Presentation: Investigating CD45 as an SLE Susceptibility Gene (2007)

838 Investigating CD45 as an SLE Susceptibility Gene

Purpose: CD45, a transmembrane protein tyrosine phosphatase encoded on chromosome 1q31, has been implicated as a susceptibility gene in systemic lupus erythematosus (SLE) by both mouse models and human linkage studies. Therefore, we investigated the role of CD45 as a candidate gene in human SLE and lupus nephritis using a 2-stage study design.
Methods: In the first stage, all exonic regions (including a minimum of 100 flanking 5’ and 3’ intronic bases) were sequenced in 54 Caucasian SLE cases and 48 unrelated healthy Caucasian controls using PCR-based methods. A polymorphism associated with SLE and lupus nephritis in the initial stage was then genotyped in a multiethnic (Caucasian, Asian, Hispanic, and African-American) cohort comprised of 700 SLE cases and 656 unrelated healthy controls using the FP-TDI method in the second stage. Chi-squared analyses stratified by ethnicity were used to assess for associations with SLE and lupus nephritis.
Results: Fifty-six sequence variants of CD45 were identified in the initial stage. Forty-three of these variants were not previously reported in public databases. Most sequence variants (77%) were rare (minor allele frequency <0.05 in healthy controls). Of the 9 exonic single nucleotide polymorphisms (SNPs) observed, 7 were non-synonymous. In this initial stage, one intronic SNP near exon 21 (rs6683595) was associated with SLE (p=0.046) and lupus nephritis (p=0.040). When this SNP was genotyped in the large multi-ethnic cohort of SLE cases and healthy controls (the second stage), the associations between this SNP with SLE and lupus nephritis were not replicated. Although this SNP was more prevalent in Asian SLE subjects with lupus nephritis compared to Asian SLE subjects without nephritis (OR 2.05, 95% CI 0.94-4.63, p=0.051), the association did not reach statistical significance.
Conclusions: This study is the most comprehensive evaluation of CD45 as a candidate gene in SLE to date. We did not find evidence of an association between a genetic variant of CD45 and SLE in a large, multiethnic cohort. An intronic SNP near exon 21 may be associated with nephritis in Asian subjects with SLE, and should be further investigated in a larger cohort of Asian SLE subjects. The linkage signal for SLE at chromosome 1q31 seen in previous reports may be due to another gene in the region or a genetic variant of CD45 not identified in this study.

 S.A. Chung, None.