Human complementC4is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) ofC4AandC4Bin relation to disease risk in systemic lupus erythematosus (SLE), and to compare the basis of race-specificC4Adeficiency between East Asiansand individuals of European descent.Methods.
The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of totalC4,C4A, andC4B, as well asC4-LongandC4-Shortgenes,were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently withC4Adeficiency.Results.
In East Asians, high GCNs of totalC4andC4Awere strongly protective against SLE, whereas low and medium GCNs of totalC4andC4A,and the absence ofC4-Shortgenes, were risk factors for SLE. HomozygousC4Adeficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P= 0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of totalC4(OR 3.19,P= 7.3 × 10−7) andC4B(OR 2.53,P= 2.5 × 10−5).Patients with low serum complement levels had high frequencies of anti–double-stranded DNA antibodies (OR 4.96,P= 9.7 × 10−17), hemolytic anemia (OR 3.89,P= 3.6 × 10−10), and renal disease (OR 2.18,P= 8.5 × 10−6). The monomodular-Shorthaplotype found to be prevalent in European Americans withC4Adeficiency, which was in linkage disequilibrium withHLA–DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects withC4Adeficiency were found to have a recombinant haplotype with bimodularC4-LongandC4-Shortgenes,encoding C4B1 and C4B96, which was linked toHLA–DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96.Conclusion.
C4CNVs and deficiency ofC4Aboth play an important role in the risk and manifestations of SLE in East Asian and European populations.