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OP0089 Association between tnf -308a and systemic lupus erythematosus in relation to hla-dr3 and six microsatellite markers on the short arm of chromosome vi
  1. MW Van der Linden1,
  2. A Van der Slik2,
  3. E Pieterman3,
  4. E Zanelli2,
  5. MJ Giphart2,
  6. FC Breedveld3,
  7. RG Westendorp4,
  8. TW Huizinga3
  1. 1Clinical Epidemiology
  2. 2Immunohaematology and Blood Transfusion
  3. 3Rheumatology
  4. 4General Internal Medicine, Leiden University Medical Centre, Leiden, Netherlands

Abstract

Background Allelic imbalance at polymorphic loci within the human HLA-DRB1 and TNF genes has been observed in association with increased susceptibility to systemic lupus erythematosus.

Objectives We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF-308A with SLE could be attributed to linkage to six polymorphic microsatellites between HLA-DRB1 and HLA-C.

Methods Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, D6S1014, D6S273, TNFa, MIB, C-1–2–5 and C-1–3–2 and for TNF promoter polymorphisms. Independent contribution of alleles to disease susceptibility was estimated by crosstabulation and multivariate regression.

Results Carriership of TNF-308A was associated with susceptibility to SLE (odds ratio [95% confidence interval], 3.70 [2.24–6.11]). This remained present after stratification on carriership of HLA-DR3 (pooled odds ratio, 2.53 [1.37–4.70]). Stratification further revealed a possible association of carriership of C-1–2–5*192 with protection from SLE beyond the effects of HLA-DR3 and TNF-308A. Gene dose effect was observed for -308A only (homozygotes, 7.75 [3.01–20.0], heterozygotes, 3.15 [1.85–5.37]). In multivariate analysis, the association between HLA-DR3, TNF-308A, and C-1–2–5*192 remained independently associated with susceptibility to SLE (2.58 [1.29–5.18], 2.76 [1.43–5.31], and 0.26 [0.10–0.66], respectively).

Conclusion An association of carriership of TNF-308A with susceptibility to SLE can not be attributed to linkage to HLA-DR3, nor to other polymorphic markers in the vicinity of the TNF gene. Further loci that are independently associated with SLE might be located in the vicinity of marker C-1–2–5.

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