This is a resubmitted renewal proposal to continue genetic studies of generalized vitiligo (GV), a common autoimmune disease in which white patches of skin and hair result from destruction of melanocytes. Striking skin depigmentation in GV particularly impacts persons of color, with frequent social isolation and psychiatric co- morbidity. In addition, GV patients have ~30% risk of developing other autoimmune diseases, resulting in direct medical co-morbidity. Our genetic studies of GV began 15 years ago with basic studies of genetic and clinical epidemiology, followed by candidate gene association studies and genomewide linkage studies. During the past grant period we organized the International VitGene Consortium to perform two highly successful GWAS in European-derived whites (EUR), as well as studies of other populations, identifying ~32 GV susceptibility genes and defining novel pathobiological pathways. Beyond the GWAS, we have gone on to NextGen re-sequencing of most of the genes detected by the first GWAS, identifying common (and some uncommon/rare) causal variants in HLA-A, TYR, NLRP1, and GZMB. Potential causal variants identified in to date, as well as those identified in this proposal, are carried forward to functioal analysis in our parallel project, "Functional Analysis of Vitiligo Genes" (AR045584). Our findings provide the basis of the first theoretical biological framework for vitiligo autoimmune pathogenesis, and have translated directly to improved patient classification and improved treatment. Nevertheless, known GV loci account for only ~18% of GV heritability (h2), and most causal gene variants remain unknown. Statistical genetic analysis of our combined GV GWAS datasets shows that considerable "hidden" h2 for GV resides in the remaining data, which can be mined at relatively low cost. Our goals are thus to augment the GV "parts list" of genes and pathways, identify causal variants, relate GV genetic and allelic architecture to clinical sub-phenotypes and disease biomarkers, and understand causal functional biology. A strong rationale to discover additional GV loci is that we do not yet know enough biology to control melanocyte-directed autoimmunity. If this could be achieved, GV would be one of the best AI disease candidates for regenerative medicine, since the skin melanocyte (or melanocyte stem cell) reservoir remains intact. Here, we thus propose to: 1) carry out a small third EUR GWAS to mine additional GV loci, powered to OR ~1.2 (probably the practical limit of GWAS);2) fine-map GV loci to identify specific genes and define common and some uncommon causal variants;followed by two innovative Aims, to 3) identify potential uncommon/rare causal variants by analyses of multiplex GV families;and 4) relate the genetic architecture of GV to specific clinical and biomarker sub-phenotypes and test whether the same GV loci/variants also cause a related phenotype, segmental vitiligo (SV). It is our goal that the resultant biological knowledge will provide the basis for new approaches to treatment and even prevention of GV and associated autoimmune diseases.

Public Health Relevance

Vitiligo is the most common pigmentary disorder, with autoimmune destruction of skin melanocytes resulting in patches of white skin and hair, particularly impacting persons of color. In addition to its pigmentary phenotype, vitiligo is highl associated with other autoimmune diseases, pointing to shared genetic risk factors and perhaps environmental triggers. We aim to extend our fragmentary understanding of vitiligo pathobiology by expanding the GV parts list of genes and pathways, identifying causal variants, and relating GV genetic and allelic architecture to clinical sub-phenotypes and disease biomarkers, so as to understand causal functional biology. If we can learn enough GV functional biology to control melanocyte-directed autoimmunity, GV would be one of the best AI disease candidates for regenerative medicine approaches to treatment, since the skin melanocyte (or melanocyte stem cell) reservoir remains intact. Our long-term goal is thus to discover key biological information that ultimately culminates in the development of new treatments that re-regulate melanocyte-directed autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR056292-05A1
Application #
8578283
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Cibotti, Ricardo
Project Start
2008-09-11
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$446,579
Indirect Cost
$157,531
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Levandowski, Cecilia B; Mailloux, Christina M; Ferrara, Tracey M et al. (2013) NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1ýý processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A 110:2952-6
Spritz, Richard A (2013) Modern vitiligo genetics sheds new light on an ancient disease. J Dermatol 40:310-8
Ferrara, Tracey M; Jin, Ying; Gowan, Katherine et al. (2013) Risk of generalized vitiligo is associated with the common 55R-94A-247H variant haplotype of GZMB (encoding granzyme B). J Invest Dermatol 133:1677-9
Birlea, Stanca A; Ahmad, Fridoon J; Uddin, Raza M et al. (2013) Association of generalized vitiligo with MHC class II loci in patients from the Indian subcontinent. J Invest Dermatol 133:1369-72
Jin, Ying; Ferrara, Tracey; Gowan, Katherine et al. (2012) Next-generation DNA re-sequencing identifies common variants of TYR and HLA-A that modulate the risk of generalized vitiligo via antigen presentation. J Invest Dermatol 132:1730-3
Spritz, Richard A (2012) Six decades of vitiligo genetics: genome-wide studies provide insights into autoimmune pathogenesis. J Invest Dermatol 132:268-73
Jin, Ying; Birlea, Stanca A; Fain, Pamela R et al. (2011) Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset. J Invest Dermatol 131:1308-12
Spritz, Richard A (2011) Recent progress in the genetics of generalized vitiligo. J Genet Genomics 38:271-8
Birlea, Stanca A; Jin, Ying; Bennett, Dorothy C et al. (2011) Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol 131:371-81
Spritz, Richard A (2010) Shared genetic relationships underlying generalized vitiligo and autoimmune thyroid disease. Thyroid 20:745-54

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