Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus

Travis Hughes, Adam Adler, Jennifer A. Kelly, Kenneth M. Kaufman, Adrienne H. Williams, Carl D. Langefeld, Elizabeth E. Brown, Graciela S. Alarcõn, Robert P. Kimberly, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, Michelle Petri, Susan A. Boackle, Anne M. Stevens, John D. Reveille, Elena Sanchez, Javier Martín, Timothy B. Niewold, Luis M. Vilá, R. Hal ScofieldGary S. Gilkeson, Patrick M. Gaffney, Lindsey A. Criswell, Kathy L. Moser, Joan T. Merrill, Chaim O. Jacob, Betty P. Tsao, Judith A. James, Timothy J. Vyse, Marta E. Alarcõn-Riquelme, John B. Harley, Bruce C. Richardson, Amr H. Sawalha

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene-gene interactions in a number of known lupus susceptibility loci. Methods Eighteen single-nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2-step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 à- 10-5 [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10-45). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively). Conclusion We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.

Original languageEnglish (US)
Pages (from-to)485-492
Number of pages8
JournalArthritis and rheumatism
Issue number2
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)


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