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Six microsatellite markers on the short arm of chromosome 6 in relation to HLA-DR3 and TNF−308A in systemic lupus erythematosus

Genes & Immunity volume 2, pages 373–380 (2001)Cite this article

Abstract

Differences in allelic distribution at loci surrounding the human HLA-DRB1 and tumor necrosis factor (TNF) genes have been observed in association with systemic lupus erythematosus (SLE). We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF−308A with SLE could be attributed to polymorphic markers in the chromosomal region encompassed by HLA-DRB1 and HLA-C. Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, microsatellites D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2 and the single nucleotide polymorphism at position −308 in the promoter of TNF. The independent contribution of alleles to disease susceptibility was estimated by cross-tabulation and multivariate logistic regression. Possession 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 possession of HLA-DR3 (pooled odds ratio, 2.53 [1.37–4.70]). Stratification revealed a possible association of possession of C1_2_5*192 with protection from SLE beyond the effects of HLA-DR3 and TNF−308A. A gene dosage effect was observed for −308A only (homozygotes, 7.75 [3.01–20.0], heterozygotes, 3.15 [1.85–5.37]). In multivariate analysis, possession of HLA-DR3, TNF−308A, and C1_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). The association of possession of TNF−308A with susceptibility to SLE cannot be attributed to linkage to HLA-DR3 alone, nor to other polymorphic markers in the vicinity of the TNF gene. Further loci that are independently associated with SLE might be in the vicinity of marker C1_2_5.

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Acknowledgements

G Jones, W Verduyn (Immunohaematology and Blood Transfusion) and BA de Jong (Clinical Epidemiology) are gratefully acknowledged for their contribution. The authors are indebted to Dr BPC Koeleman (Immunohaematology and Blood Transfusion) and Dr FW Dekker (Clinical Epidemiology) for critical discussions.

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  1. MW van der Linden: MW van der Linden is supported by a grant of the Dutch Organization for Scientific Research (N.W.O.), grant no. 904–61–110.

Authors and Affiliations

  1. Department of Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden, 2300, RC, The Netherlands

    MW van der Linden

  2. Department of Rheumatology, Leiden University Medical Center, PO Box 9600, Leiden, 2300, RC, The Netherlands

    MW van der Linden, E Pieterman & TWJ Huizinga

  3. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, PO Box 9600, Leiden, 2300, RC, The Netherlands

    AR van der Slik, E Zanelli, MJ Giphart & GM T h Schreuder

  4. Department of General Internal Medicine, Leiden University Medical Center, PO Box 9600, Leiden, 2300, RC, The Netherlands

    RGJ Westendorp

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Correspondence to TWJ Huizinga.

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van der Linden, M., van der Slik, A., Zanelli, E. et al. Six microsatellite markers on the short arm of chromosome 6 in relation to HLA-DR3 and TNF−308A in systemic lupus erythematosus . Genes Immun 2, 373–380 (2001). https://doi.org/10.1038/sj.gene.6363794

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