Douroudis, K.

Karelson, M.

Kingo, K.

Kõks, S.

Reimann, E.

Silm, H.

Traks, T.

Vasar, E.

English

Research Repository

Acta Derm Venereol 91189Letters to the Editor© 2011 The Authors. doi: 10.2340/00015555-0999Journal Compilation © 2011 Acta Dermato-Venereologica. ISSN 0001-5555Vitiligo is a complex depigmentary disorder characterised by the appearance of white patches as a result of the de-struction of melanocytes in the skin and hair (1). Several loci, including AIS1 (1p31) and AISI4 (4q13-q21), have been shown to confer susceptibility to the disease (2–3). However, the genetic factors involved in vitiligo are yet to be clarified. The PRO2268 gene has been mapped, by analysis of a cDNA clone (FLB8424) from human foetal liver, to the 12q14 chromosomal region, which harbours the genes encoding interferon-gamma (IFN-g), interleukin (IL)-26 and IL-22. Of note, the IFN-g-IL26-IL22 gene cluster is associated with autoimmune diseases including rheumatoid arthritis and type 1 diabetes (4–6). Although the PRO2268 protein (AF119871) has as yet unknown functions, a putative role for the PRO2268 gene is suggested based on our unpublished observation (data not shown), by its significantly higher expression in the peripheral blood mononuclear cells (PBMCs) of vitiligo patients compared to those of control subjects (p = 0.036). As part of our ongoing research into the impact of susceptibility genetic variants on the risk of vitiligo, we selected the rs10784680 single nucleotide polymorphism (SNP) within the PRO2268 gene as a candidate in our analysis. PATIENTS AND METHODS A cohort of 194 unaffected controls (106 females, 88 males; mean age ± SD 35.49 ± 13.82 years) with no personal or family history of vitiligo and 100 vitiligo patients (69 females, 31 ma-les; mean age ± SD 44.74 ± 15.86 years; mean age at onset ± SD 28.69 ± 16.24 years) of Caucasian origin were enrolled into a case-control study. Diagnoses of vitiligo were made in the De-partment of Dermatology and Venereology, University of Tartu, based on the characteristic loss of skin pigmentation at typical locations and Wood’s lamp examinations. The clinical types of vitiligo were classified as focal (one or a few macules with a nondermatomal distribution; n = 3), acrofacial (affecting the distal extremities and face; n = 11), vulgaris (scattered over the body; n = 83) and universal (over 90% depigmentation; n = 3). In addition, patients were deemed to have active vitiligo if new areas of depigmentation had been observed during the previous 3 months (n = 74) and stable vitiligo if no new depigmentation or enlargement of pre-existing depigmented areas had been observed for more than 3 months (n = 26). Moreover, vitiligo pa-tients were categorised with respect to the presence of comorbid disorders: 38 had no other disease, 32 one or more autoimmune disorders, and 30 other diseases. The Ethics Committee of the University of Tartu approved the study and informed consent was obtained from all participants.The rs10784680 SNP was genotyped using the SNPlex Geno-typing System and analysed using a 3730 DNA Analyzer (App-lied Biosystems, Foster City, CA) according to manufacturer’s instructions. In brief, the assay workflow includes an allele-specific oligonucleotide reaction, exonuclease purification, and PCR amplification. The resulting amplicons are immo-bilised on streptavidin-coated microtitre plates. ZipChute probes are hybridised to complementary ZipCode sequences, and non-hybridised ZipChute probes and then washed away. Bound ZipChute probes are eluted and analysed by capillary electrophoresis (7). Data analysis was performed using R software (available from www.rproject.org). Logistic regression was used to obtain odds ratio (OR) values, as well as Wald’s confidence intervals (CI), for alleles and genotypes. A p value of < 0.05 was considered statistically significant.RESULTS AND DISCUSSIONData analysis revealed that the frequency of the rs10784680 G allele was significantly higher in vitiligo patients (96%) than in controls (83.5%) (OR = 4.74, 95% CI 2.22–10.10; p = 0.000055) (Table I). Ac-cordingly, the rs10784680 GG genotype was signifi-cantly more frequent in vitiligo patients (92%) than in controls (67%) (OR = 5.67, 95% CI 2.59–12.37; p = 0.000013). Notably, none of the test subjects car-ried the rs10784680 AA genotype. However, this observation is in accordance with the available data in the GenBank database, the rs10784680 AA genotype being