/SSB autoantibodies (OR=4.0, CI_95%: 2.1-8.0).

The common C4A loss-of-function (LoF) variant rs760602547 was overrepresented in SLE patients with low C4A copy number (Fig. 1d), and lower plasma C4 levels were detected in LoF carriers compared to non-carriers (p_LoF=1x10^-4, n=369). There was a negative correlation between C4A copy number and number of DRB1*03:01 alleles (r =-0.69).

Conclusions

Our data suggest that C4A has an important role in the development of autoantibodies against Ro/SSA and La/SSB, and that patients with low C4A copy number may constitute a defined subset of SLE.