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MHC class II, tumour necrosis factor α, and lymphotoxin α gene haplotype associations with serological subsets of systemic lupus erythematosus
  1. N J McHugh1,2,
  2. P Owen2,
  3. B Cox2,
  4. J Dunphy2,
  5. K Welsh3
  1. 1Royal National Hospital for Rheumatic Diseases, Bath, Somerset, UK
  2. 2Bath Institute for Rheumatic Diseases
  3. 3National Heart and Lung Institute, London SW3, UK
  1. Correspondence to:
    Dr Neil McHugh
    Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, Somerset BA1 1RL UK; neil.mchugh{at}rnhrd-tr.swest.nhs.uk

Abstract

Objective: To conduct a case–control study to investigate whether there are independent tumour necrosis factor α (TNFα) or lymphotoxin α (LTα) haplotype associations with SLE or with any of the major serological subsets of SLE.

Methods: 157 patients with SLE were genotyped for HLA-DRB1, HLA-DQB1, TNFα, and LTα alleles by polymerase chain reaction and compared with 245 normal white controls. For TNFα, six single nucleotide polymorphisms (SNPs) at positions −1031, −863, −857, −308, −238, and +488 and for LTα three SNPs at positions +720, +365, and +249 were studied to assign six TNFα haplotypes (TNF1-6) and four LTα haplotypes (LTA1-4). All SLE patients had full serological profiles on serial samples.

Results: The most significant association with SLE overall was with HLA-DR3 (p<0.001; odds ratio (OR) = 2.5 (95% confidence interval, 1.6 to 3.8)) and the extended haplotype HLA-DQB1*0201;DRB1*0301;TNF2;LTA2 (p<0.001; OR = 2.3 (1.4 to 3.7)). Associations were strongest in the anti-La positive group (13%) of SLE patients (HLA-DR3, OR = 71 (9 to 539); HLA-DQB1*0201, OR = 35 (5 to 267); TNF2, OR = 10 (2.8 to 36), and LTA2, OR = 4.9 (1.1 to 21)). There was an increase in the HLA-DR2 associated extended haplotype (HLA-DQB1*0602;DRB1*1501;TNF1;LTA1) in patients with anti-Ro in the absence of anti-La (p<0.005; OR = 3.9 (1.5 to 10)). The HLA-DR7 extended haplotype (HLA-DQB1*0303; DRB1*0701/2; TNF5;LTA3) was decreased in SLE overall (p<0.02; OR = 0.2 (0.05 to 0.8)).

Conclusions: The strongest association in this predominantly white population with SLE was between HLA-DR3 and anti-La, which seemed to account for any associations with TNFα alleles on an extended DR3 haplotype.

  • aCL, anticardiolipin antibodies
  • ANA, antinuclear antibodies
  • LTα, lymphotoxin α
  • MHC, major histocompatibility complex
  • SLE, systemic lupus erythematosus
  • SSP, sequence specific primer
  • TNFα, tumour necrosis factor α
  • lupus erythematosus
  • MHC class II
  • tumour necrosis factor
  • lymphotoxin
  • autoantibody

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Footnotes

  • Published Online First 17 August 2005

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