Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis.
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ABSTRACT:
SUBMITTER: Spritz RA
PROVIDER: S-EPMC1181907 | biostudies-literature | 2004 Jan
REPOSITORIES: biostudies-literature
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Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis.
Spritz Richard A RA Gowan Katherine K Bennett Dorothy C DC Fain Pamela R PR
American journal of human genetics 20040101 1
Similar Datasets
Project description:Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there is strong association between vitiligo and other autoimmune diseases. To map genetic loci that confer susceptibility to generalized vitiligo and perhaps other autoimmune diseases, we performed a genomewide linkage scan in 71 white multiplex families with vitiligo from North America and the United Kingdom. Linkage was assessed by multipoint nonparametric linkage analyses. One linkage signal, AIS1, located at 1p31, met genomewide criteria for highly significant linkage (nonparametric LOD 5.56; P=.000000282), establishing its importance as a major vitiligo susceptibility locus. An additional seven signals, on chromosomes 1, 7, 8, 11, 19, and 22, met genomewide criteria for "suggestive linkage," and will thus be of particular importance for follow-up studies.
| S-EPMC1180316 | biostudies-literature
Project description:Generalized vitiligo is the most common pigmentation disorder, the result of autoimmune loss of melanocytes from the skin and hair, with a high frequency of other autoimmune diseases in vitiligo patients and their relatives. We previously reported the linkage signals on chromosomes 1, 7, and 17 in Caucasian families with generalized vitiligo and associated autoimmune diseases and identified the risk loci of chromosomes 17 and 1 as NLRP1 (NALP1) and FOXD3, respectively. Here, we describe fine-scale genetic association analyses in two independent series of Caucasian multiplex families, refining localization of the chromosome 7 locus and a locus on chromosome 9. Three susceptibility signals, represented by single-nucleotide polymorphisms (SNPs) rs6960920 in 7p13, rs734930 in 7q11, and rs4744411 in 9q22, were significantly associated with vitiligo and other autoimmune diseases. We also detected significant three-way interaction effects of chromosome 7 SNP rs6960920, chromosome 9 SNP rs4744411, and NLRP1 SNP rs6502867 on both the vitiligo phenotype and an expanded autoimmune disease phenotype, and significant three-way interaction effects of both chromosome 7 SNPs and NLRP1 SNP rs6502867 on the vitiligo phenotype. These support the validity of the chromosomes 7 and 9 linkage/association signals and underscore the utility of gene-gene interaction analysis in characterizing the genetic effects of candidate association signals.
| S-EPMC3513759 | biostudies-literature
Project description:Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo.
| S-EPMC4740779 | biostudies-literature
Project description:Although genome-wide association studies (GWAS) have identified several hundred loci associated with autoimmune diseases, their mechanistic insights are still poorly understood. The human genome is more complex than single nucleotide polymorphisms (SNPs) that are interrogated by GWAS arrays. Apart from SNPs, it also comprises genetic variations such as insertions-deletions, copy number variations, and somatic mosaicism. Although previous studies suggest that common copy number variations do not play a major role in autoimmune disease risk, it is possible that certain rare genetic variations with large effect sizes are relevant to autoimmunity. In addition, other layers of regulations such as gene-gene interactions, epigenetic-determinants, gene and environmental interactions also contribute to the heritability of autoimmune diseases. This review focuses on discussing why studying these elements may allow us to gain a more comprehensive understanding of the aetiology of complex autoimmune traits.
| S-EPMC6115971 | biostudies-literature
Project description:BackgroundGeneralized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases.MethodsTo identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families.ResultsWe detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.ConclusionsWe observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.
| S-EPMC2891985 | biostudies-literature
Project description:Linkage studies were performed in six European families with hyperkalaemic periodic paralysis (PPII) with myotonia, an autosomal dominantly inherited disorder characterised by episodic weakness. The weakness is caused by non-inactivating sodium channels of reduced single channel conductance of the muscle fibre membrane. Recently, portions of the gene coding for the alpha subunit of the sodium channel of the adult human skeletal muscle (h-Na2) have been cloned and localised on chromosome 17q with no recombinants to the human growth hormone locus (GH1). Linkage between these two chromosome 17 markers and the disease was shown in our families (Z = 7.14, 0 = 0.00). These results, combined with the linkage data of a single large American family, suggest that the disease is caused by dominant mutations of the adult sodium channel, and that it is probably a genetically homogeneous disorder. Hyperkalaemic periodic paralysis is the first non-progressive myotonic disorder to be localised on the human genome.
| S-EPMC1015786 | biostudies-other
Project description:We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10(-8)), MC1R (P = 1.82 × 10(-13)), a region near TYR (P = 1.57 × 10(-13)), IFIH1 (P = 4.91 × 10(-15)), CD80 (P = 3.78 × 10(-10)), CLNK (P = 1.56 × 10(-8)), BACH2 (P = 2.53 × 10(-8)), SLA (P = 1.58 × 10(-8)), CASP7 (P = 3.56 × 10(-8)), CD44 (P = 1.78 × 10(-9)), IKZF4 (P = 2.75 × 10(-14)), SH2B3 (P = 3.54 × 10(-18)) and TOB2 (P = 6.81 × 10(-10)). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration.
| S-EPMC3366044 | biostudies-literature
Project description:To investigate a shared genetic aetiology for skin involvement in psoriasis and psoriatic arthritis (PsA) by genotyping single-nucleotide polymorphisms (SNPs), reported to be associated in genome-wide association studies of psoriasis, in patients with PsA.SNPs with reported evidence for association with psoriasis were genotyped in a PsA case and control collection from the UK and Ireland. Genotype and allele frequencies were compared between PsA cases and controls using the Armitage test for trend.Seven SNPs mapping to the IL1RN, TNIP1, TNFAIP3, TSC1, IL23A, SMARCA4 and RNF114 genes were successfully genotyped. The IL23A and TNIP1 genes showed convincing evidence for association (rs2066808, p = 9.1×10(-7); rs17728338, p = 3.5×10(-5), respectively) whilst SNPs mapping to the TNFAIP3, TSC1 and RNF114 genes showed nominal evidence for association (rs610604, p = 0.03; rs1076160, p = 0.03; rs495337, p = 0.0025). No evidence for association with IL1RN or SMARCA4 was found but the power to detect association was low.SNPs mapping to previously reported psoriasis loci show evidence for association to PSA, thus supporting the hypothesis that the genetic aetiology of skin involvement is the same in both PsA and psoriasis.
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Project description:A candidate gene study was conducted on 10 established type II diabetes genes and 45 genes associated with autoimmune diseases, including type I diabetes (T1D), in a maximum of 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. Associations at P values <10(-3) were found for three known T1D regions at chromosomes 4q27, 12q13.2 and 12q24.13 (http://www.T1DBase.org). Support was obtained for a newly identified T1D candidate locus on chromosome 12q13.3-12q14.1 (rs1678536/KIF5A: P=8.1 x 10(-3); relative risk (RR) for minor allele=0.89, 95% CI=0.82-0.97), which has a separate association from the previously reported T1D candidate locus ERBB3/12q13.2-q13.3. Our new evidence adds to that previously published for the same gene region in a T1D case-control study (rs1678542; P=3.0 x 10(-4); odds ratio (OR)=0.92, 95% CI=0.88-0.96). This region, which contains many genes, has also been associated with rheumatoid arthritis.
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