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

Comment on: Lundtoft, et al., Arthritis Rheumatol, June 21 2022 (Accepted) DOI: 10.1002/art.42270

Comment by: Marta E. Alarcón-Riquelme

Since long ago, we are aware that complement deficiencies are related with the appearance of SLE, particularly in the youth. However, we are not completely aware of the role of complement deficiencies in relation to the risk to develop SLE in the adult, and less so, if there are combined effects of the deficiencies in the risk to develop SLE. Several studies pointed particularly to C4A deficiency and the presence of a gene deletion that could explain the relative lack of C4 protein in the serum of SLE patients 1,2. Others, did identify an homozygous C4A deficiency also known as the C4A null allele (C4AQ0)1. Later, a 2bp deletion was identified and reported as increased in SLE patients, which is associated with an HLA haplotype, being C4, as well as C2, both located within the MHC3. C2 protein deficiency was also observed and studied, associated with SLE4, as well as a 28-bp deletion in C25 that leads to C2 protein deficiency.
In todays’ commented work, Lundtoft and cols analyzed whether the heterozygous C2 deficiency and C4 copy number variation (CNV) are risk factors of SLE and Sjögren´s syndrome (SjS).
The authors studied the 28-bp C2 deletion, most frequent in the heterozygous form (represented by the single nucleotide polymorphism rs9332736) and the C4 CNV in 958 SLE patients, 911 Sjögren´s syndrome patients and 2,262 healthy controls, all of Scandinavian origin. The individuals’ DNA was analyzed using a targeted DNA sequencing approach to extract both, genotype data including not only single nucleotide variation but also deletions and CNVs. In addition, the authors did analyses with clinical data and measured the protein.
The numbers of patients who showed heterozygosity for the C2 28-bp deletion was small: 3.3% in SLE and SjS patients, but more frequent than in the healthy controls (1.9%), and 3 patients were homozygous for the deletion. Performing analyses, the authors found an increased risk with the presence of the 28-bp in C2 in both diseases, with OR of 1.08-2.81 (SLE) and 1.05-2.81 (SjS).
Then the authors investigated if there was an increased risk for SLE or SjS of the heterozygosity of the 28-bp deletion in C2 in the presence or absence of the C4A CNVs. They observed that all individuals heterozygous for the 28-bp C2 deletion carried 1-3 copies of C4A due to linkage disequilibrium between the C4 and C2 genes. However, only an increased risk was observed with the combination of C2 heterozygous deficiency and the presence of 1 copy of C4A, but no risk was observed when 2 or 3 copies of C4A were present. Also, no association was observed with low copy number of C4B. In addition, one C4A copy number in combination with the C2 heterozygous deficiency increased the risk substantially in both diseases (OR = 10 for SLE; OR = 4.9, for SjS). Importantly, the association was not due to linkage disequilibrium with HLA risk alleles, such as DRB1*0301 or DRB1*1501.
When analyzing the functional consequences of the C2 deletion, the levels of complement proteins was lower, for instance, that of C2 in patients heterozygous for the C2 deletion as compared with non-carriers of the deletion. However, there were other SLE patients who did not carry the deletion who also showed lower C2 protein in their serum and who also had a lower concentration of C3 and C4 proteins. On the other hand, individuals with C2 heterozygous deletion had normal concentrations of C3 and C4 proteins. Finally, the authors described that individuals with the C2 heterozygous deficiency had a lower age at diagnosis of their disease and earlier occurrence of nephritis when compared with normal C2. No difference was observed for C4A patients with 2 copies. Also, while previously reported that autoantibodies were associated with C4A copy number, the authors found no association between any of the autoantibody specificities studied.
This is the first time that the study of the C2 28-bp deletion and C4 CNV have been studied in combination in a very large set of patients with SLE and SjS as never before, providing important conclusions on the role of both deficiencies and their combination in the risk of SLE and SjS, despite the somewhat low number of C2 heterozygous carriers. Importantly showing that there are indeed some monogenic cases of the C2 29-bp deletion (2 homozygous identified), that it is the association, in combination with the C4A 1 copy CNV having increased risk for SLE and that the age of onset is at least 7 years earlier (at diagnosis) and with an increased risk of nephritis.


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