Comprehensive Association Analysis of Candidate Genes for Generalized Vitiligo Supports XBP1, FOXP3, and TSLP

Abstract

We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P = 3.0E-04, odds ratio (OR)= 1.60; meta-P for rs3806933= 3.1E-03), XBP1 (rs6005863, P = 3.6E-04, OR= 1.17; meta-P for rs2269577= 9.5E-09), and FOXP3 (rs11798415, P = 5.8E-04, OR= 1.19). Association of GV with CTLA4 (rs12992492, P = 5.9E-05, OR= 1.20; meta-P for rs231775= 1.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P = 5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions.

The Pathogenesis of Vitiligo

“…11 Birlea and colleagues conducted a large genome-wide association study for 33 candidate loci in vitiligo patients and controls. 12 Of the 33 candidate loci tested, only 3 (FOXP3, TSLP, and XBP1) demonstrated a primary association with GV. 12 Whereas the exact function of the genes TSLP and XBP1 is not fully known, FOXP3 is known to be erroneous in the X-linked recessive multiple autoimmune disease syndrome.…”

“…Genome-wide linkage analysis/genotyping/ heterogeneity testing of vitiligo patients with and without concomitant autoimmune disease Alkhateeb and Qaraz, 2010 9 26 vitiligo patients from Jordan Genotyped and analyzed patients for 8 variants of NALP1 promoter and gene Birlea et al, 2011 12 1,392 unrelated non-Hispanic white vitiligo patients and 2,629 non-Hispanic white healthy controls…”

The Pathogenesis of Vitiligo

“…Further meta-analysis suggested XBP1 is the most significant GV susceptibility locus. Lastly, they determined that the locus CTLA4 maintains a secondary association with GV, having its primary association with the autoimmune diseases epidemiologically related to vitiligo (Birlea et al, 2011). Other studies have gone beyond identifying what genes are involved, to the mechanisms behind how the expression of those genes may be modified in order to create the vitiligo phenotype.…”

“…Another means of investigating the genetic basis of vitiligo predisposition is to carry out a genome-wide association study. Birlea et al (2011) used genotype data from 1,392 unrelated non-Hispanic white vitiligo patients and compared these to 2,629 non-Hispanic white www.intechopen.com…”

-119C/G in MYG1 Gene and 49A/G in CTLA4 Gene Polymorphisms in Turkish Patients with Vitiligo

“…[6][7][8][9][10][11][12][13] To determine whether CTLA4 and MYG1 genes are the genetic risk factor for vitiligo in Turkish study group, we analyzed CTLA4 rs231775 and MYG1 rs1465073 polymorphisms in patients with vitiligo and healthy controls.…”