Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM)

H Chinoy; H Platt; JE Lamb; Z Betteridge; H Gunawardena; N Fertig; J Davidson; CV Oddis; NJ McHugh; LR Wedderburn; WER Ollier; RG Cooper

Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM)

H Chinoy, H Platt, JE Lamb, Z Betteridge, H Gunawardena, N Fertig, J Davidson, CV Oddis, NJ McHugh, LR Wedderburn, WER Ollier, RG Cooper

Division of Population Health, Health Services Research & Primary Care (L5)

Research output: Contribution to conference › Poster

Abstract

Purpose: In IIM, an increasingly recognised problem is treatment resistant muscle wasting. TNF-α is thought to induce muscle catabolic effects, in part, via nuclear factor kappa B (NF-κB) activation. Several identified genes share homology with the NF-κB family. We investigated the role of NF-κB genes in a large cohort of UK Caucasian IIM patients. Methods: 408 IIM cases (300 adult, 49±14.0 years, 72% female; 108 juvenile, 6±3.6 years 73% female), recruited from the UK Adult Onset Myositis Immunogenetic Collaboration and the Juvenile Dermatomyositis (JDM) National Registry and Repository, were compared to 310 Caucasian controls. Myositis was confirmed as probable/definite (Bohan & Peter, 1975). DNA was genotyped for 56 SNPs in the NF-κB1, NF-κB1A, NF-κB1B, NF-κB1E, IκBL (NF-κBIL1), REL, RELB and BCL3 genes using Sequenom iPlex™. HLA and TNF genotyping were performed as described (Chinoy et al 2006, 2007). Serotyping used radio-immunoprecipitation. Data were stratified by IIM disease subtype (polymyositis [PM], dermatomyositis [DM], myositis/connective tissue disease [CTD]-overlap, JDM) and serotype (anti-synthetase, Mi-2, SRP, U1-RNP, Ku, PM-Scl, 155/140). Results: Significant allele associations were observed in the overall IIM group vs. controls for the IKBL-62T allele (rs2071592), which strengthened after stratification by anti-Jo-1 or -PM-Scl (see table). Genotype analysis revealed an increase of the AT genotype in cases, with a significant association noted under a dominant model (overall IIM group, odds ratio [OR] 2.0, 95% confidence interval [CI] 1.4-2.8, p=1x10-5). No other SNP was significantly associated in the overall IIM group. Strong pairwise linkage disequilibrium (LD) existed between IKBL-62T, TNF-308A and HLA-B*08 (D′=1). Using multivariate logistic regression, the IKBL-62T IIM association was lost after adjusting for either TNF-308A or HLA-B*08. Conclusions: The IKBL-62T allele is associated with IIM, the risk strengthened in anti-Jo-1 and -PM-Scl patients. However, the association is dependent on TNF-308A and HLA-B*08, due to strong shared LD. Thus, after adjustment of the 8.1 haplotype, NF-κB genes do not appear to confer susceptibility in IIM.

Original language	English
Pages	S226-S227
Publication status	Published - Sept 2008
Event	72nd Annual Scientific Meeting of the American-College-of-Rheumatology - San Francisco, CA Duration: 24 Oct 2008 → 29 Oct 2008

Conference

Conference	72nd Annual Scientific Meeting of the American-College-of-Rheumatology
City	San Francisco, CA
Period	24/10/08 → 29/10/08

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Chinoy, H., Platt, H., Lamb, JE., Betteridge, Z., Gunawardena, H., Fertig, N., Davidson, J., Oddis, CV., McHugh, NJ., Wedderburn, LR., Ollier, WER., & Cooper, RG. (2008). Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM). S226-S227. Poster session presented at 72nd Annual Scientific Meeting of the American-College-of-Rheumatology, San Francisco, CA.

