Kadir Mutlu HAYRAN, Seray KÜLCÜ, Refika Ferda ARTÜZ, Başak YALÇIN, Ahu YORULMAZ, Duru ONAN TABANLIOĞLU, Fatih Süheyl EZGÜ

The role of IFIH1 gene rs1990760 and rs2111485 single-nucleotide polymorphisms in generalized vitiligo predisposition

Background/aim: Interferon-induced helicase (IFIH1) is a gene locus that has been recently defined as a candidate for susceptibilityto generalized vitiligo (GV). The objectives of this study were to assess the association of IFIH1 gene, rs2111485, and rs1990760 singlenucleotide polymorphisms (SNP) with susceptibility to GV and the autoimmune diseases accompanying GV.Materials and methods: We prospectively studied GV patients and frequency-matched healthy controls by age and sex. The genotypesof the participants were determined for rs1990760 and rs2111485 SNPs of IFIH1. Dominant, recessive, and additive models wereevaluated for each SNP adjusted for age and sex.Results: The patients and their controls were observed to be in the Hardy–Weinberg equilibrium for SNP1 (2q24.2, rs1990760, IFIH1,T/C) and SNP2 (2q24.2, rs2111485, IFIH1, G/A), respectively (all P > 0.7). For SNP1, every T allel addition was significantly associatedwith 1.53 times protectiveness in terms of vitiligo risk (P = 0.033). As for SNP2, every G allel addition was associated with 1.42 timesprotectiveness, close to statistical significance (P = 0.100).Conclusions: We detected that for SNP1, each T allel and for Background/aim: Interferon-induced helicase (IFIH1) is a gene locus that has been recently defined as a candidate for susceptibilityto generalized vitiligo (GV). The objectives of this study were to assess the association of IFIH1 gene, rs2111485, and rs1990760 singlenucleotide polymorphisms (SNP) with susceptibility to GV and the autoimmune diseases accompanying GV.Materials and methods: We prospectively studied GV patients and frequency-matched healthy controls by age and sex. The genotypesof the participants were determined for rs1990760 and rs2111485 SNPs of IFIH1. Dominant, recessive, and additive models wereevaluated for each SNP adjusted for age and sex.Results: The patients and their controls were observed to be in the Hardy–Weinberg equilibrium for SNP1 (2q24.2, rs1990760, IFIH1,T/C) and SNP2 (2q24.2, rs2111485, IFIH1, G/A), respectively (all P > 0.7). For SNP1, every T allel addition was significantly associatedwith 1.53 times protectiveness in terms of vitiligo risk (P = 0.033). As for SNP2, every G allel addition was associated with 1.42 timesprotectiveness, close to statistical significance (P = 0.100).Conclusions: We detected that for SNP1, each T allel and for SNP2, each G allel are protective in terms of vitiligo development. Hereby,we confirmed that IFIH1 gene locus has a role in GV susceptibility.SNP2, each G allel are protective in terms of vitiligo development. Hereby,we confirmed that IFIH1 gene locus has a role in GV susceptibility.

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1. Jin Y, Andersen G, Yorgov D, Ferrara TM, Ben S, Brownson KM, Holland PJ, Birlea SA, Siebert J, Hartmann A et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 2016; 48: 1418-1424.
2. Spritz RA. The genetics of generalized vitiligo and associated autoimmune diseases. Pigment Cell Res 2007; 20: 271-278.
3. Czajkowski R, Mecinska-Jundzill K. Current aspects of vitiligo genetics. Postepy Dermatol Alergol 2014; 31: 247-255.
4. Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol 2013; 25: 676-682.
5. Gill L, Zarbo A, Isedeh P, Jacobsen G, Lim HW, Hamzavi I. Comorbid autoimmune diseases in patients with vitiligo: a cross-sectional study. J Am Acad Dermatol 2016; 74: 295-302.
6. Spritz RA. Recent progress in the genetics of generalized vitiligo. J Genet Genomics 2011; 38: 271-278.
7. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, Guja C, Ionescu-Tirgoviste C, Widmer B, Dunger DB et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 2006; 38: 617-619.
8. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006; 441: 101-105.
9. Looney BM, Xia CQ, Concannon P, Ostrov DA, Clare-Salzler MJ. Effects of type 1 diabetes-associated IFIH1 polymorphisms on MDA5 function and expression. Curr Diab Rep 2015; 15: 96.
10. Jin Y, Andersen GH, Santorico SA, Spritz RA. Multiple functional variants of IFIH1, a gene involved in triggering innate immune responses, protect against vitiligo. J Invest Dermatol 2017; 137: 522-524.
11. Nakashima R, Imura Y, Kobayashi S, Yukawa N, Yoshifuji H, Nojima T, Kawabata D, Ohmura K, Usui T, Fujii T et al. The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositisspecific autoantigen identified by the anti-CADM-140 antibody. Rheumatology 2010; 49: 433-440.
12. Li Y, Liao W, Cargill M, Chang M, Matsunami N, Feng BJ, Poon A, Callis-Duffin KP, Catanese JJ, Bowcock AM et al. Carriers of rare missense variants in IFIH1 are protected from psoriasis. J Invest Dermatol 2010; 130: 2768-2772.
13. Yin X, Low HQ, Wang L, Li Y, Ellinghaus E. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility. Nat Commun 2015; 6: 6916.
14. Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1228-1233.
15. Martinez A, Santiago JL, Cenit MC, de Las Heras V, de la Calle H, Fernandez-Arquero M, Arroyo R, de la Concha EG, Urcelay E. IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk. Eur J Hum Genet 2008; 16: 861-864.
16. Sutherland A, Davies J, Owen CJ, Vaikkakara S, Walker C, Cheetham TD, James RA, Perros P, Donaldson PT, Cordell HJ et al. Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves’ disease susceptibility. J Clin Endocrinol Metab 2007; 92: 3338-3341.
17. Jin Y, Birlea SA, Fain PR, Ferrara TM, Ben S, Riccardi SL, Cole JB, Gowan K, Holland PJ, Bennett DC, et al. Genomewide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet 2012; 44: 676-680.
18. Spritz RA, Andersen GH. Genetics of Vitiligo. Dermatol Clin 2017; 35: 245-55.
19. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 2009; 324: 387-389.
20. Molineros JE, Maiti AK, Sun C, Looger LL, Han S, KimHoward X, Glenn S, Adler A, Kelly JA, Niewold TB, et al. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genet 2013; 9: e1003222.
21. Cen H, Wang W, Leng RX, Wang TY, Pan HF, Fan YG, Wang B, Ye DQ. Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Autoimmunity 2013; 46: 455-462.
22. Shigemoto T, Kageyama M, Hirai R, Zheng J, Yoneyama M, Fujita T. Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes. J Biol Chem 2009; 284: 13348-13354.