Vitiligo-Associated Multiple Autoimmune Disease Susceptibility 6

For a phenotypic description and a discussion of genetic heterogeneity of vitiligo susceptibility, see VAMAS1 (606579).

Mapping

Arcos-Burgos et al. (2002) collected pedigree data on vitiligo from a set of 56 multigeneration families belonging to the Paisa community in Antioquia, Colombia, with the goal of applying the unified model of complex segregation and linkage disequilibrium analyses to test the hypotheses of the existence of a major gene predisposing to vitiligo and that allelic or haplotype polymorphisms of microsatellite loci at 6p21.4-p21.3 spanning HLA are associated with this predisposition. Among the 15 models of complex segregation used, the one that best fit the data was that of a major dominant gene and the existence of strong environmental effects acting on the recessive genotype. The penetrance and risk estimations discriminated 2 sets of vitiligo patients: those with early onset of vitiligo cosegregating with a dominant mode of inheritance without environmental effects, and those with late onset of vitiligo cosegregating with the recessive genotype and being influenced by environmental effects. After establishing the normal distribution of allelic frequencies and performing correction for multiple comparisons, the linkage disequilibrium analysis suggested that a major genetic factor could be located at 6p21.3, because significant case-control differences for allele 122 at marker D6S265 and significant linkage disequilibrium between D6S276 and D6S273 were detected in cases but not in controls. The results could not be explained as a consequence of evolutionary forces or as genetic stratification acting differentially on cases and controls, because there was neither deviation from the Hardy-Weinberg expectations nor genetic subdivision between cases and controls.

By genomewide analysis of 1,392 unrelated patients of European origin with vitiligo and 2,629 controls, Jin et al. (2010) found significant linkage to the MHC loci on chromosome 6p21.3. The most significant associations were with 3 SNPs in the HLA-A (142800) region: rs12206499 (p = 1.24 x 10(-19); odds ratio (OR), 1.58); rs3823355 (p = 2.13 x 10(-19); OR, 1.57); and rs6904029 (p = 7.89 x 10(-19); OR, 1.56). The second peak was in the class II gene region, between HLA-DRB1 (142857) and HLA-DQA1 (146880) characterized by rs532098 (p = 4.83 x 10(-30); OR, 1.74) and rs3806156 (p = 4.97 x 10(-18); OR, 1.53). The highest odds ratio in the genomewide association study was 2.48, for rs7758128 (p = 7.21 x 10(-15)). The regions encompassing HLA class I and HLA class II showed independent associations with vitiligo. Replication in a case-control cohort of 677 patients and 1,106 controls and a family-based cohort of 183 simplex trios and 332 multiplex families yielded combined p values of 9.05 x 10(-23) for rs3823355 and 4.50 x 10(-34) for rs532098. Overall, the findings were consistent with an association between vitiligo and the HLA-A*02 and HLA-DRB1*04 alleles.

Quan et al. (2010) conducted a genomewide association study of generalized vitiligo in a Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. Quan et al. (2010) identified 2 independent association signals within the MHC region (rs11966200, combined P = 1.48 x 10(-48), OR = 1.90; rs9468925, combined P = 2.21 x 10(-33), OR = 0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602, and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele.