Identification of new SLE-associated genes with a two-step Bayesian study design

Armstrong, D. L.; Reiff, A.; Myones, B. L.; Quismorio, F. P., Jr.; Klein-Gitelman, M.; McCurdy, D.; Wagner-Weiner, L.; Silverman, E.; Ojwang, J. O.; Kaufman, K. M.; Kelly, J. A.; Merrill, J. T.; Harley, J. B.; Bae, S. C.; Vyse, T. J.; Gilkeson, G. S.; Gaffney, P. M.; Moser, K. L.; Putterman, C.; Edberg, J. C.; Brown, E. E.; Ziegler, J.; Langefeld, C. D.; Zidovetzki, R.; Jacob, C. O.

Genes Immun. 2009 May 15; 10(5):446-56

Abstract

In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

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