Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo

Abstract

Background: Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases.

Methods: To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families.

Results: We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.

Conclusions: We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.

Figure 1. Genomewide Association Results

The genomewide distribution of –log₁₀ P values from the unadjusted Cochran–Armitage trend test is shown across the chromosomes. Values are shown for 520,460 polymorphic SNPs that were of sufficient quality, after quality-control filtering, in 1392 unrelated CEU patients with generalized vitiligo and 2629 unrelated CEU controls, after genetic matching and correction for the inflation factor of 1.048. The dotted line indicates the genomewide significance threshold (P<5×10^–8). The inset shows quantile–quantile plots of the observed versus expected –log₁₀ P values from the unadjusted Cochran–Armitage trend test. The plot in red shows P values for all 520,460 SNPs, whereas the plot in blue shows P values for all 520,460 SNPs excluding the 3417 SNPs located across the extended major histocompatibility complex (MHC) (on chromosome 6, spanning 26.0 to 33.5 Mb). C1QTNF6 denotes the C1q and tumor necrosis factor–related protein 6 gene, HLA-A the MHC class I, HLA-A gene, HLA-DRB1 the MHC class II, DR beta 1 gene, IL2RA the interleukin-2–receptor alpha gene, LPP the LIM domain–containing preferred translocation partner in lipoma gene, PTPN22 the lymphoid-specific protein tyrosine phosphatase, nonreceptor type 22 gene, RERE the arginine–glutamic acid dipeptide (RE) repeats gene, TYR the tyrosinase gene, and UBASH3A the ubiquitin-associated and SH3 domain–containing A gene.

Figure 2. Detailed Results from the Genomewide Association Study and the Linkage-Disequilibrium Plot across the Major Histocompatibility Complex (MHC) on Chromosome 6p21.3.

Panel A shows the distribution of –log₁₀ P values from the unadjusted Cochran–Armitage trend test in the genomewide association analysis, corrected by the genomic inflation factor of 1.048, for the 3417 SNPs located across the extended MHC region (on chromosome 6, spanning 26.0 to 33.5 Mb). Panel B shows the plot of linkage disequilibrium (r²) for the 22 NPs in the MHC region that were highly associated with generalized vitiligo and that were included in the logistic-regression analysis. The plot gives the physical positions of the markers (according to build 36.1 from the National Center for Biotechnology Information). Darker boxes indicate stronger linkage disequilibrium (range of possible r² values, 0.0 to 1.0). BTNL2 denotes the butyrophilin-like protein 2 gene, HCG9 the HLA complex group 9 gene, HLA-A the MHC class I, HLA-A gene, HLA-DQA1 the MHC class II, DQ alpha 1 gene, and HLA-DRB1 the MHC class II, DR beta 1 gene.