Evidence for Gene-gene Epistatic Interactions Among Susceptibility Loci for Systemic Lupus Erythematosus

Overview

Journal Arthritis Rheum

Specialty Rheumatology

Date 2011 Sep 29

PMID 21952918

Citations 24

Authors

Travis Hughes

Adam Adler

Jennifer A Kelly

Kenneth M Kaufman

Adrienne H Williams

Carl D Langefeld

Elizabeth E Brown

Graciela S Alarcon

Robert P Kimberly

Jeffrey C Edberg

Rosalind Ramsey-Goldman

Michelle Petri

Susan A Boackle

Anne M Stevens

John D Reveille

Elena Sanchez

Javier Martin

Timothy B Niewold

Luis M Vila

R Hal Scofield

Gary 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 Alarcon-Riquelme

John B Harley

Bruce C Richardson

Amr H Sawalha

Affiliations

Soon will be listed here.

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).

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.

Citing Articles

Genetic interrogation for sequence and copy number variants in systemic lupus erythematosus.

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Calcium-sensing receptor gene (CASR) polymorphisms and CASR transcript level concerning dyslipidemia in hemodialysis patients: a cross-sectional study.

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