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Helmut H. Wolff - One of the best experts on this subject based on the ideXlab platform.

  • investigation of selected cytokine genes suggests that IL2RA and the tnf lta locus are risk factors for severe alopecia areata
    British Journal of Dermatology, 2012
    Co-Authors: Silke Redler, F. Albert, Felix F. Brockschmidt, Christine Herold, Sandra Hanneken, Sibylle Eigelshoven, Kathrin A. Giehl, Rudolf Kruse, Gerhard Lutz, Helmut H. Wolff
    Abstract:

    Summary Background  Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. Objectives  To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. Methods  Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. Results  Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10−6). Conclusions  Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

  • Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata
    The British journal of dermatology, 2012
    Co-Authors: Silke Redler, F. Albert, Felix F. Brockschmidt, Christine Herold, Sandra Hanneken, Sibylle Eigelshoven, Kathrin A. Giehl, Rudolf Kruse, Gerhard Lutz, Helmut H. Wolff
    Abstract:

    Summary Background  Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. Objectives  To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. Methods  Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. Results  Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10−6). Conclusions  Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

J. Cañal - One of the best experts on this subject based on the ideXlab platform.

Twj Huizinga - One of the best experts on this subject based on the ideXlab platform.

  • IL2RA is associated with persistence of rheumatoid arthritis
    Arthritis Research and Therapy, 2015
    Co-Authors: H.w. Van Steenbergen, J. A. B. Van Nies, Twj Huizinga, Alain Cantagrel, Francis Berenbaum, A. Ruyssen-witrand, A. H. M. Van Der Helm-van Mil
    Abstract:

    Introduction: Although rheumatoid arthritis (RA) is generally a chronic disease, a proportion of RA-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence. To explore mechanisms underlying RA-persistence, we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission. Methods: 645 Dutch RA-patients were studied on DMARD-free sustained remission during a maximal follow-up duration of 10-years. Variants associated with radiographic progression under an additive model in the total RA-population (Human Leukocyte Antigens (HLA)-DRB1-shared epitope (SE), Dickkopf-1 (DKK1)-rs1896368, DKK1-rs1896367, DKK1-rs1528873, C5Orf30-rs26232, Interleukin-2 receptor-α (IL2RA)-rs2104286, Matrix metalloproteinase-9 (MMP-9)-rs11908352, rs451066 and Osteoprotegerin (OPG)-rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2Rα (sIL2Rα)-levels were studied. For replication, 622 RA-patients included in the French Evaluation et Suivi de POlyarthrites Indifférenciées Récentes cohort (ESPOIR)-cohort were investigated. Results were combined in inverse-variance weighted meta-analysis. Results: Similar as previously reported, the SE-alleles associated with less remission (hazard ratio (HR) = 0.57, 95 % confidence interval (95 % CI) = 0.42-0.77, p = 2.72×10 −4). Variants in DKK-1, C5orf30, MMP-9 and OPG were not associated with remission. The IL2RA-rs2104286 minor allele associated with a higher chance on remission (HR = 1.52, 95 % CI = 1.16-1.99, p = 2.44×10 −3). The rs2104286 minor allele associated with lower sIL2Rα-levels (p = 1.44×10 −3); lower sIL2Rα-levels associated with a higher chance on remission (HR per 100 pg/L = 0.81, 95 % CI = 0.68-0.95, p = 0.012). When including rs2104286 and sIL2Rα-levels in one analysis, the HR for rs2104286 was 2.27 (95 % CI = 1.06-4.84, p = 0.034) and for sIL2Rα 0.83 (95 % CI = 0.70-0.98, p = 0.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95 % CI = 0.90-1.90). The meta-analysis revealed a p-value of 1.01×10 −3. Conclusion: IL2RA-rs2104286 and sIL2Rα-level associated with RA-persistence. IL2RA variants are known to protect against multiple sclerosis, diabetes mellitus and RA. Besides HLA-SE, IL2RA-rs2104286 is thus far the only known genetic variant associated with both joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA.

