title: Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus.
abstract: 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 × 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Hughes
authors.forename: Adam
authors.initials: A
authors.lastname: Adler
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Williams
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Susan A
authors.initials: SA
authors.lastname: Boackle
authors.forename: Anne M
authors.initials: AM
authors.lastname: Stevens
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Elena
authors.initials: E
authors.lastname: Sanchez
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
authors.forename: Luis M
authors.initials: LM
authors.lastname: Vilá
authors.forename: R Hal
authors.initials: RH
authors.lastname: Scofield
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Richardson
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
mesh_terms: D000328:Adult; D000483:Alleles; D004843:Epistasis, Genetic; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide