Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2

Abstract

Generalized vitiligo is a common autoimmune disorder in which patchy loss of skin and hair pigmentation results from loss of pigment-forming melanocytes from the involved regions. Vitiligo occurs with a frequency of about 1% in most populations, and is highly associated with other autoimmune disorders, particularly Hashimoto thyroiditis. Most cases of vitiligo are sporadic, although some cases cluster in families, and the disorder is thought to be oligogenic in origin. We have studied a large family cluster in which vitiligo and Hashimoto thyroiditis occur in numerous individuals. A whole-genome scan of 24 family members, including 14 affected with autoimmune disease, showed significant linkage of an oligogenic autoimmune susceptibility locus, termed AIS1, to a 14.4 cM interval in 1p31.3-p32.2. A two-locus analysis of Hashimoto thyroiditis in family members segregating an AIS1 susceptibility allele showed suggestive linkage to markers in chromosome 6p22.3-q14.1, in a region spanning both the major histocompatibility complex and AITD1, a susceptibility locus for autoimmune thyroid disease. Our results indicate that the 1p AIS1 locus is associated with susceptibility to autoimmunity, particularly vitiligo, in this family, and that a chromosome 6 locus, most likely AITD1, may mediate the occurrence of Hashimoto's thyroiditis in AIS1-susceptible family members.

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

“…[10][11][12] Vitiligo can also develop as 36 Likewise, the autoimmune susceptibility loci AIS1, AIS2 and SLEV1 are associated with generalised vitiligo that occurs with other autoimmune conditions. [13][14][15] In contrast, generalised vitiligo that presents in individuals without other autoimmune disorders is associated with AIS3. [13][14][15] In the present study, the disease-associated PTPN22 1858T allele appears to be associated with generalised vitiligo that develops without the concomitant occurrence of other autoimmune diseases, suggesting that the basis of generalised vitiligo might still be autoimmune in nature.…”

“…[13][14][15] In contrast, generalised vitiligo that presents in individuals without other autoimmune disorders is associated with AIS3. [13][14][15] In the present study, the disease-associated PTPN22 1858T allele appears to be associated with generalised vitiligo that develops without the concomitant occurrence of other autoimmune diseases, suggesting that the basis of generalised vitiligo might still be autoimmune in nature. The finding that the 1858T allele of the PTPN22 R620W polymorphism is associated with generalised vitiligo and other autoimmune conditions supports the hypothesis that there are common genetic variants that contribute to general immune-dysregulation and susceptibility to autoimmunity.…”

“…[7][8][9] Furthermore, several genes that have a role in regulating immunity have been associated with susceptibility to vitiligo including: polymorphic markers in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, the autoimmune susceptibility loci AIS1, AIS2, AIS3 and SLEV1 and certain human leukocyte antigen specificities of the major histocompatibility complex. [10][11][12][13][14][15][16][17] Recently, the missense R620W polymorphism in the PTPN22 gene at nucleotide 1858 (1858C-T) in codon 620 (620Arg-Trp) has been associated with autoimmune diseases including type I diabetes mellitus, Graves' disease, systemic lupus erythematosus and rheumatoid arthritis. [18][19][20][21][22][23][24][25] The gene, located on chromosome 1p13, 19 encodes lymphoid protein tyrosine phosphatase (LYP), which is important in the negative control of T lymphocyte activation.…”

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

“…Using a whole genome scan of a large family cluster with both vitiligo and Hashimoto thyroiditis, a general autoimmune susceptibility locus (AIS1) was mapped to human chromosome 1, and evidence was reported for a Hashimoto disease susceptibility locus within a chromosome 6 region spanning both the MHC and AIDT1, a non-MHC locus associated with susceptibility to both Hashimoto thyroiditis and Graves' disease. 24 A linkage disequilibrium analysis of 56 multigeneration Columbian families with vitiligo using microsatellite markers spanning the entire human MHC region revealed a major genetic factor within the MHC at 6p21.3-21.4, with a dominant mode of inheritance in vitiligo patients with an early age of onset and a recessive mode of inheritance influenced by environmental effects in vitiligo patients with an age of onset after 30 years of age. 10 Comparisons of a variety of inheritance models suggested that the most parsimonious genetic model was that of a major 10 Many other HLA associations have been reported between specific alleles of complement, class I and class II MHC genes with vitiligo in various ethnic and racial subpopulations (reviewed in Friedmann 9 ), but no common HLA association is observed.…”

“…21,22 Vitiligo susceptibility does not follow a simple Mendelian inheritance pattern, and much of the available data support the hypothesis that vitiligo is a complex hereditary disease influenced by a set of recessive alleles occurring at several unlinked autosomal loci that collectively confer the vitiligo phenotype. [22][23][24] Vitiligo may therefore be considered a polygenic disease, with alleles at multiple loci possibly contributing to increased susceptibility to and/or direct pathogenesis of vitiligo. We have recently reported association of the catalase gene and vitiligo susceptibility in support of the self-destruct model of vitiligo pathogenesis.…”