Haplotype structure of TNFRSF5-TNFSF5 (CD40–CD40L) and association analysis in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is caused by genetic and environmental factors. The tumour necrosis factor (TNF) superfamily of genes play a central role in immune regulation and have been proposed to be involved in the development of SLE. TNFRSF5 (CD40) falls on 20q11 -13, a region linked with SLE in three independent genome-wide studies. TNFSF5 (CD40L) falls on Xq26 and is the ligand for TNFRSF5. Seven single-nucleotide polymorphisms (SNPs) in CD40 and eight SNPs in CD40L were looked at for linkage disequilibrium (LD) and haplotype analysis in EuropeanCaucasians. Limited haplotype diversity was observed across CD40 and CD40L, and 497% of the diversity was captured. We also examined the association of SNPs and haplotypes in CD40 and CD40L with SLE in European-Caucasians. There was no evidence of association for CD40 or CD40L in 408 European-Caucasian families with SLE from UK. Haplotype tagging SNPs (htSNPs) are made known, which will facilitate analysis for susceptibility in other autoimmune diseases and risk for infectious disease.

A novel polymorphism of the human CD40 receptor with enhanced function

“…In this sample, the rs11086998 ancestral haplotype was present at a frequency of 27.5% in the Americas, compared with 2.4% in Central Asia and 1.8% in East Asia. The rs11086998 G allele was not found in European samples, consistent with Chadha et al 14 No lower frequency haplotypes (Figure 1Dviii-xiii) in the other 3 populations were observed in samples from the Americas.Because rs11086998 G is a proline-to-alanine substitution near important signaling motifs, we hypothesized that the G allele might lead to altered function of CD40. To examine functional effects of hCD40-P227A on B-cell activation, cDNA constructs were first stably expressed in mouse B-cell lines CH12.LX and M12.4.1, which are frequently used models for studying CD40-mediated B-cell activation.…”

“…14 The results of this study failed to provide convincing evidence of association with the occurrence of SLE and single nucleotide polymorphisms (SNPs) or SNP CD40 haplotypes. However, the possibility that CD40 contributes to particular disease symptoms or severity was not explored in either this or the GD studies.…”

A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis

“…Other studies have also suggested the CD40–CD40L pair as strong SLE candidate genes because of their ability to induce T-cell mediated humoral responses. However, in a previous family-based genetic study of CD40 in SLE36 no association was found; probably, the SNP data available at the time of the previous study did not allow for detection of the effect from rs4810485. Notably, an association between CD40 polymorphisms and genetic susceptibility to Grave's disease37 and Kawasaki disease,38 but not to T1D, has been reported, an observation that may help to delineate pathogenic mechanisms in the aforementioned autoimmune diseases.…”

Individual and epistatic effects of genetic polymorphisms of B-cell co-stimulatory molecules on susceptibility to pemphigus foliaceus

“…24 To date, other autoimmune diseases were not analyzed for association with the CD40LÀ726T4C SNP. Chadha et al 32 examined the association of SNPs and haplotypes of the CD40 and CD40L genes in SLE and no evidence of association was found in European families. Although the segment analyzed included nucleotide À726, this SNP was not tested.…”