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Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis.

Carr EJ, Clatworthy MR, Lowe CE, Todd JA, Wong A, Vyse TJ, Kamesh L, Watts RA, Lyons PA, Smith KG - BMC Med. Genet. (2009)

Bottom Line: The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA.We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV.We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK. ejc58@cam.ac.uk

ABSTRACT

Background: Autoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA.

Methods: Using a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients), and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D) and rs2104286 with multiple sclerosis (MS) and T1D.

Results: We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV.

Conclusion: We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease.

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Serum soluble IL-2RA in SLE and AAV and its relationship with disease activity and genotype at rs11594656. (a) A comparison of SLE and AAV soluble IL-2RA (sIL-2RA) at time 0 and 3 months compared with controls, as assessed by ELISA. Each dot represents a patient. (b, c) Correlation between disease activity and sIL-2RA. (BILAG for SLE; BVAS for AAV; see supplementary information). r2 and P values from linear regression modelling are shown. (d, e) sIL-2RA levels stratified by genotype at rs11594656 at both time 0 and 3 months for SLE (d) and AAV (e). P values for panels (a), (d) & (e) were generated using the Mann-Whitney test.
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Figure 2: Serum soluble IL-2RA in SLE and AAV and its relationship with disease activity and genotype at rs11594656. (a) A comparison of SLE and AAV soluble IL-2RA (sIL-2RA) at time 0 and 3 months compared with controls, as assessed by ELISA. Each dot represents a patient. (b, c) Correlation between disease activity and sIL-2RA. (BILAG for SLE; BVAS for AAV; see supplementary information). r2 and P values from linear regression modelling are shown. (d, e) sIL-2RA levels stratified by genotype at rs11594656 at both time 0 and 3 months for SLE (d) and AAV (e). P values for panels (a), (d) & (e) were generated using the Mann-Whitney test.

Mentions: In both SLE and AAV, sIL-2RA concentrations were significantly higher than controls (Figure 2a). In SLE, disease activity as assessed by BILAG score did not show a significant correlation with sIL-2RA concentrations (Figure 2b), despite previous reports of a correlation between sIL-2RA concentrations and disease activity [5]. However, in AAV, disease activity as assessed by BVAS showed a positive correlation with sIL-2RA concentration (Figure 2c, [10]). Three months after commencement of treatment, when both diseases were considerably less active (mean BILAG decreased from 16.1 to 4.7 and mean BVAS from 13.9 to 4.4), sIL-2RA concentrations correlated with the SLE associated rs11594656 genotype (Figures 2d &2e). In active AAV this correlation no longer held true (figure 2e).


Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis.

Carr EJ, Clatworthy MR, Lowe CE, Todd JA, Wong A, Vyse TJ, Kamesh L, Watts RA, Lyons PA, Smith KG - BMC Med. Genet. (2009)

Serum soluble IL-2RA in SLE and AAV and its relationship with disease activity and genotype at rs11594656. (a) A comparison of SLE and AAV soluble IL-2RA (sIL-2RA) at time 0 and 3 months compared with controls, as assessed by ELISA. Each dot represents a patient. (b, c) Correlation between disease activity and sIL-2RA. (BILAG for SLE; BVAS for AAV; see supplementary information). r2 and P values from linear regression modelling are shown. (d, e) sIL-2RA levels stratified by genotype at rs11594656 at both time 0 and 3 months for SLE (d) and AAV (e). P values for panels (a), (d) & (e) were generated using the Mann-Whitney test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2662820&req=5

Figure 2: Serum soluble IL-2RA in SLE and AAV and its relationship with disease activity and genotype at rs11594656. (a) A comparison of SLE and AAV soluble IL-2RA (sIL-2RA) at time 0 and 3 months compared with controls, as assessed by ELISA. Each dot represents a patient. (b, c) Correlation between disease activity and sIL-2RA. (BILAG for SLE; BVAS for AAV; see supplementary information). r2 and P values from linear regression modelling are shown. (d, e) sIL-2RA levels stratified by genotype at rs11594656 at both time 0 and 3 months for SLE (d) and AAV (e). P values for panels (a), (d) & (e) were generated using the Mann-Whitney test.
Mentions: In both SLE and AAV, sIL-2RA concentrations were significantly higher than controls (Figure 2a). In SLE, disease activity as assessed by BILAG score did not show a significant correlation with sIL-2RA concentrations (Figure 2b), despite previous reports of a correlation between sIL-2RA concentrations and disease activity [5]. However, in AAV, disease activity as assessed by BVAS showed a positive correlation with sIL-2RA concentration (Figure 2c, [10]). Three months after commencement of treatment, when both diseases were considerably less active (mean BILAG decreased from 16.1 to 4.7 and mean BVAS from 13.9 to 4.4), sIL-2RA concentrations correlated with the SLE associated rs11594656 genotype (Figures 2d &2e). In active AAV this correlation no longer held true (figure 2e).

Bottom Line: The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA.We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV.We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK. ejc58@cam.ac.uk

ABSTRACT

Background: Autoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA.

Methods: Using a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients), and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D) and rs2104286 with multiple sclerosis (MS) and T1D.

Results: We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV.

Conclusion: We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease.

Show MeSH
Related in: MedlinePlus