Combined genetic deficiencies of the classical complement pathway are strongly associated with both systemic lupus erythematosus and primary Sjögren's syndrome

Christian Lundtoft, Anders A. Bengtsson, Andreas Jönsen, Emeli Lundström, Daniel Hammenfors, Thomas Mandl, Lennart Truedsson, Kerstin Lindblad‐Toh, Lars Rӧnnblom, Elke Theander (medarbetare), DISSECT consortium, ImmunoArray consortium

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

Objective
Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (pSS) has not been studied systematically. Here we investigated heterozygous C2 deficiency and C4 copy number variation in relation to clinical manifestations in SLE and pSS.
Methods
The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients diagnosed with SLE (n=958) or pSS (n=911), and 2,262 controls using DNA sequencing. Plasma concentration of complement proteins and classical complement function was analysed in a subgroup of patients.
Results
Heterozygous C2 deficiency – when present in combination with a low C4A copy number – substantially increased the risk of SLE (OR=10.2, CI95%: 3.5-37.0) and pSS (OR=13.0, CI95%: 4.5-48.4) when compared to individuals with two C4A copies and normal C2. For patients heterozygous for rs9332736 with one C4A copy, the median age of diagnosis was 7 years and 12 years earlier in SLE and pSS, respectively. Reduced plasma C2 (p=2x10-9) and impaired function of the classical complement pathway (p=0.03) was detected in SLE patients with heterozygous C2 deficiency. Finally, we describe a pSS patient with homozygous C2 deficiency.
Conclusion
We demonstrate that the combination of partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and pSS. Our results emphasise the central role of the complement system in the pathogenesis of both diseases.
Originalspråkengelska
Sidor (från-till)1842-1850
TidskriftArthritis & Rheumatology
Volym74
Nummer11
Tidigt onlinedatum2022 juni 22
DOI
StatusPublished - 2022

Ämnesklassifikation (UKÄ)

  • Reumatologi och inflammation

Fingeravtryck

Utforska forskningsämnen för ”Combined genetic deficiencies of the classical complement pathway are strongly associated with both systemic lupus erythematosus and primary Sjögren's syndrome”. Tillsammans bildar de ett unikt fingeravtryck.

Citera det här