  • OP0123 IL2RA is Associated with Persistence of Rheumatoid Arthritis
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: H.w. Van Steenbergen, J. A. B. Van Nies, Twj Huizinga, Alain Cantagrel, Francis Berenbaum, A. H. M. Van Der Helm-van Mil
    Abstract:

    Background Chronic inflammation is a hallmark of rheumatoid arthritis (RA). Thus far, the biologic mechanisms underlying disease persistence are largely unknown. A proportion of RA-patients achieve DMARD-free sustained remission (persistent absence of arthritis after cessation of DMARD-therapy) over time, reflecting loss of disease persistence. To identify genetic variants indicative for processes underlying disease persistence we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission. Methods 645 Dutch RA-patients were studied on achieving DMARD-free sustained remission during a maximal follow-up of 10-years. Variants replicated to be associated with radiographic progression under an additive model ( HLA-DRB1- shared epitope (SE), DKK1 -rs1896368, DKK1 -rs1896367, DKK1 -rs1528873, C5Orf30 -rs26232, IL2RA -rs2104286, MMP- 9-rs11908352, rs451066 and OPG -rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2RA (sIL2RA)-levels were studied in relation to remission. For replication, 622 RA-patients included in the ESPOIR cohort were studied. Results were combined in inverse-variance weighted meta-analysis. Results 119 patients achieved DMARD-free sustained remission after median disease duration of 4.3 years. The SE-alleles associated with a lower chance on remission, similar as previously reported (hazard ratio (HR)=0.57 95% confidence interval (95%CI)=0.42-0.77 p=2.72x10 -4 ). Variants in DKK-1 , C5orf30 , MMP-9 and OPG were not associated with remission. The IL2RA -rs2104286 minor allele associated with a higher chance on remission (HR=1.52 95%CI=1.16-1.99 p=2.44x10 -3 ), also after additional adjustment for anti-citrullinated peptide antibody status (HR=1.47, 95%CI=1.12-1.93, p=5.78x10 -3 ). The rs2104286 minor allele associated with lower sIL2RA-levels (p=1.43x10 -3 ) and lower sIL2RA-levels associated with a higher chance on remission (HR=0.81 per 100 pg/L 95%CI=0.68-0.95 p=0.012). When including both rs2104286 and sIL2RA-levels in one analysis the HR for rs2104286 was 2.27 (95%CI=1.06-4.84 p=0.034) and for sIL2RA 0.83 per 100 pg/L (95%CI=0.70-0.98 p=0.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95%CI=0.90-1.90). Meta-analysis of the two cohorts revealed a p-value of 1.01x10 -3 . Conclusions IL2RA -rs2104286 and sIL2RA-level associated with loss of disease persistence in RA. Variants in IL2RA are known to protect against development of multiple sclerosis, diabetes and RA. Present data revealed that IL2RA -rs2104286, in addition to HLA -SE, is the only genetic factor that is associated with both radiographic joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA. Disclosure of Interest None declared

  • Association of variants in IL2RA with progression of joint destruction in rheumatoid arthritis.
    Arthritis and rheumatism, 2013
    Co-Authors: Rachel Knevel, G. Grondal, A. Krabben, Kristjan Steinsson, G. Cavet, Rene E M Toes, D. P. C. De Rooy, Alexandra Zhernakova, Cisca Wijmenga, Twj Huizinga
    Abstract:

    Objective Heritability studies have suggested an important role of genetic predisposition in the progression of joint destruction in rheumatoid arthritis (RA); the heritability is estimated at 45–58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of joint destruction. Methods We studied 1,750 RA patients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with joint destruction were tested in 596 Dutch RA patients. Subsequently, significant SNPs were studied in data sets of RA patients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped. Results In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of joint destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of joint destruction (P = 7.2 × 10−4). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77–0.93], P = 1.4 × 10−3) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of joint destruction (P = 3.4 × 10−3). The association of IL2RA with the rate of joint destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5′ region of IL2RA and RBM17. Conclusion The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.

  • OP0209 Genetic variance in IL2RA associates with progression of joint destruction and circulating SIL-2RA levels in rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: R. Knevel, Twj Huizinga, D. De Rooy, S. Zhernakova, G. Grondal, A. Krabben, Kristjan Steinsson, G. Cavet, R. Toes, Peter K. Gregersen
    Abstract:

    Background Since most therapeutic strategies are targeted to affect pathways of disease progression, interrogation of the genome with disease progression as an outcome is attractive. At this moment, 32 regions have been associated with RA susceptibility and 20 of these loci have been tested for an association with joint destruction. Objectives In the current study, we investigated the remaining 12 susceptibility loci for their association with rate of joint destruction. Methods The associations of the 12 susceptibility loci ( AFF3, ANKRD55, BLK, CCL21, CTAL4, IL21, IL2RA, IL2RB, IRF5, REL, SPRED2 and STAT4 ) with the rate of joint destruction were tested in 596 Dutch patients with yearly X-rays during 7 follow-up years. Significant associations were subsequently tested in three additional cohorts from the USA and Iceland. Results were combined in a meta-analysis, consisting of 7,732 X-rays of 1,750 patients in total. X-rays of all cohorts were scored according to the Sharp-van der Heijde Score by Dutch trained scorers (all ICCs>0.9). The locus associated with rate of joint destruction ( IL2RA ) was further studied with serum levels (sIL-2RA) measured with ELISA. Finally the region of the identified SNP was fine-mapped using the ImmunoChip platform. Results In the discovery cohort, an association with rate of joint destruction was found for AFF3 (p=2.8×10 -2 ), BLK (p=3.1×10 -2 ) and IL2RA (p=4.4×10 -3 ). Of these, the minor allele of IL2RA (rs2104286) was associated with a lower rate of joint destruction in the meta-analysis (p=7.2×10 -4 ). Furthermore, the IL2RA minor allele was associated with a 0.85-fold change in circulating levels of soluble IL-2RA (p=1.0×10 -3 ). In addition, lower sIL-2RA level was associated with a lower rate of joint destruction per year (p=4.2×10 -3 ). The association of IL2RA with rate of joint destruction was further focused to a region of 40kb encompassing the IL2RA intron 1 and the 5’ region of IL2RA and RBM17 . Conclusions We found an association of IL2RA with rate of joint destruction and supported this with the association of IL2RA with sIL-2RA in serum. The present results comprising high-quality phenotypic outcome data, genotyping, fine-mapping and serologic data, support the role of IL2RA in severity of progression of RA. Acknowledgement The authors acknowledge deCODE Genetics for providing the genetic and genealogic data. Specifically we want to thank Ari Karason and Stacy Steinberg for their assistance in the logistics and the analyses. Disclosure of Interest R. Knevel: None Declared, D. de Rooy: None Declared, S. Zhernakova: None Declared, G. Grondal: None Declared, A. Krabben: None Declared, K. Steinsson: None Declared, G. Cavet Grant/Research support from: Crescendo Bioscience measured sIL2RA levels, R. Toes: None Declared, T. Huizinga: None Declared, P. Gregersen: None Declared, A. van der Helm-van Mil: None Declared

  • association of IL2RA and il2rb with rheumatoid arthritis a replication study in a dutch population
    Annals of the Rheumatic Diseases, 2009
    Co-Authors: Fina A S Kurreeman, Twj Huizinga, Nina A Daha, M Chang, Joseph J Catanese, Ann B Begovich, Rene E M Toes
    Abstract:

    Rheumatoid arthritis (RA) is an autoimmune disease with a worldwide prevalence of approximately 1%. The aetiology of RA is largely unknown, but it is thought that both genetic and environmental factors play a role in the pathogenesis of the disease. Genome-wide association studies (GWAS) and candidate gene approaches have led to the association of a number of genetic susceptibility loci.1 2 3 4 5 6 7 The Wellcome Trust case-control consortium (WTCCC), the first GWAS in RA, identified a number of loci reaching genome-wide significance including the HLA region and the PTPN22 gene.5 To identify new genetic risk factors, Thomson et al investigated whether tier 2 single nucleotide polymorphisms (SNPs) (p = 1×10−5−1×10−7) in the WTCCC-GWAS showed an association with RA in an independent validation study …

Constantin Polychronakos - One of the best experts on this subject based on the ideXlab platform.

  • The type I diabetes association of the IL2RA locus
    Genes and Immunity, 2009
    Co-Authors: J P Bradfield, A Bélisle, S F A Grant, H Hakonarson, Constantin Polychronakos
    Abstract:

    To confirm and fine map previous reports of association, the Type I Diabetes (T1D) Genetics Consortium (T1DGC) assembled a large collection of DNA samples from affected sib-pair (ASP) families with T1D (5003 affected individuals) and genotyped polymorphic markers. One of these loci, involving the IL2RA gene, had been reported to be due to three independent effects. The T1DGC genotyped 69 single-nucleotide polymorphisms (SNPs) that span ∼88 kb from the 5′ flanking to 3′ flanking region of the IL2RA locus. The most highly associated SNP reported earlier (ss52580101) was not included in the genotyping list; however, a 5-SNP (rs3134883, rs3118470, rs7072793, rs4749955 and rs12251307) haplotype (H5) was identified that strongly tagged its minor allele with r2=0.869 (95% CI, 0.850–0.885). This haplotype was significantly protective (P=3.2 × 10−5) in the T1D ASP families, with an odds ratio virtually identical to that reported for ss52580101. The SNP marking the second independent locus, (rs11594656) showed no association in the T1DGC set and the third (rs2104286) could not be distinguished, by conditional regression, from H5. Instead, the most significant independent effect was detected from the 5′ flanking IL2RA SNP rs4749955, which remained significant after regression for H5. Thus, we confirm independent effects at the IL2RA locus.

