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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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SLE and AAV are associated with different SNPs in the IL2RA region. The genomic context of rs2104286, rs41295061 and rs11594656 is shown, using the GBrowse implementation in T1DBase . All are non-coding SNPs. Negative decimal logarithms of P values (χ2 test; 1 degree of freedom) from each cohort from SLE and AAV are plotted for rs41295061 and rs11594656 but not for rs2104286, as an association of this MS-associated SNP was not detected with SLE or AAV (table 1). Open circles represent the KRUK case-control cohort; filled circles the Imperial case-control cohort and open squares the Imperial family trios (P value from TDT). The filled square represents the combined P value for rs11594656 in SLE. Crosses are used for the AAV cohort. The dashed lines correspond to P = 0.05.
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Figure 1: SLE and AAV are associated with different SNPs in the IL2RA region. The genomic context of rs2104286, rs41295061 and rs11594656 is shown, using the GBrowse implementation in T1DBase . All are non-coding SNPs. Negative decimal logarithms of P values (χ2 test; 1 degree of freedom) from each cohort from SLE and AAV are plotted for rs41295061 and rs11594656 but not for rs2104286, as an association of this MS-associated SNP was not detected with SLE or AAV (table 1). Open circles represent the KRUK case-control cohort; filled circles the Imperial case-control cohort and open squares the Imperial family trios (P value from TDT). The filled square represents the combined P value for rs11594656 in SLE. Crosses are used for the AAV cohort. The dashed lines correspond to P = 0.05.

Mentions: In all three of our SLE cohorts, rs11594656 was found to be significantly associated with disease (protective minor allele, as seen in T1D), combined P = 3.87 × 10-7 (KRUK case control P = 1 × 10-4, Imperial case control P = 0.0221 and Imperial family trio TDT P = 2.8 × 10-3) (Figure 1 and Table 1). Neither of the other two SNPs were associated with SLE (Figure 1 and Table 1). In AAV, in contrast, some evidence for an association was found with rs41295061 (P = 0.0122; minor allele odds ratio = 0.7739; 95% OR CI 0.6330 – 0.9461). The minor allele is protective as in T1D. However, neither rs2104286 or rs11594656 showed any association with AAV (Figure 1 and Table 1). At 80% power, we can detect effect sizes larger than 1.25 for rs11594656 in AAV and 1.4 for rs41295061 in SLE, across all the SLE cases and controls.


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)

SLE and AAV are associated with different SNPs in the IL2RA region. The genomic context of rs2104286, rs41295061 and rs11594656 is shown, using the GBrowse implementation in T1DBase . All are non-coding SNPs. Negative decimal logarithms of P values (χ2 test; 1 degree of freedom) from each cohort from SLE and AAV are plotted for rs41295061 and rs11594656 but not for rs2104286, as an association of this MS-associated SNP was not detected with SLE or AAV (table 1). Open circles represent the KRUK case-control cohort; filled circles the Imperial case-control cohort and open squares the Imperial family trios (P value from TDT). The filled square represents the combined P value for rs11594656 in SLE. Crosses are used for the AAV cohort. The dashed lines correspond to P = 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: SLE and AAV are associated with different SNPs in the IL2RA region. The genomic context of rs2104286, rs41295061 and rs11594656 is shown, using the GBrowse implementation in T1DBase . All are non-coding SNPs. Negative decimal logarithms of P values (χ2 test; 1 degree of freedom) from each cohort from SLE and AAV are plotted for rs41295061 and rs11594656 but not for rs2104286, as an association of this MS-associated SNP was not detected with SLE or AAV (table 1). Open circles represent the KRUK case-control cohort; filled circles the Imperial case-control cohort and open squares the Imperial family trios (P value from TDT). The filled square represents the combined P value for rs11594656 in SLE. Crosses are used for the AAV cohort. The dashed lines correspond to P = 0.05.
Mentions: In all three of our SLE cohorts, rs11594656 was found to be significantly associated with disease (protective minor allele, as seen in T1D), combined P = 3.87 × 10-7 (KRUK case control P = 1 × 10-4, Imperial case control P = 0.0221 and Imperial family trio TDT P = 2.8 × 10-3) (Figure 1 and Table 1). Neither of the other two SNPs were associated with SLE (Figure 1 and Table 1). In AAV, in contrast, some evidence for an association was found with rs41295061 (P = 0.0122; minor allele odds ratio = 0.7739; 95% OR CI 0.6330 – 0.9461). The minor allele is protective as in T1D. However, neither rs2104286 or rs11594656 showed any association with AAV (Figure 1 and Table 1). At 80% power, we can detect effect sizes larger than 1.25 for rs11594656 in AAV and 1.4 for rs41295061 in SLE, across all the SLE cases and controls.

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