Background: Complement component C1q plays a critical role in immune regulation and autoimmunity. Complete C1q deficiency is strongly associated with systemic lupus erythematosus (SLE), while genetic variation within the C1q gene cluster has been implicated in susceptibility to multiple autoimmune diseases. SLE and rheumatoid arthritis (RA) share some overlapping clinical manifestations, particularly in early disease, but differ substantially in pathogenesis, prognosis and management. Given the immunoregulatory role of C1q and its genetic association with autoimmunity, identification of C1q variants that contribute to disease-specific susceptibility or discriminate between SLE and RA is of clinical and biological importance.

Objectives: To investigate allele and genotype distributions of two previously identified single nucleotide polymorphisms (SNPs) within the C1q genetic cluster in patients with RA and SLE and in healthy controls, and to evaluate their potential to discriminate between RA and SLE.

Methods: Two SNPs in the C1q genetic cluster (rs665691, rs292001) were genotyped by TaqMan allelic discrimination assay in 61 patients with RA, 53 patients with SLE, and 67 healthy controls. Allele and genotype frequencies in controls were compared with published European and Bulgarian population data to assess population comparability. Associations with RA and SLE were evaluated, using direct comparison and logistic regression models, applying additive allele-dosage and genotype-based approaches. Odds ratios (ORs), 95% confidence intervals (CIs), and p-values were calculated and ROC curves were constructed.

Results: Allele and genotype frequencies in healthy controls were comparable to those reported in other European and Bulgarian cohorts. Direct comparison between RA and SLE demonstrated that both the G allele of rs665691 (59% vs. 40%; OR for SLE = 0.59, 95% CI: 0.34–1.00, p = 0.05) and the A allele of rs292001 (46% vs. 32%; OR for SLE = 0.56, 95% CI: 0.32–0.97, p = 0.04) were more frequent in RA. Under a dominant model (GG+CG vs. CC), carriage of the rs665691 G allele significantly discriminated RA from SLE (OR for SLE = 0.42, 95% CI: 0.18–0.93, p = 0.03).

In single additive logistic regression models, rs292001 showed the strongest association, with each additional A allele associated with increased odds for RA (OR per allele 1.84, 95% CI 1.08–3.23, p = 0.047), while rs665691 showed a borderline effect (OR per G allele 1.63, 95% CI 0.98–2.79, p = 0.076). In multivariable additive logistic regression model, including both SNPs, neither variant retained independent statistical significance (rs665691: OR 1.23, 95% CI 0.64–2.38, p>0.05; rs292001: OR 1.62, 95% CI 0.83–3.24, p>0.05). Despite this, the combined additive model significantly discriminated RA from SLE (AUC 0.62, 95% CI 0.52–0.73; p = 0.026), indicating a modest but statistically meaningful cumulative genetic contribution.

In genotype-based multivariable logistic analyses, no genotype retained independent statistical significance after mutual adjustment for rs665691 G/C versus C/C (OR 2.50, 95% CI 0.85–7.86, p>0.05) or rs292001 A/A versus G/G (OR 4.31, 95% CI 0.69–32.37, p>0.05).

Conclusions: In our representative cohort, genetic variation within the C1q gene cluster contributes to differential susceptibility between RA and SLE. rs292001 shows the strongest additive association with RA versus SLE, in unadjusted analysis, while rs665691 demonstrates a consistent but weaker effect. Together, these variants contribute to modest yet significant disease discrimination, supporting a cumulative rather than single-variant genetic role of the C1q cluster.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.