Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations

Ann Rheum Dis. 2016 May;75(5):891-8. doi: 10.1136/annrheumdis-2014-206367. Epub 2015 Apr 10.


Objectives: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility.

Methods: The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction.

Results: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets.

Conclusions: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.

Keywords: Autoimmune Diseases; Gene Polymorphism; Systemic Lupus Erythematosus.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Proteins / genetics*
  • Adult
  • Asian Continental Ancestry Group / genetics*
  • B7-1 Antigen / genetics*
  • Case-Control Studies
  • Epistasis, Genetic / genetics*
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Lupus Erythematosus, Systemic / genetics*
  • Male
  • Oncogene Proteins, Fusion / genetics
  • Polymorphism, Single Nucleotide
  • Tetraspanins
  • fas Receptor / genetics


  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • B7-1 Antigen
  • LHFPL6 protein, human
  • Oncogene Proteins, Fusion
  • Tetraspanins
  • fas Receptor