Ann Dermatol.  2018 Oct;30(5):529-535. 10.5021/ad.2018.30.5.529.

TSLP Polymorphisms in Atopic Dermatitis and Atopic March in Koreans

• Heo WI
• Park KY
• Lee MK
• Moon NJ
• Seo SJ

• KMID: 2419741
• DOI: http://doi.org/10.5021/ad.2018.30.5.529

Abstract

BACKGROUND
Atopic march (AM) is the progression from atopic dermatitis (AD) to allergic rhinitis and asthma. The development of AD is as high as 20% in children worldwide and continues to increase. AD seems to be caused by both genetic and environmental factors. Recently, polymorphisms of the thymic stromal lymphopoietin (TSLP) gene associated with allergic disorders were reported in ethnic groups from various countries.
OBJECTIVE
Identification of TSLP polymorphisms in Koreans with AD or AM.
METHODS
Whole-exome sequencing was performed in 20 AD and 20 AM patients.
RESULTS
Nine single nucleotide polymorphisms (SNPs) of TSLP were detected (rs191607411, rs3806933, rs2289276, rs2289277, rs2289278, rs139817258, rs11466749, rs11466750, rs10073816). These SNPs have been correlated with susceptibility to allergic diseases in ethnic groups from China, Japan, Turkey, and Costa Rica in previous studies. Remarkably, one of 20 patients in the AD group lacked all SNPs, compared to six of 20 patients in the AM group. Odds ratios showed that Korean patients without the nine TSLP variants had an 8.14 times higher risk of moving from AD to AM. Two haplotype blocks were validated in 60 AD and 59 AM patients using Sanger sequencing. The haplotype blocks (rs3806933 and rs2289276) and (rs11466749 and rs11466750) were in high linkage disequilibrium, respectively (D"²=0.97, D"²=1).
CONCLUSION
The increase of major allele frequency of respective nine TSLP variants may enhance the risk of AM. These data will contribute to improved genetic surveillance system in the early diagnosis technology of allergic disease.

Keyword

Atopic dermatitis; Atopic march; Korean; Polymorphisms; Thymic stromal lymphopoietin

MeSH Terms

Asthma
Child
China
Costa Rica
Dermatitis, Atopic*
Early Diagnosis
Ethnic Groups
Gene Frequency
Haplotypes
Humans
Japan
Linkage Disequilibrium
Odds Ratio
Polymorphism, Single Nucleotide
Rhinitis, Allergic
Turkey

Figure

• 

  Fig. 1 Pairwise linkage disequilibrium (LD) map for six single nucleotide polymorphisms of thymic stromal lymphopoietin gene. (A) Pairwise D′/LOD and (B) r2 value are indicated as colors. White to red colors (closer to 1) representing the increasing strength of LD.

Reference

1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015; 66(Suppl 1):8–16. PMID: 25925336.

2. Bjerg A, Hedman L, Perzanowski MS, Platts-Mills T, Lundbäck B, Rönmark E. Family history of asthma and atopy: in-depth analyses of the impact on asthma and wheeze in 7- to 8-year-old children. Pediatrics. 2007; 120:741–748. PMID: 17908760.

3. Bantz SK, Zhu Z, Zheng T. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. J Clin Cell Immunol. 2014; 5:pii: 202.

4. Li MX, Kwan JS, Bao SY, Yang W, Ho SL, Song YQ, et al. Predicting mendelian disease-causing non-synonymous single nucleotide variants in exome sequencing studies. PLoS Genet. 2013; 9:e1003143. PMID: 23341771.

5. Kryukov GV, Pennacchio LA, Sunyaev SR. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet. 2007; 80:727–739. PMID: 17357078.

6. Pabinger S, Dander A, Fischer M, Snajder R, Sperk M, Efremova M, et al. A survey of tools for variant analysis of next-generation genome sequencing data. Brief Bioinform. 2014; 15:256–278. PMID: 23341494.

7. Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med. 2005; 202:541–549. PMID: 16103410.

8. Zhu Z, Oh MH, Yu J, Liu YJ, Zheng T. The role of TSLP in IL-13-induced atopic march. Sci Rep. 2011; 1:23. PMID: 22355542.

9. Han H, Roan F, Ziegler SF. The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol Rev. 2017; 278:116–130. PMID: 28658558.

10. Ziegler SF. The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol. 2010; 22:795–799. PMID: 21109412.

11. Leyva-Castillo JM, Hener P, Jiang H, Li M. TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J Invest Dermatol. 2013; 133:154–163. PMID: 22832486.

12. Harada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, et al. Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2009; 40:368–374. PMID: 18787178.

13. Garmhausen D, Hagemann T, Bieber T, Dimitriou I, Fimmers R, Diepgen T, et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy. 2013; 68:498–506. PMID: 23452057.

14. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21:263–265. PMID: 15297300.

15. Zhang MH, Kim YS, Jin EH, Kim KM, Lee JH, Li CS, et al. Identification of polymorphisms in thymic stromal lymphopoietin (TSLP) gene and their association with allergic rhinitis. Genes Genomics. 2008; 30:461–468.

16. Birben E, Sahiner UM, Karaaslan C, Yavuz TS, Cosgun E, Kalayci O, et al. The genetic variants of thymic stromal lymphopoietin protein in children with asthma and allergic rhinitis. Int Arch Allergy Immunol. 2014; 163:185–192. PMID: 24525665.

17. Harada M, Hirota T, Jodo AI, Hitomi Y, Sakashita M, Tsunoda T, et al. Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma. Am J Respir Cell Mol Biol. 2011; 44:787–793. PMID: 20656951.

18. Hunninghake GM, Soto-Quirós ME, Avila L, Kim HP, Lasky-Su J, Rafaels N, et al. TSLP polymorphisms are associated with asthma in a sex-specific fashion. Allergy. 2010; 65:1566–1575. PMID: 20560908.

19. Liu L, Xu LS, Liu QJ, Dong FZ, Qiu RF, Wen MC, et al. Two single nucleotide polymorphisms in TSLP gene are associated with asthma susceptibility in Chinese Han population. Exp Lung Res. 2012; 38:375–382. PMID: 22913730.

20. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011; 365:1315–1327. PMID: 21991953.

21. Barrett LW, Fletcher S, Wilton SD. Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell Mol Life Sci. 2012; 69:3613–3634. PMID: 22538991.