Two single-nucleotide polymorphisms in the 5' and 3' ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus.

OBJECTIVE: To test the association of osteopontin (OPN) polymorphisms with systemic lupus erythematosus (SLE). METHODS: The coding 5' and 3' flanking regions of the OPN gene were scanned for polymorphisms by denaturing high-performance liquid chromatography. A case-control association study was performed in 394 Italian SLE patients and 479 matched controls. OPN serum levels were determined by enzyme-linked immunosorbent assay in 40 patients and 124 controls, and the mean levels were compared between the different OPN genotypes. RESULTS: Among the 13 detected single-nucleotide polymorphisms (SNPs), alleles -156G (frequency 0.714 versus 0.651; P = 0.006, corrected P [P(corr)] = 0.036) and +1239C (0.377 versus 0.297; P = 0.00094, P(corr) = 0.0056) were significantly increased in the SLE patients compared with the controls. The presence of the associated allele in single or double dose conferred an odds ratio (OR) of 2.35 (95% confidence interval [95% CI] 1.38-4.02) for SNP -156 and an OR of 1.57 (95% CI 1.16-2.13) for SNP +1239. These effects were independent of each other, i.e., not a consequence of linkage disequilibrium between the 2 alleles. The risk associated with a double dose of susceptibility alleles at both SNPs was 3.8-fold higher (95% CI 2.0-7.4) relative to the complete absence of susceptibility alleles. With regard to individual clinical and immunologic features, a significant association was seen between lymphadenopathy and -156 genotypes (overall P = 0.0011, P(corr) = 0.046). A significantly increased OPN serum level was detected in healthy individuals carrying +1239C (P = 0.002), which is indicative of an association between the SLE susceptibility allele and OPN levels. CONCLUSION: These data suggest the independent effect of a promoter (-156) and a 3'-untranslated region (+1239) SNP in SLE susceptibility. We can speculate that these sequence variants (or others in perfect linkage disequilibrium) create a predisposition to high production of OPN, and that this in turn may confer susceptibility to SLE.

Elevated bioactive prolactin levels in systemic lupus erythematosus--association with disease activity.

OBJECTIVE: To assess the possibility that prolactin (PRL) is involved in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: We determined serum PRL levels in 122 serum samples from 78 unselected patients with SLE (73 women, 5 men, age range 16-71 yrs). Disease activity was defined according to Lupus Activity Criteria Count (LACC) and scored by Systemic Lupus Disease Activity Index (SLEDAI). Serum PRL concentrations were determined by immunoradiometric assay (IRMA) and by biological assay (BA) that evaluates Nb2 lymphoma cell proliferation. RESULTS: Hyperprolactinemia (> 20 ng/ml) was found in 21 patients (26.9%) by IRMA and in 31 (39.7%) by BA. A significant correlation between IRMA and BA PRL levels was found (rs 0.46, p < 0.001). According to LACC, SLE was active in 29 patients and inactive in 49. In those with active disease median PRL levels were higher both by IRMA (18.5 ng/ml, range 2.2-51.2 vs 10.6 ng/ml, range 3.9-29.6; p < 0.001) and BA (21.0 ng/ml, range 12.4-84 vs 14.9 ng/ml, range 4.2-46.1; p < 0.001). Hyperprolactinemia was associated with active disease in 13/21 patients (61.9%) by IRMA and in 18/31 (58.1%) by BA (p < 0.01). SLEDAI scores correlated with PRL levels both by IRMA (rs 0.5, p < 0.001) and BA (rs 0.41, p < 0.02). A followup analysis on serum samples from 44 patients seen again after 6-8 mo confirmed the above results. There was no difference in the rate of different clinical manifestations in hyperprolactinemic and normoprolactinemic subjects, apart from the increased prevalence of malar rash and central nervous system manifestations in the patients with hyperprolactinemia (p < 0.03 and p < 0.01, respectively). CONCLUSION: Hyperprolactinemia was frequently detected in patients with SLE by IRMA and by BA and was associated with disease activity. Our findings suggest that PRL may play a role in the pathogenesis of SLE.