10 Genetic Loci Linked to Vitiligo

Ten different gene susceptibility loci have been identified as associated with generalized vitiligo, in a study published online April 21 in the New England Journal of Medicine.

Many of the loci are also associated with other autoimmune diseases, several of which have been linked epidemiologically with vitiligo, said Dr. Ying Jin, of the Human Medical Genetics Program at the University of Colorado, Aurora, and associates.

Generalized vitiligo, which results from the autoimmune loss of melanocytes, has been assumed to arise from the effects of multiple susceptibility genes and unknown environmental factors. Dr. Jin and colleagues performed a genome-wide association study to identify the genetic loci, genotyping 1,514 patients in North America and the United Kingdom who were of white European ancestry.

A total of 579,146 single-nucleotide polymorphisms (SNPs) of these subjects were compared with those of 2,813 unaffected control subjects from a National Institutes of Health database. Genotyping of the SNPs that showed genome-wide significance or near significance was then carried out in two replication studies: one comprised 677 patients and 1,106 controls, and the other comprised 183 simplex trios with the disorder and 332 multiplex families.

Generalized vitiligo was significantly associated with SNPs at or near the HLA-A*02 allele and the HLA-DRB1*04 allele, both of which have been reported previously to be associated with other autoimmune diseases.

Generalized vitiligo also was associated with the following genes: RERE (highly expressed in lymphoid cells and thought to regulate apoptosis), PTPN22 (involved in T-cell-receptor signaling), LPP (associated with celiac disease and rheumatoid arthritis), IL2RA (associated with type 1 diabetes, Graves' disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus), GZMB (involved in immune-induced apoptosis), UBASH3A (associated with T-cell signalling and type 1 diabetes), C1QTNF6, and TYR.

"Most of these genes encode immune-system proteins involved in the biologic pathways that probably influence the development of autoimmunity," the investigators said (N. Engl. J. Med. 2010 April 21 [doi:10.1056/NEJMoa0908547]).

The exception - the TYR gene - was "perhaps the most interesting association that we found," they noted.

The TYR gene encodes tyrosinase, which is not a component of the immune system but "is an enzyme of the melanocyte that catalyzes the rate-limiting steps of melanin biosynthesis. It is also a major autoantigen in generalized vitiligo."

The TYR SNPs that were associated with generalized vitiligo also have been associated previously with susceptibility to malignant melanoma, but in a mutually exclusive fashion.

This study was supported by the National Institutes of Health and a grant from the Anna and John Sie Foundation. No relevant conflicts of interest were reported.

Ten different gene susceptibility loci have been identified as associated with generalized vitiligo, in a study published online April 21 in the New England Journal of Medicine.

Many of the loci are also associated with other autoimmune diseases, several of which have been linked epidemiologically with vitiligo, said Dr. Ying Jin, of the Human Medical Genetics Program at the University of Colorado, Aurora, and associates.

Generalized vitiligo, which results from the autoimmune loss of melanocytes, has been assumed to arise from the effects of multiple susceptibility genes and unknown environmental factors. Dr. Jin and colleagues performed a genome-wide association study to identify the genetic loci, genotyping 1,514 patients in North America and the United Kingdom who were of white European ancestry.

A total of 579,146 single-nucleotide polymorphisms (SNPs) of these subjects were compared with those of 2,813 unaffected control subjects from a National Institutes of Health database. Genotyping of the SNPs that showed genome-wide significance or near significance was then carried out in two replication studies: one comprised 677 patients and 1,106 controls, and the other comprised 183 simplex trios with the disorder and 332 multiplex families.

Generalized vitiligo was significantly associated with SNPs at or near the HLA-A*02 allele and the HLA-DRB1*04 allele, both of which have been reported previously to be associated with other autoimmune diseases.

Generalized vitiligo also was associated with the following genes: RERE (highly expressed in lymphoid cells and thought to regulate apoptosis), PTPN22 (involved in T-cell-receptor signaling), LPP (associated with celiac disease and rheumatoid arthritis), IL2RA (associated with type 1 diabetes, Graves' disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus), GZMB (involved in immune-induced apoptosis), UBASH3A (associated with T-cell signalling and type 1 diabetes), C1QTNF6, and TYR.

"Most of these genes encode immune-system proteins involved in the biologic pathways that probably influence the development of autoimmunity," the investigators said (N. Engl. J. Med. 2010 April 21 [doi:10.1056/NEJMoa0908547]).

The exception - the TYR gene - was "perhaps the most interesting association that we found," they noted.

The TYR gene encodes tyrosinase, which is not a component of the immune system but "is an enzyme of the melanocyte that catalyzes the rate-limiting steps of melanin biosynthesis. It is also a major autoantigen in generalized vitiligo."

The TYR SNPs that were associated with generalized vitiligo also have been associated previously with susceptibility to malignant melanoma, but in a mutually exclusive fashion.

This study was supported by the National Institutes of Health and a grant from the Anna and John Sie Foundation. No relevant conflicts of interest were reported.

Ten different gene susceptibility loci have been identified as associated with generalized vitiligo, in a study published online April 21 in the New England Journal of Medicine.

Many of the loci are also associated with other autoimmune diseases, several of which have been linked epidemiologically with vitiligo, said Dr. Ying Jin, of the Human Medical Genetics Program at the University of Colorado, Aurora, and associates.

Generalized vitiligo, which results from the autoimmune loss of melanocytes, has been assumed to arise from the effects of multiple susceptibility genes and unknown environmental factors. Dr. Jin and colleagues performed a genome-wide association study to identify the genetic loci, genotyping 1,514 patients in North America and the United Kingdom who were of white European ancestry.

A total of 579,146 single-nucleotide polymorphisms (SNPs) of these subjects were compared with those of 2,813 unaffected control subjects from a National Institutes of Health database. Genotyping of the SNPs that showed genome-wide significance or near significance was then carried out in two replication studies: one comprised 677 patients and 1,106 controls, and the other comprised 183 simplex trios with the disorder and 332 multiplex families.

Generalized vitiligo was significantly associated with SNPs at or near the HLA-A*02 allele and the HLA-DRB1*04 allele, both of which have been reported previously to be associated with other autoimmune diseases.

Generalized vitiligo also was associated with the following genes: RERE (highly expressed in lymphoid cells and thought to regulate apoptosis), PTPN22 (involved in T-cell-receptor signaling), LPP (associated with celiac disease and rheumatoid arthritis), IL2RA (associated with type 1 diabetes, Graves' disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus), GZMB (involved in immune-induced apoptosis), UBASH3A (associated with T-cell signalling and type 1 diabetes), C1QTNF6, and TYR.

"Most of these genes encode immune-system proteins involved in the biologic pathways that probably influence the development of autoimmunity," the investigators said (N. Engl. J. Med. 2010 April 21 [doi:10.1056/NEJMoa0908547]).

The exception - the TYR gene - was "perhaps the most interesting association that we found," they noted.

The TYR gene encodes tyrosinase, which is not a component of the immune system but "is an enzyme of the melanocyte that catalyzes the rate-limiting steps of melanin biosynthesis. It is also a major autoantigen in generalized vitiligo."

The TYR SNPs that were associated with generalized vitiligo also have been associated previously with susceptibility to malignant melanoma, but in a mutually exclusive fashion.

This study was supported by the National Institutes of Health and a grant from the Anna and John Sie Foundation. No relevant conflicts of interest were reported.