  • The type I diabetes association of the IL2RA locus.
    Genes and immunity, 2009
    Co-Authors: J P Bradfield, A Bélisle, S F A Grant, H Hakonarson, Constantin Polychronakos
    Abstract:

    To confirm and fine map previous reports of association, the Type I Diabetes (T1D) Genetics Consortium (T1DGC) assembled a large collection of DNA samples from affected sib-pair (ASP) families with T1D (5003 affected individuals) and genotyped polymorphic markers. One of these loci, involving the IL2RA gene, had been reported to be due to three independent effects. The T1DGC genotyped 69 single-nucleotide polymorphisms (SNPs) that span approximately 88 kb from the 5' flanking to 3' flanking region of the IL2RA locus. The most highly associated SNP reported earlier (ss52580101) was not included in the genotyping list; however, a 5-SNP (rs3134883, rs3118470, rs7072793, rs4749955 and rs12251307) haplotype (H5) was identified that strongly tagged its minor allele with r(2)=0.869 (95% CI, 0.850-0.885). This haplotype was significantly protective (P=3.2 x 10(-5)) in the T1D ASP families, with an odds ratio virtually identical to that reported for ss52580101. The SNP marking the second independent locus, (rs11594656) showed no association in the T1DGC set and the third (rs2104286) could not be distinguished, by conditional regression, from H5. Instead, the most significant independent effect was detected from the 5' flanking IL2RA SNP rs4749955, which remained significant after regression for H5. Thus, we confirm independent effects at the IL2RA locus.

  • Toward Further Mapping of the Association Between the IL2RA Locus and Type 1 Diabetes
    Diabetes, 2007
    Co-Authors: Alexander Montpetit, Thomas J. Hudson, Constantin Polychronakos
    Abstract:

    A novel type 1 diabetes locus was mapped to the interleukin-2 receptor α gene ( IL2RA ) on chromosome 10p15.1, encoding an important modulator of immunity. The aim of the current study was to confirm the association of IL2RA with type 1 diabetes and to attempt further mapping of the genetic effect with a new set of 12 single nucleotide polymorphisms (SNPs). We genotyped 949 nuclear family trios with one type 1 diabetes–affected offspring and two parents (2,847 individuals). Two of the 12 IL2RA SNPs genotyped (rs706778 and rs3118470) had statistically significant type 1 diabetes association ( P = 6.96 × 10 −4 and 8.63 × 10 −4 , respectively). Both SNPs are located in the 5′ end of the long intron 1 within 3 kb of each other and are in high linkage disequilibrium (D′ = 0.997, r 2 = 0.613). The A-C haplotype (frequency = 0.331) was associated with increased type 1 diabetes risk ( P = 3.02 × 10 −4 ). Our study identifies two markers in the IL2RA gene that are significantly associated with type 1 diabetes, supporting IL2RA as a promising candidate gene for type 1 diabetes and suggesting a potential role of IL2Rα in the pathogenesis of type 1 diabetes, likely involving regulatory T-cells.

Silke Redler - One of the best experts on this subject based on the ideXlab platform.

  • investigation of selected cytokine genes suggests that IL2RA and the tnf lta locus are risk factors for severe alopecia areata
    British Journal of Dermatology, 2012
    Co-Authors: Silke Redler, F. Albert, Felix F. Brockschmidt, Christine Herold, Sandra Hanneken, Sibylle Eigelshoven, Kathrin A. Giehl, Rudolf Kruse, Gerhard Lutz, Helmut H. Wolff
    Abstract:

    Summary Background  Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. Objectives  To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. Methods  Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. Results  Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10−6). Conclusions  Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

  • Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata
    The British journal of dermatology, 2012
    Co-Authors: Silke Redler, F. Albert, Felix F. Brockschmidt, Christine Herold, Sandra Hanneken, Sibylle Eigelshoven, Kathrin A. Giehl, Rudolf Kruse, Gerhard Lutz, Helmut H. Wolff
    Abstract:

    Summary Background  Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. Objectives  To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. Methods  Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. Results  Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10−6). Conclusions  Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

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