Genetic variations associated with susceptibility to systemic lupus erythematosus and response to cyclophosphamide

Abstract

Complex traits are determined by multiple genetic and environmental factors. Here, I indentify genetic variants associated with a complex disease, systemic lupus erythematosus (SLE), and with response to an immunosuppressant drug, cyclophosphamide, by genome-wide and candidate association study using large-scale control-case cohorts. PART I: SLE is a chronic autoimmune disease with etiology that includes high genetic contribution relative to environmental factors. Using candidate gene association study, I identify the genetic and possible functional association of polymorphisms in the ICAM1-ICAM4-ICAM5 (intercellular adhesion molecule 1, 4, and 5) locus, IFNG (interferon-gamma), and CDKN1A (Cyclin-dependent kinase inhibitor 1A; p21; Cip1) with susceptibility to SLE. Several common variants in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 are associated with increased susceptibility to SLE in a large-scale case-control study using 17,481 unrelated participants from 4 ancestry populations. Specifically, the minor A allele in rs3093030, previously associated with increased plasma levels of soluble ICAM1, shows the strongest association with increased SLE susceptibility (P = 4.88 ?? 10??10; OR = 1.16, 95% CI 1.11??1.22) not only in the trans-ancestry meta-analysis but also in all individual ancestry populations. This finding supports the contribution of an ICAM-mediated pathway to SLE susceptibility. For the IFNG locus, SLE susceptibility association was significant with rs2069705 in the promoter (adjusted OR = 2.27, P = 0.0024) and marginal with rs3181032 in the promoter (P = 0.037), rs2430561 on an NF-??B binding site in the first intron (P = 0.022) and rs2069718 in the third intron (P = 0.026) in a recessive genetic model for a discovery population of 742 Korean SLE patients and 1,017 unaffected controls. Furthermore, the replication study on the regulatory SNP rs2430561 reveals that the SNP was marginally associated with SLE in an validation population of 85...