Generalized vitiligo is the most common pigmentation disorder, white patches of skin and overlying hair resulting from autoimmune loss of melanocytes from the involved areas. Moreover, generalized vitiligo is highly associated with a number of other autoimmune diseases, both in patients and in their close relatives. Generalized vitiligo has a complex and heterogeneous etiology, involving both genetic and environmental causal factors. No causal environmental triggers are yet known. However, several genes have yielded repeated, though not perfectly consistent, association or linkage disequilibrium (LD) from case-control or family-based studies, and genome-wide linkage studies using multiplex families have provided evidence for involvement of several chromosomal regions in risk of generalized vitiligo. Discovery of underlying genetic components of vitiligo is key to understanding disease pathogenesis, with the long-term goal of developing novel treatments that suppress or re-regulate the autoimmune process, enhancing treatments that stimulate skin re-pigmentation by melanocyte re-population. This proposal represents a collaborative international consortium, """"""""VitGene"""""""", which includes most of the world's leading investigators studying the genetics of vitiligo, most of the world's leading vitiligo clinical groups, and the world's largest vitiligo patient support groups. Together, we have accumulated a large collection of DNAs from patients with generalized vitiligo, and many extended families with multiple cases of generalized vitiligo. We propose to search for causal genes by carrying out a genome-wide association study (GWAS) of generalized vitiligo, using a multi-stage study design that utilizes available patient material to maximize statistical power and efficiency while minimizing cost. An initial genome-wide discovery stage will be carried out in 1,500 Caucasian patients and 1,500 Caucasian controls. Two subsequent sequential followup stages will follow-up selected candidate association signals, first by testing in a second cohort of 2,750 Caucasian cases and 2,750 Caucasian controls, and then by family-based association analysis of at least 200 Caucasian multiplex families and at least 150 trios. Finally, in an extension stage, association signals confirmed in Caucasians will then be tested in case-control cohorts derived from a number of different non- Caucasian ethnic groups, including USA Hispanic/Latino, Columbian Hispanic, African-American/Afro- Caribbean, east-central Pakistani, South Korean, and Japanese. This will thus extend analyses to a number of other ethic populations from around the world that are relevant to minority populations in the USA.

Public Health Relevance

Generalized vitiligo is the most common pigmentation disorder, autoimmune death of melanocytes resulting in white patches of skin and hair, and patients are at high risk of other autoimmune diseases such as thyroid disease, adult type 1 diabetes, rheumatoid arthritis, lupus, and others. Generalized vitiligo involves both genes and environmental triggers. Here, an international consortium, VitGene, proposes a multi-stage genome-wide association study (GWAS) aimed at discovering genes that control susceptibility to generalized vitiligo, with the long-term goal of understanding disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056292-04
Application #
8104003
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Cibotti, Ricardo
Project Start
2008-09-11
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$571,906
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Spritz, Richard A; Andersen, Genevieve H L (2017) Genetics of Vitiligo. Dermatol Clin 35:245-255
Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying et al. (2016) MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo. Proc Natl Acad Sci U S A 113:1363-8
Jin, Ying; Andersen, Genevieve; Yorgov, Daniel et al. (2016) Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 48:1418-1424
Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel et al. (2016) Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo. Proc Natl Acad Sci U S A 113:1357-62
Jin, Ying; Hayashi, Masahiro; Fain, Pamela R et al. (2015) Major association of vitiligo with HLA-A*02:01 in Japanese. Pigment Cell Melanoma Res 28:360-2
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; Birlea, Stanca A; Fain, Pamela R et al. (2012) Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet 44:676-80

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