Ann Dermatol.  2015 Jun;27(3):275-282. 10.5021/ad.2015.27.3.275.

Are Podoplanin Gene Polymorphisms Associated with Atopic Dermatitis in Koreans?

• Namkung JH
• Kim E
• Park YD
• Park G
• Yang JM

• KMID: 2352498
• DOI: http://doi.org/10.5021/ad.2015.27.3.275

Abstract

BACKGROUND
The histologic characteristics of atopic dermatitis (AD) include perivascular edema and dilated tortuous vessels in the papillary dermis. A single nucleotide polymorphism (SNP) of the fms-related tyrosine kinase 4 (FLT4) gene is associated with AD.
OBJECTIVE
To investigate the associations between podoplanin (PDPN) gene SNPs and AD.
METHODS
We genotyped 9 SNPs from 5 genes of 1,119 subjects (646 AD patients and 473 controls). We determined the promoter activity of 1 SNP (rs355022) by luciferase assay; this SNP was further investigated using 1,133 independent samples (441 AD patients and 692 controls).
RESULTS
The rs355022 and rs425187 SNPs and the C-A haplotype in the PDPN gene were significantly associated with intrinsic AD in the initial experiment. The rs355022 SNP significantly affected promoter activity in the luciferase assay. However, these results were not replicated in the replication study.
CONCLUSION
Two SNPs and the C-A haplotype in the PDPN gene are significantly associated with intrinsic AD; although, the results were confirmed by luciferase assay, they could not be replicated with independent samples. Nevertheless, further replication experiments should be performed in future studies.

Keyword

Atopic dermatitis; Luciferases; Podoplanin protein; Genetic polymorphisms

MeSH Terms

Dermatitis, Atopic*
Dermis
Edema
Haplotypes
Humans
Luciferases
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Protein-Tyrosine Kinases
Luciferases
Protein-Tyrosine Kinases

Figure

• 

  Fig. 1 Map of the podoplanin gene on chromosome 1p36.21 (41.7 kb). Black and grey blocks indicate coding exons, and the 5' and 3' untranslated regions, respectively. The first nucleotide of the translation start site is denoted as nucleotide +1. Genotyped polymorphisms are marked. Black and grey lines indicate minor allele frequencies of the polymorphisms in 48 samples >10% and <10%, respectively. Dots indicate polymorphisms genotyped in the larger population (n=1,119). Linkage disequilibrium between the tag single nucleotide polymorphisms (SNPs) and their tagged SNPs are presented as r2.

• 

  Fig. 2 Effect of the rs355022 single nucleotide polymorphism (SNP) of podoplanin on transcriptional activity. (A) Reporter gene constructs. Three concatenated oligonucleotides of the rs355022 T or C SNP allele were inserted into a pGL3-SV40 promoter vector. (B) The relative luciferase activity of the p3X1562C construct is presented as the ratio to that of the p3X1562T construct. The experiment was repeated three times in duplicate. HEK293 cells were used for transfection.

Reference

1. Bieber T. Atopic dermatitis. Ann Dermatol. 2010; 22:125–137.

2. Shi VY, Bao L, Chan LS. Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model. Microcirculation. 2012; 19:567–579.

3. Genovese A, Detoraki A, Granata F, Galdiero MR, Spadaro G, Marone G. Angiogenesis, lymphangiogenesis and atopic dermatitis. Chem Immunol Allergy. 2012; 96:50–60.

4. Durchdewald M, Guinea-Viniegra J, Haag D, Riehl A, Lichter P, Hahn M, et al. Podoplanin is a novel fos target gene in skin carcinogenesis. Cancer Res. 2008; 68:6877–6883.

5. Honma M, Minami-Hori M, Takahashi H, Iizuka H. Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22. J Dermatol Sci. 2012; 65:134–140.

6. Gröger M, Niederleithner H, Kerjaschki D, Petzelbauer P. A previously unknown dermal blood vessel phenotype in skin inflammation. J Invest Dermatol. 2007; 127:2893–2900.

7. Henno A, Blacher S, Lambert CA, Deroanne C, Noël A, Lapière C, et al. Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: an approach of vascular development chronology in psoriasis. J Dermatol Sci. 2010; 57:162–169.

8. Lee JH, Cho EY, Namkung JH, Kim E, Kim S, Shin ES, et al. Single-nucleotide polymorphisms and haplotypes in the VEGF receptor 3 gene and the haplotype GC in the VEGFA gene are associated with psoriasis in Koreans. J Invest Dermatol. 2008; 128:1599–1603.

9. Namkung JH, Lee JE, Kim E, Huh IS, Park T, Shin ES, et al. Single nucleotide polymorphism in the FLT4 gene is associated with atopic dermatitis in Koreans. Cytokine. 2013; 62:110–114.

10. Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH, et al. Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR. Clin Exp Allergy. 2003; 33:1717–1724.

11. Rho NK, Kim WS, Lee DY, Lee JH, Lee ES, Yang JM. Immunophenotyping of inflammatory cells in lesional skin of the extrinsic and intrinsic types of atopic dermatitis. Br J Dermatol. 2004; 151:119–125.

12. