Human Molecular Genetics, 2002, Vol. 11, No. 6 661-667
© 2002 Oxford University Press
Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3–p32.2
1Human Medical Genetics Program, 2Department of Medicine and 3Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA and 4Department of Anatomy and Developmental Biology, St George’s Hospital Medical School, London, UK
Received November 7, 2001; Revised and Accepted January 14, 2002.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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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.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Autoimmune diseases are a diverse group of acquired disorders that collectively account for a large fraction of all disease morbidity and mortality in virtually all populations (1). At least one autoimmune disease is known for almost every organ in the body. Generalized vitiligo is a common autoimmune skin disorder (2–4), characterized by the appearance of sharply delimited patches of white skin, overlying hair, oral mucosa, and occasionally the eyes, due to non-inflammatory loss of pigment-forming melanocytes from the affected areas. The disorder is progressive, and the white patches usually become larger and coalesce, sometimes eventually involving the entire body surface, with severe sun sensitivity of the involved areas. The stark contrast between patches of white and dark skin, particularly of the face, hands, and genitals, is socially stigmatizing and psychologically traumatic, especially for affected individuals from darkly pigmented ethnic groups. Indeed, the word ‘vitiligo’ is derived from the Latin ‘vitium’, meaning ‘fault’ (3).
Vitiligo occurs with a frequency of 
1% in the United States (3–5), the prevalence increasing with age. Most cases are sporadic, although family clustering of vitiligo cases can occur (6,7), in a complex pattern suggestive of multigenic inheritance (8–15). About 20% of probands have at least one affected first-degree relative (14), and the concordance of vitiligo in monozygotic twin pairs is high (16,17), with heritability estimated at 46–72% (10,11,15). Vitiligo is frequently associated with other autoimmune disorders, particularly Hashimoto thyroiditis, and vitiligo is an occasional component of the APECED (APS1; MIM 240300) and Schmidt (APS2; MIM 269200) autoimmune polyendocrine syndromes (18–20). In addition, immunotherapy of malignant melanoma frequently induces t cell-mediated vitiligo in both humans (21) and mice (22), further supporting an autoimmune origin for vitiligo.
We have studied a large family in which there is a strong, multi-generation tendency towards generalized vitiligo and Hashimoto thyroiditis. Thirteen related individuals are affected with vitiligo and seven with clinical Hashimoto disease, neither inherited in a simple Mendelian manner in this family. This striking family cluster is not consistent with the prevalence of these diseases among Caucasians; clinical Hashimoto thyroiditis occurs in 0.3–0.4% (23,24) and vitiligo in 0.4–1% (3–5,25). The unusually large size of this family cluster afforded us the opportunity to map a gene for autoimmune susceptibility while avoiding the problem of locus heterogeneity incumbent to studies that combine data from numerous small families. By this approach, we obtained strong evidence for an autoimmunity susceptibility locus, AIS1, in chromosome segment 1p31.3–p32.2, which may be involved in about one-sixth to one-fourth of families with multiple closely related individuals with vitiligo. Furthermore, we carried out a two-locus analysis for Hashimoto thyroiditis in this family, by conditioning family members on the basis of inheritance of an autoimmunity susceptibility allele at AIS1, and obtained suggestive evidence for a Hashimoto disease susceptibility locus in this family located in chromosome segment 6p22.3–q14.1. This region contains both the major histocompatibility complex (MHC) and AITD1, a non-MHC locus associated with susceptibility to both Hashimoto thyroiditis and Graves’ disease (26). We suggest that variant alleles of AIS1 result in a general tendency towards autoimmunity, perhaps autosomal dominant, whereas other genes (perhaps AITD1) and/or environmental triggers determine the occurrence of specific autoimmune disorders in AIS1-susceptible individuals, such as vitiligo or Hashimoto thyroiditis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The vitiligo phenotype is linked to markers in 1p
The pedigree of the study family is shown in Figure 1. Thirteen family members were affected with generalized vitiligo over three generations. Seven of these individuals also had clinical Hashimoto thyroiditis, as did two other family members (one not founder-related) who did not manifest vitiligo. The pedigree is suggestive of dominance; however, neither of the founder individuals, I.1 (now 94 years of age) and I.2 (who died of cancer at age 85), had any form of autoimmunity, nor had any of their siblings nor their parents. Thus, neither vitiligo nor Hashimoto disease is inherited as a simple Mendelian trait in this family, although a priori we could not exclude the possibility that either I.1 or I.2 was a germ-line mosaic for a new mutation at an autosomal dominant vitiligo locus associated with age-dependent penetrance.
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To evaluate this hypothesis, we carried out a genome-wide linkage screen with 382 autosomal microsatellite markers spaced at
10 cM intervals, and initially performed parametric genetic linkage analysis, under autosomal dominant and recessive models with age-dependent penetrance, incorporating into the analysis six age-dependent liability classes with lifetime penetrance of 80%. This genome-wide parametric linkage analysis provided suggestive evidence for linkage to several chromosomal regions, the most striking of which was a multipoint LOD score maximizing at 2.69 at 89.46 cM on chromosome 1p (Marshfield Center for Medical Genetics comprehensive human genetic map; http://research.marshfieldclinic.org/genetics/Map_Markers/maps/IndexMapFrames.html) under an autosomal dominant model. This same region was also identified by genome-wide non-parametric linkage (NPL) analysis, which yielded a maximum multipoint NPL score of 21.95 (P = 0.00049), also at position 89.46 cM on chromosome 1p. Inspection of the pedigree showed that the ‘affected’ 1p haplotype had also been inherited by a number of clinically unaffected family members, some of whom were well beyond the typical age of onset for vitiligo, including the apparent ‘founder’, individual I.1. This suggested that the true maximum penetrance of a dominantly acting vitiligo susceptibility locus on 1p might be considerably lower than 0.8. To eliminate the problem posed by our inability to distinguish between truly unaffected family members versus ‘affected’ family members who fail to manifest vitiligo due to their being either pre-symptomatic or non-penetrant, we repeated the genome-wide parametric linkage analyses, now considering only those family members affected with vitiligo, plus founders. This ‘affecteds-only’ parametric linkage analysis detected no positive LOD scores under a recessive model, but under a dominant model the genome-wide maximum multipoint LOD score increased to 3.13 at 89.46 cM on chromosome 1p. Thus both parametric and NPL analyses support localization of a vitiligo susceptibility locus, termed AIS1, to chromosome segment 1p.
To achieve greater resolution of the AIS1 genetic interval, we next genotyped 32 additional markers across chromosome 1, which provided an average marker density of 5 cM across the chromosome. The maximum multipoint LOD score was 2.90 at 90.75 cM on chromosome 1p, and the maximum affecteds-only multipoint LOD score was 3.24 at the same position (Fig. 2). NPL analysis yielded a maximum NPL score of 26.59 (P = 0.00040) (Fig. 2), also 90.75 cM on 1p. Together, these results strongly support the existence of a vitiligo susceptibility locus in chromosome segment 1p31.2–p32.3.
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Locus heterogeneity of vitiligo susceptibility
To evaluate the role played by AIS1 in other families with multiple closely related individuals affected with vitiligo, we genotyped 26 additional multiplex vitiligo families for markers at 10 cM intervals across chromosome 1. Six of these families also showed linkage maxima in the AIS1 region and nowhere else on chromosome 1. Combined affecteds-only parametric linkage analysis of all 27 families yielded a maximum HLOD of 3.63 at 85.0 cM, with
= 0.267. The overall NPL score at that position was 4.16 (P = 0.00085), with a maximum NPL score of 6.01 (P = 0.00046) at 89.5 cM on 1p. Excluding the index study family, the maximum HLOD was 1.24 at 82.77 cM, with = 0.166; the overall NPL score at that position was only 1.25 (P = 0.106). These results indicate that the 1p AIS1 locus may play a significant role in about one-sixth to one-fourth of multiplex vitiligo families.
Refinement of the AIS1 genetic interval
Assembly of marker allele haplotypes from the 5 cM chromosome 1 analysis of the original study family permitted identification of apparent recombinants (Fig. 1) that defined D1S2652 and D1S198 as the respective proximal and distal flanking boundaries of the 18.5 cM AIS1 genetic interval. To further resolve the boundaries of the interval, we genotyped selected family members for nine additional markers near D1S2652 and D1S198. These new markers narrowed the AIS1 genetic interval to an 14.4 cM region of 1p31.3–p32.2, bounded proximally by D1S2742 and distally by D1S515.
Two-locus analysis of Hashimoto thyroiditis
Inspection of the pedigree of the study family (Fig. 1) showed that all founder-related family members with clinical Hashimoto thyroiditis inherited the AIS1 autoimmunity susceptibility haplotype derived from founder I.1; several additional family members exhibited antibody or biochemical evidence of thyroid disease, but were clinically asymptomatic. We therefore considered a two-locus model of clinical Hashimoto disease in this family, in which the AIS1 autoimmunity susceptibility allele on 1p interacts with one or more other loci that govern developing clinical Hashimoto disease in AIS1-susceptible individuals. To localize these genes, we ‘conditioned’ the family by considering only founders and those family members who carried the AIS1 susceptibility haplotype, and performed genome-wide parametric linkage analysis for clinical Hashimoto thyroiditis under autosomal dominant and recessive models using the affecteds-only approach outlined above. As shown in Figure 3, the genome-wide affecteds-only multipoint LOD score maximized at 1.52 at 29.3 cM on chromosome 6 under an autosomal dominant model. Genome-wide affecteds-only NPL analysis yielded a maximum multipoint NPL score of 7.53 (P = 0.0029) at the same position.
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Haplotype analysis (Fig. 4) demonstrated that all founder-related family members with clinical Hashimoto disease shared a haplotype, apparently inherited from founder I.2, comprised of marker alleles at D6S422, D6S276, D6S1610 and D6S257. This haplotype spans chromosome segment 6p22.3–q14.1, a region that includes the entire MHC as well as AITD1, a locus proximal to the MHC that has been linked to both Hashimoto disease and Graves’ disease (26). We carried out HLA typing of three founder-related family members with Hashimoto disease, and all three shared an uncommon DRB1-(DQA1)-DQB1 haplotype, 14-(0103)-0603.
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More than half the family members who inherited both the 1p autoimmune susceptibility haplotype and the apparent chromosome 6 Hashimoto susceptibility haplotype manifest clinical Hashimoto disease. However, several family members (II.6, III.16, III.27) who inherited the 1p susceptibility haplotype but are recombinant within the chromosome 6 susceptibility haplotype do not have Hashimoto disease (Fig. 4). This suggests that the Hashimoto disease susceptibility locus on chromosome 6 may be located in the proximal part of the region, and thus that it is more likely to be AITD1 than the MHC.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We have obtained strong evidence for the existence of AIS1, a locus responsible for susceptibility to autoimmunity, including at least generalized vitiligo and Hashimoto thyroiditis, within chromosome segment 1p31.3–p32.2. Although the occurrence of vitiligo in the study family appears generally vertical, a single-locus autosomal dominant model for vitiligo in this family is less attractive than a multigenic model. At least six family members (I:1, II:6, III:18, III:20, III:22, III:25) carry the AIS1 susceptibility haplotype but are not affected with vitiligo despite being considerably older than the modal age of onset. This suggests that additional factors besides AIS1 are required for occurrence of vitiligo, even in this family. Indeed, parametric LOD scores maximized at a penetrance of 0.52, indicating that a simple Mendelian dominant model of vitiligo in this family is probably not correct. We suggest that vitiligo in this family is most likely oligogenic, AIS1 on 1p conferring general susceptibility to autoimmunity, perhaps in an autosomal dominant manner, and other genes, such as AITD1 on chromosome 6, governing tissue-specific autoimmune responses. Only individuals who inherit both types of susceptibility genes, perhaps acting in concert with exposure to environmental triggers, eventually manifest autoimmune disease. This hypothesis is in line with the current multilocus theory of autoimmune disease in Man (1) and with an oligogenic model for vitiligo previously proposed on the basis of segregation analyses (12,13).
Zamani et al. (27) recently reported both linkage and association between vitiligo and the HLA class II DRB4*0101 and DQB1*0303 alleles in Dutch patients. However, we found no evidence of linkage of vitiligo to markers spanning the MHC in the current study family, and HLA typing in this family was not consistent with this reported association. Nevertheless, we obtained suggestive evidence of linkage between Hashimoto disease and a marker allele haplotype on chromosome 6 in this family. The chromosome 6 linkage region contains two features of interest. The distal half of the region includes the entire MHC; however, there have been no reports of genetic linkage or association between Hashimoto disease and the MHC. Graves’ disease has been associated with HLA-DRB1*08, DRB1*03/DRB3*0101 and DRB3*0202 (28–30), but HLA typing in the current family was not consistent with these associations. The proximal half of the chromosome 6p linkage region contains AITD1, a locus proximal to the MHC that has shown strong linkage to both Hashimoto disease and Graves’ disease in genome-wide studies (26). The occurrence of several recombinants between the MHC and AITD1 in the study family suggest that epistasis between AITD1 in the centromeric region of chromosome 6 and AIS1 on 1p may account for much of the genetic liability to Hashimoto disease in this family. Although in this family we cannot distinguish a dominant versus a recessive mode of action for AITD1-related susceptibility to Hashimoto disease, Tomer et al. (26) suggested that it is most likely recessive with low penetrance.
The opportunity to study a single very large family with vitiligo allowed us to avoid the problems of locus heterogeneity and reduced penetrance, and to identify recombinant haplotypes that define a specific genetic interval for AIS1, between D1S2742 and D1S515. Although this 14.4 cM interval is broad, it often has not been possible to define discrete intervals for loci associated with complex inheritance at all. Correcting for several major assembly errors in this region, the NCBI Entrez MapViewer (http://www.ncbi.nlm.nih.gov/) and UCSC Genome Browser (http://genome.ucsc.edu) list 20 known and approximately 15 predicted genes within the AIS1 interval, of which several have known functions that might be involved in susceptibility to autoimmunity and aberrant melanocyte survival. These genes thus constitute attractive candidates for future analyses of other families with vitiligo and perhaps other forms of autoimmunity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Family ascertainment and collection
The project was approved by the Colorado Multiple Institutional Review Board. The study family was ascertained by questionnaire survey to the entire membership of the National Vitiligo Foundation (USA), and family members were contacted through the proband. Additional families were also ascertained from the membership of the National Vitiligo Foundation (USA) and the Vitiligo Society (UK). Diagnosis of generalized vitiligo was based on acquired patchy, progressive depigmentation involving the extremities, trunk, genitalia or central face (3,4), documented by a detailed self-report that included a detailed lesional map and was followed up by a detailed in-person or telephone questionnaire interview. Most cases were confirmed by physician diagnosis, including personal examination by one of the study researchers.
Diagnosis of clinical Hashimoto thyroiditis was by self-report of physician diagnosis, with confirmation by physician records in several cases. For all family members, serum thyrotropin (TSH) was measured using a sensitive chemiluminescent assay with a detection limit of 0.01 µU/ml and a normal range of 0.5–5.0 µU/ml (31); serum free thyroxin (FT4) was measured by equilibrium dialysis with a normal range of 0.7–2.7 ng/ml (32); and serum anti-thyroid peroxidase (TPO) antibodies were measured by a chemiluminescent assay (33).
Genotyping and statistical analyses
We collected peripheral blood samples from members of the study family, and prepared DNA from the blood mononuclear cells using the Gentra Systems (Minneapolis, MN) PureGene kit. Twenty-four family members were genotyped for the Applied Biosystems (Foster City, CA) Prism Linkage Mapping Set Version 2 (LMSv2-MD10) panel of microsatellite markers, and subsequently for the 32 chromosome 1 markers from the Applied Biosystems LMSv2-HD5 panel to provide 5 cM average marker density across chromosome 1. Selected family members were additionally genotyped for D1S200, D1S2742, D1S2690, D1S476, D1S2867, D1S438, D1S246, D1S2638, D1S2835 and D1S515 to provide greater resolution. Markers were amplified using an Applied Biosystems 877 Catalyst, pooled in panels of 10–20 markers, and products were separated by electrophoresis in 5% polyacrylamide gels using an Applied Biosystems 377 semiautomated sequencer. Allele sizing was carried out using Applied Biosystems GENESCAN 3.1, and individual genotypes were assigned using Applied Biosystems GENOTYPER 2.5, with manual checking to minimize data errors. Mendelian inheritance of marker alleles was checked manually within GENOTYPER, and with PEDCHECK (34). All data were imported into the Genomica (Boulder, CO) DISCOVERY MANAGER database.
Initial two-point parametric LOD scores for vitiligo were calculated using MLINK (35) under assumptions of an autosomal dominant or autosomal recessive trait with maximum penetrance of 0.8, varying over six liability classes defined by age, ranging from 0.19 to 0.80, with corresponding phenocopy rates ranging from 0.001 to 0.005, and an overall disease prevalence of 1%. The gradations in penetrance by age were derived from the age-of-onset distribution among 2122 unrelated Caucasian vitiligo patients (unpublished data). Similar analyses were performed for clinical thyroid disease using parameters described in other linkage studies (26). Multipoint parametric and NPL analyses were performed using GENEHUNTER 2.1 (36). The maximum likelihood of vitiligo penetrance under an autosomal dominant model was calculated using ILINK (35). Multilocus haplotypes were constructed using SimWalk2 (37).
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ACKNOWLEDGEMENTS |
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We thank Donna Curtis, Katherine Gowan and Kathy Yeiser for technical assistance. We are indebted to the National Vitiligo Foundation (Tyler, TX) for its cooperation and assistance in this study, and for travel funding during the planning of this project, and to the Vitiligo Society (UK) for the initial encouragement to begin this project. This work was supported by grants AR45584 and AI46374 from the National Institutes of Health (to R.A.S.). This paper is dedicated to the memory of Charlie, a victim of autoimmune disease.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: Human Medical Genetics Program, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B161, Denver, CO 80262, USA. Tel: +1 303 315 0409; Fax +1 303 315 0407; Email: richard.spritz@uchsc.edu
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