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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. 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. 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.
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], repsectively).
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.