reportedly absent in Hapmap-CEU, a referent population of European ancestry. When we analysed the vitiligo patients according to their clinical subgroups, no significant differences in rs10784680 SNP allele frequency were observed when comparing patients on the basis of age at onset (> 20 ye-ars vs. ≤ 20 years; p = 0.26), sex (male vs. female; p = 1), family history (familial vs. sporadic; p = 1) or disease activity (active vs. stable vitiligo; p = 0.11) (data not shown). Furthermore, no significant differences in allele The PRO2268 Gene as a Novel Susceptibility Locus for VitiligoKonstantinos Douroudis1,2, Külli Kingo2,3, Maire Karelson3, Helgi Silm2,3, Ene Reimann2,3, Tanel Traks1,2, Eero Vasar1,2 and Sulev Kõks1,21Department of Physiology, 2Centre of Translational Medicine, 3Department of Dermatology and Venereology, University of Tartu, Ravila 19, EE-50411 Tartu, Estonia. E-mail: drkmb@email.comAccepted August 20, 2010.Table I. Allele and genotype frequencies for the rs10784680  single nucleotide polymorphism in vitiligo patients and control subjectsrs10784680Controln (%)Vitiligon (%) OR (95% CI) p-valueAlleleA 64 (16.5) 8 (4.0) 1 (ref.) G 324 (83.5) 192 (96.0) 4.74 (2.22–10.10) 0.000055 Total 388 (100.0) 200 (100.0)GenotypeAG 64 (33.0) 8 (8.0) 1 (ref.)GG 130 (67.0) 92 (92.0) 5.66 (2.59–12.37) 0.000013Total 194 (100.0) 100 (100.0)OR: odds ratio; CI: confidence interval.190 Letters to the Editordistribution were detected between vitiligo patients with autoimmune and other diseases and patients with no co-morbidity (p = 0.70 and p = 0.63, respectively) (data not shown). In addition, further analysis of our patients according to clinical subtype revealed that the frequency of the rs10784680 G allele was significant higher in the vitiligo vulgaris subgroup than in the control group (OR = 4.48, 95% CI 2.01–10.01; p = 0.00024). It should be noted that stratifying patients according to clinical groups diminished the power to detect associations. In conclusion, to our knowledge the present study is the first to address the possible influence of the PRO2268 gene on the risk of vitiligo. Although the function of the PRO2268 protein remains unknown, it is of particular interest to note that the PRO2268 gene lies adjacent to a region containing the IFN-g-IL26-IL22 gene cluster, whose gene products play key roles in im-mune signalling. For this region in particular, extensive re-sequencing, further genotyping and targeted functio-nal studies are essential in order to identify the gene(s) that play causal roles in vitiligo. It should be noted that we cannot exclude the possibility that new susceptibi-lity variants of the PRO2268 gene may be discovered, or that the PRO2268 gene may play important roles in other skin disorders.ACKNOWLEDGEMENTSThis study was supported by a grant from the European Union, allocated through the European Regional Development Fund and the Archimedes Foundation; by an Estonian Ministry of Education grant (no. SF0180043s07); and by an Estonian Sci-ence Foundation Grant (no. 7549).REFERENCESCho S, Kang HC, Hahm JH. Characteristics of vitiligo in 1. Korean children. Pediatr Dermatol 2000; 17: 189–193. Fain PR, Gowan K, LaBerge GS, Alkhateeb A, Stetler 2. GL, Talbert J, et al. A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am J Hum Genet 2003; 72: 1560–1564.Chen JJ, Huang W, Gui JP, Yang S, Zhou FS, Xiong QG, 3. et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet 2005; 76: 1057–1065.Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura 4. K, Ueki K, et al. Expression of interleukin-22 in rheuma-toid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum 2005; 52: 1037–1046.Jahromi M, Millward A, Demaine A. A CA repeat poly-5. morphism of the IFN-gamma gene is associated with susceptibility to type 1 diabetes. J Interferon Cytokine Res 2000; 20: 187–190. Hanjani-Khani A, Lacaille D, Hoar D, Chalmers A, Horsman 6. D, Anderson M, et al. Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis. Lancet 2000; 356: 820–825.Tobler AR, Short S, Andersen MR, Paner TM, Briggs JC, 7. Stephen M, et al. The SNPlex genotyping system: a flexible and scalable platform for SNP genotyping. J Biomol Tech 2005; 16: 398–406.Acta Derm Venereol 91

The PRO2268 Gene as a Novel Susceptibility Locus for Vitiligo

https://researchrepository.murdoch.edu.au/id/eprint/51907/1/vitiligo.pdf

The PRO2268 Gene as a Novel Susceptibility Locus for Vitiligo

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