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Genetic study emphasizes ‘central role’ of complement pathway in SLE, pSS

By Claire Barnard, medwireNews Reporter

A combination of partial deficiencies affecting the C2 and C4A classical complement pathway genes may represent a risk factor for the development of systemic lupus erythematosus (SLE) or primary Sjögren’s syndrome (pSS), shows research from Lars Rönnblom (Uppsala University, Sweden) and team.

These findings “emphasise the central role of the complement system in the pathogenesis of both diseases”, write the researchers in Arthritis & Rheumatology.

The study involved 958 Scandinavian patients with SLE, 911 with pSS and 2262 controls without these conditions, all of whom underwent DNA sequencing to evaluate the presence of heterozygous C2 deficiency due to a 28-base pair deletion (rs9332736) and C4A copy number variations.

Rönnblom and colleagues report that 3.3% of patients in both the SLE and pSS groups had heterozygous C2 deficiency, compared with just 1.9% of controls. This translated into a significant 1.75-fold increased risk of SLE and a significant 1.72-fold increased risk of pSS associated with heterozygous presence of this deletion.

The C4A copy number ranged from zero to five across the whole study population, but all individuals with heterozygous C2 deficiency carried between one and three copies.

When the combined effect of these deficiencies was evaluated, the researchers found that people with both heterozygous C2 deficiency and a C4A copy number of one had “a substantially increased risk of both SLE and pSS” compared with individuals with wild-type C2 and a C4A copy number of two, at an odds ratio of 10.2 for SLE and 13.0 for pSS. They also note that there was a tendency towards interaction between heterozygous C2 deficiency and C4A copy number, albeit without reaching statistical significance.

“These results show that partial deficiencies affecting multiple genes of the classical complement pathway may increase risk of disease substantially when present in combination”, remark Rönnblom et al.

The study authors also demonstrated that having both genetic deficiencies was associated with younger age at diagnosis. Specifically, among SLE patients, those with heterozygous C2 deficiency and a C4A copy number of one were diagnosed a median of 7 years earlier than those with wild-type C2, while the corresponding difference among pSS patients was 12 years.

Conversely, heterozygous C2 deficiency was not associated with age at diagnosis among patients with two copies of C4A, which the team says “is in line with the observation that heterozygous C2 deficiency only is a genetic risk factor for SLE and pSS when present in combination with a C4A copy number of 1.”

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Arthritis Rheumatol 2022; doi:10.1002/art.42270