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title = "Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM)",

abstract = "Purpose: In IIM, an increasingly recognised problem is treatment resistant muscle wasting. TNF-α is thought to induce muscle catabolic effects, in part, via nuclear factor kappa B (NF-κB) activation. Several identified genes share homology with the NF-κB family. We investigated the role of NF-κB genes in a large cohort of UK Caucasian IIM patients. Methods: 408 IIM cases (300 adult, 49±14.0 years, 72% female; 108 juvenile, 6±3.6 years 73% female), recruited from the UK Adult Onset Myositis Immunogenetic Collaboration and the Juvenile Dermatomyositis (JDM) National Registry and Repository, were compared to 310 Caucasian controls. Myositis was confirmed as probable/definite (Bohan & Peter, 1975). DNA was genotyped for 56 SNPs in the NF-κB1, NF-κB1A, NF-κB1B, NF-κB1E, IκBL (NF-κBIL1), REL, RELB and BCL3 genes using Sequenom iPlex{\texttrademark}. HLA and TNF genotyping were performed as described (Chinoy et al 2006, 2007). Serotyping used radio-immunoprecipitation. Data were stratified by IIM disease subtype (polymyositis [PM], dermatomyositis [DM], myositis/connective tissue disease [CTD]-overlap, JDM) and serotype (anti-synthetase, Mi-2, SRP, U1-RNP, Ku, PM-Scl, 155/140). Results: Significant allele associations were observed in the overall IIM group vs. controls for the IKBL-62T allele (rs2071592), which strengthened after stratification by anti-Jo-1 or -PM-Scl (see table). Genotype analysis revealed an increase of the AT genotype in cases, with a significant association noted under a dominant model (overall IIM group, odds ratio [OR] 2.0, 95% confidence interval [CI] 1.4-2.8, p=1x10-5). No other SNP was significantly associated in the overall IIM group. Strong pairwise linkage disequilibrium (LD) existed between IKBL-62T, TNF-308A and HLA-B*08 (D′=1). Using multivariate logistic regression, the IKBL-62T IIM association was lost after adjusting for either TNF-308A or HLA-B*08. Conclusions: The IKBL-62T allele is associated with IIM, the risk strengthened in anti-Jo-1 and -PM-Scl patients. However, the association is dependent on TNF-308A and HLA-B*08, due to strong shared LD. Thus, after adjustment of the 8.1 haplotype, NF-κB genes do not appear to confer susceptibility in IIM.",

author = "H Chinoy and H Platt and JE Lamb and Z Betteridge and H Gunawardena and N Fertig and J Davidson and CV Oddis and NJ McHugh and LR Wedderburn and WER Ollier and RG Cooper",

note = "IDS Number: 348XU ISSN: 0004-3591; 72nd Annual Scientific Meeting of the American-College-of-Rheumatology ; Conference date: 24-10-2008 Through 29-10-2008",

year = "2008",

month = sep,

language = "English",

pages = "S226--S227",

}

Chinoy, H, Platt, H, Lamb, JE, Betteridge, Z, Gunawardena, H, Fertig, N, Davidson, J, Oddis, CV, McHugh, NJ, Wedderburn, LR, Ollier, WER & Cooper, RG 2008, 'Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM)', 72nd Annual Scientific Meeting of the American-College-of-Rheumatology, San Francisco, CA, 24/10/08 - 29/10/08 pp. S226-S227.

TY - CONF

T1 - Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM)

