| 〖Mapping and Identification of vitiligo Susceptibility Genes〗Vitiligo (OMIM: #193200) is an acquired depigmentation disorder of the skin and hair caused by the selective destruction of melanocytes from the skin and hair that gives rise to well-defined white patches. About 0.5% of the world's population is affected by the disease, regardless of age, gender or skin color. However, relatively little is known of its pathogenesis. Several theories have been proposed to explain the destruction of melanocytes in vitiligo. These include melanocyte self-destruction, biochemical hypothesis, neural hypothesis, and autoimmune mediated melanocyte elimination. Strong evidences from twin and family studies underline the importance of genetic factors in the development of vitiligo, with polygenic features. And genetic evidences are also consistent with the basis of other theories.Up to date, four susceptibility loci has been reported on different chromosomes, 17p13 (SLEV1), 1p31 (AIS1), 7q (AIS2) and 8p (AIS3). By association analysis for 9 candidates in the 1p31 (AIS1), -639G/T in the promoter region of FOXD3 gene showed significantly related with vitiligo; Variants in or around NALP1 on chromosome 17p13 gene showed an association with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. The NALP1 findings are discussed on《New England Journal of Medicine》(IF: 44.016/2005), also indicating the autoimmunity basis on another view.In 2004, we have performed a genome-wide scan for 106 Chinese Han vitiligo families. Linkage results provided significant evidence for a major vitiligo susceptibility locus 4q13-q21 (max NPL=4.62, p=0.000003), which was later named AIS4 with OMIM#609400, and suggestive evidences for linkage on other regions, 22q12(max NPL=3.49, p=0.0003), 6p21-p22(max NPL=3.16, p=0.00092), 6q24-q25(max NPL=2.98, p=0.0016), 1p36(max NPL=2.37, p=0.0093), 14q12-q13(max NPL =1.4, p=0.077).〖Objectives〗Regarding the successful identification of susceptibility genes from the AIS1 and SLEV1 with mapping and functional candidate strategy, we aim to search susceptibility genes from the significant region AIS4 with large scale and high-through method (still being on the process). To make clear whether susceptibility genes are really covered in the suggestive loci, we would like to finely map the 5 suggestive loci with more families and high density markers (the major contents of this paper).〖Materials and Methods〗We have finely scanned 143 families of 736 individuals (369 affected and 367 unaffected) for the 5 suggestive loci with 40 microsattellites. Genotypes were corrected with Merlin software. Parameter or nonparameter linkage analysis were made with GENEHUNTER software 2.0 Version.〖Results〗1. significant linkage findings:(1) 22q12:As we reported elsewhere, a suggestive signal was indicated by a maximal nonparametric linkage score of 1.75 (p = 0.039) by two marks (D22S280 and D22S283). In this study, we saturate this region with additional 5 markers. Hence, a total of 7 markers (D22S1167-D22S1163-D22S1150-D22S280-D22S1265-D22S283-D22S272) were included to maximize the information content. The average information of markers at 22q12 reached 79%, with average genetic distance of 2.7 cM. To determine the extent of allele sharing at chromosome 22q12, we have genotyped the joint 143 vitiligo families. With higher marker intensity studied here, finer mapping of the same 106 families cohort used in our previous genome-wide scan has improved the linkage results, respectively by multipoint NPL score from 1.75 (p=0.039) to 3.49(p=0.0003), and HLOD from 0.72(α=19%) to 2.28(α=35%). Multipoint nonparametric linkage analysis of the combined 143 families yielded a maximum NPL score of 4.14 (p=0.000015) at the marker position D22S1163. Once the evidence of linkage at 22q12 was found, we performed parametric multipoint analyses, employing simple dominant and recessive models. A significant evidence of linkage is found by assuming genetic heterogeneity (HLOD=3.26) under a dominant model, and about 37.3% families are estimated to be linked with this locus. These summary data achieved genome-wide criteria for highly significant linkage, providing 22q12 as a vitiligo susceptibility locus that contributes to vitiligo.(2) 6p21-p22:Similar analysis was performed in the 143 families on 6p21-p22, another region designated as"suggestive linkage locus"in previous report. The marker density of original 12 markers was saturated with an interval distance of 1.9 cM. In this view, we have genotyped the same 12 markers in the new 37 families. two-point analysis showed the max NPL of 2.9(p =0.0016)and a dominant HLOD of 3.54(α=49.4%), which are consistent with multipoint parameter and nonparameter score (NPL=4.1, p=0.000018;HLOD=3.73,α=42.3%). Both two and multiple point linkage analysis provided significant linkage signals on 6p21-p22.2. negative linkage signal (14q12-q13):With respect to the suggested vitiligo susceptibility locus on chromosome 14q, no suggestive indications of linkage were obtained either with nonparametric or parametric analyses for 4 microsatellite markers flanking D14S70. The previous signal seems to be a false positive linkage locus by the present negative results;3. Suggestive linkage signals: (1) 6q24-q25:Both two and multiple point linkage analysis provided stronger linkage signals on 6q24-q25 than what we got from the 106 families in the genome-wide scanning, with max NPL of 3.3 3(p=0.00038) and HLOD of 1.95(α=17.1%), which also indicated suggestive signal;(2) 1p36:Fine mapping of the 1p36 region, flanked by D1S2828 (50.1 cM) and D1S449 (60.9 cM), was performed with 6 original STRs. When the 37 new families were analyzed in combination with the previous family, we obtained a summary multipoint nonparametric LOD score of 2.59 (P=0.0042) at the 1.1 cM interval D1S234-D1S2885 .The recessive heterogeneity LOD (HLOD) at this interval was 0.78 withα=10%. These summary data still achieve genome-wide criteria for suggestive linkage;〖Conclusions〗1. Identification 22q12 and 6p21-p22 as significant susceptibility loci,which potentially contain the susceptibility genes;2. Stronger linkage signals on 6q24-q25and1p36, but still in suggestive threshold;3. Exclusion of 14q12-q13 as susceptibility locus in Chinese Han vitiligo families;...
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