Session Title: Sjögren's Syndrome - Pathogenesis
Session Type: Abstract Submissions (ACR)
Candidate gene studies in primary Sjögren’s syndrome (pSS) have identified polymorphisms in genes involved in the type I interferon (IFN) system and the type I IFN system is activated in pSS. NK cells have been shown to increase the immune complex stimulated IFN-alpha production by plasmacytoid dendritic cells but the role for NK cells in pSS autoimmunity has not been well studied. The natural cytotoxicity triggering receptor 3 (NCR3) gene locus (6p21.3) encodes the NKp30 activating receptor on NK cells. A French study identified an association between two rare alleles in the NCR3 promoter region and pSS, independent of the association to HLA-DRB1-03 (6p21.3) (1). The aim of this investigation was to analyze if the two NCR3 single nucleotide polymorphisms (SNPs) were associated with pSS in Scandinavian samples. The potential association with anti-SSA/SSB positivity or clinical phenotypes was investigated. In addition, the association with the HLA-DRB1-03 SNP proxy was studied.
A total of 671 Caucasian pSS patients from Sweden (n=478) and Norway (n=193) and 1586 healthy controls (Sweden, n=1369 and Norway, n=217) were included in the study. Two SNPs in the NCR3 locus, rs11575837 and rs2736191 and the SNP rs2187668 as a marker for HLA-DRB1-03 were selected. Genotyping was performed by single base extension with Fluorescent Polarization Template Dye Incorporation (FP-TDI). Data on anti-SSA and/or anti-SSB positivity and clinical manifestations were extracted from the patient files. Case-control and case-only allelic association analyses were performed using PLINK.
In our case-control analysis we did not find any association between the NCR3 SNPs and pSS in Sweden or Norway or in meta-analysis of the two cohorts. In case-only analysis of the combined cohorts, comparing anti-SSA/SSB positive (n=496, 74%) versus negative (n=175, 26%) pSS patients, we found an association between the SNP rs11575837 and anti-SSA/SSB positivity, p=0.006, OR 0.27 (95% CI 0.10-0.73). There were no associations between the NCR3 SNPs and clinical phenotype. The HLA-DRB1-03 SNP marker rs2187668 was strongly associated with pSS, p=1×10-51, OR 3.2 (95% CI 2.8-3.8). When analyzing only anti-SSA/SSB positive patients versus controls the association was even stronger, p=6.9×10-67, OR 4.1 (95% CI 3.5-4.9). In case-only analysis rs2187668 was associated with major salivary gland swelling and leucopenia (p<0.05), dermal vasculitis (p<0.01), hypergammaglobulinemia (p=7.4x10-8) and anti-SSA/SSB positivity (p=1.6×10-12, OR 3.0, 95% CI 2.2-4.1).
We found an association between anti-SSA/SSB positivity and genetic variation in the NCR3 locus and confirmed the strong HLA-DRB1-03 association with anti-SSA/SSB positive pSS. We conclude that different mechanisms, possibly involving NK cell functions, might contribute to this autoimmune disease in anti-SSA/SSB positive versus negative patients. The potential functional implications for this rare promoter SNP on NKp30 receptor activity has yet to be elucidated.
1. Miceli-Richard et al. Ann Rheum Dis 2011;70(Suppl3):212
M. L. Eloranta,
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