AU - Chinoy, H

AU - Platt, H

AU - Lamb, JE

AU - Betteridge, Z

AU - Gunawardena, H

AU - Fertig, N

AU - Davidson, J

AU - Oddis, CV

AU - McHugh, NJ

AU - Wedderburn, LR

AU - Ollier, WER

AU - Cooper, RG

N1 - IDS Number: 348XU ISSN: 0004-3591

PY - 2008/9

Y1 - 2008/9

N2 - Purpose: In IIM, an increasingly recognised problem is treatment resistant muscle wasting. TNF-α is thought to induce muscle catabolic effects, in part, via nuclear factor kappa B (NF-κB) activation. Several identified genes share homology with the NF-κB family. We investigated the role of NF-κB genes in a large cohort of UK Caucasian IIM patients. Methods: 408 IIM cases (300 adult, 49±14.0 years, 72% female; 108 juvenile, 6±3.6 years 73% female), recruited from the UK Adult Onset Myositis Immunogenetic Collaboration and the Juvenile Dermatomyositis (JDM) National Registry and Repository, were compared to 310 Caucasian controls. Myositis was confirmed as probable/definite (Bohan & Peter, 1975). DNA was genotyped for 56 SNPs in the NF-κB1, NF-κB1A, NF-κB1B, NF-κB1E, IκBL (NF-κBIL1), REL, RELB and BCL3 genes using Sequenom iPlex™. HLA and TNF genotyping were performed as described (Chinoy et al 2006, 2007). Serotyping used radio-immunoprecipitation. Data were stratified by IIM disease subtype (polymyositis [PM], dermatomyositis [DM], myositis/connective tissue disease [CTD]-overlap, JDM) and serotype (anti-synthetase, Mi-2, SRP, U1-RNP, Ku, PM-Scl, 155/140). Results: Significant allele associations were observed in the overall IIM group vs. controls for the IKBL-62T allele (rs2071592), which strengthened after stratification by anti-Jo-1 or -PM-Scl (see table). Genotype analysis revealed an increase of the AT genotype in cases, with a significant association noted under a dominant model (overall IIM group, odds ratio [OR] 2.0, 95% confidence interval [CI] 1.4-2.8, p=1x10-5). No other SNP was significantly associated in the overall IIM group. Strong pairwise linkage disequilibrium (LD) existed between IKBL-62T, TNF-308A and HLA-B*08 (D′=1). Using multivariate logistic regression, the IKBL-62T IIM association was lost after adjusting for either TNF-308A or HLA-B*08. Conclusions: The IKBL-62T allele is associated with IIM, the risk strengthened in anti-Jo-1 and -PM-Scl patients. However, the association is dependent on TNF-308A and HLA-B*08, due to strong shared LD. Thus, after adjustment of the 8.1 haplotype, NF-κB genes do not appear to confer susceptibility in IIM.

AB - Purpose: In IIM, an increasingly recognised problem is treatment resistant muscle wasting. TNF-α is thought to induce muscle catabolic effects, in part, via nuclear factor kappa B (NF-κB) activation. Several identified genes share homology with the NF-κB family. We investigated the role of NF-κB genes in a large cohort of UK Caucasian IIM patients. Methods: 408 IIM cases (300 adult, 49±14.0 years, 72% female; 108 juvenile, 6±3.6 years 73% female), recruited from the UK Adult Onset Myositis Immunogenetic Collaboration and the Juvenile Dermatomyositis (JDM) National Registry and Repository, were compared to 310 Caucasian controls. Myositis was confirmed as probable/definite (Bohan & Peter, 1975). DNA was genotyped for 56 SNPs in the NF-κB1, NF-κB1A, NF-κB1B, NF-κB1E, IκBL (NF-κBIL1), REL, RELB and BCL3 genes using Sequenom iPlex™. HLA and TNF genotyping were performed as described (Chinoy et al 2006, 2007). Serotyping used radio-immunoprecipitation. Data were stratified by IIM disease subtype (polymyositis [PM], dermatomyositis [DM], myositis/connective tissue disease [CTD]-overlap, JDM) and serotype (anti-synthetase, Mi-2, SRP, U1-RNP, Ku, PM-Scl, 155/140). Results: Significant allele associations were observed in the overall IIM group vs. controls for the IKBL-62T allele (rs2071592), which strengthened after stratification by anti-Jo-1 or -PM-Scl (see table). Genotype analysis revealed an increase of the AT genotype in cases, with a significant association noted under a dominant model (overall IIM group, odds ratio [OR] 2.0, 95% confidence interval [CI] 1.4-2.8, p=1x10-5). No other SNP was significantly associated in the overall IIM group. Strong pairwise linkage disequilibrium (LD) existed between IKBL-62T, TNF-308A and HLA-B*08 (D′=1). Using multivariate logistic regression, the IKBL-62T IIM association was lost after adjusting for either TNF-308A or HLA-B*08. Conclusions: The IKBL-62T allele is associated with IIM, the risk strengthened in anti-Jo-1 and -PM-Scl patients. However, the association is dependent on TNF-308A and HLA-B*08, due to strong shared LD. Thus, after adjustment of the 8.1 haplotype, NF-κB genes do not appear to confer susceptibility in IIM.

M3 - Poster

SP - S226-S227

T2 - 72nd Annual Scientific Meeting of the American-College-of-Rheumatology

Y2 - 24 October 2008 through 29 October 2008

ER -

Genetic association study of NF-KB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopath (IIM)

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