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

medwireNews: A combination of partial impairments affecting 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), according to research by Lars Rönnblom (Uppsala University, Sweden) and his crew.

These findings “underscore the central role of the complement system in the pathogenesis of both diseases,” the researchers write in Arthritis and rheumatology.

The study involved 958 Scandinavian patients with SLE, 911 with pSS and 2,262 controls without these conditions, all of whom underwent DNA sequencing to assess the presence of heterozygotes. C2 impairment due to a deletion of 28 base pairs (rs9332736) and C4A copy number variations.

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

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

When the combined effect of these deficiencies was assessed, researchers found that people who were both heterozygous C2 deficiency and a C4A copy number one had “significantly increased risk of SLE and pSS” compared to individuals with wild type C2 and one C4A copy number two, at an odds ratio of 10.2 for LES and 13.0 for pSS. They also note that there was a tendency for interaction between heterozygotes C2 deficiency and C4A number of copies, but without reaching statistical significance.

“These results show that partial deficiencies affecting multiple classical complement pathway genes can significantly increase disease risk when present in combination,” note Rönnblom et al.

The study authors also demonstrated that having both genetic deficiencies was associated with a younger age at diagnosis. Specifically, among patients with SLE, those with heterozygotes C2 deficiency and a C4A copy number of ones were diagnosed a median of 7 years earlier than wild-type ones C2while the corresponding difference among pSS patients was 12 years.

Conversely, heterozygous C2 deficiency was not associated with age at diagnosis in patients with two copies of C4Awhich, according to the team, “is consistent with the observation that heterozygotes C2 only deficiency is a genetic risk factor for SLE and pSS when combined with a C4A copy number of 1.”

The stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

This independent reporting was supported by a scholarship from L’Institut Servier, Suresnes, France.

Rheumatol arthritis 2022; doi:10.1002/art.42270

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