EXTENDED REPORT

MHC class II, tumour necrosis factor , and lymphotoxin gene haplotype associations with serological subsets of systemic lupus erythematosus

N J McHugh^1,2, P Owen², B Cox², J Dunphy², K Welsh³

¹ Royal National Hospital for Rheumatic Diseases, Bath, Somerset, UK
² Bath Institute for Rheumatic Diseases
³ National Heart and Lung Institute, London SW3, UK

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

Objective: To conduct a case–control study to investigate whether there are independent tumour necrosis factor (TNF) or lymphotoxin (LT) 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, TNF, and LT alleles by polymerase chain reaction and compared with 245 normal white controls. For TNF, six single nucleotide polymorphisms (SNPs) at positions –1031, –863, –857, –308, –238, and +488 and for LT three SNPs at positions +720, +365, and +249 were studied to assign six TNF haplotypes (TNF1-6) and four LT 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 TNF alleles on an extended DR3 haplotype.

Abbreviations: aCL, anticardiolipin antibodies; ANA, antinuclear antibodies; LT, lymphotoxin ; MHC, major histocompatibility complex; SLE, systemic lupus erythematosus; SSP, sequence specific primer; TNF, tumour necrosis factor

Keywords: lupus erythematosus; MHC class II; tumour necrosis factor; lymphotoxin; autoantibody

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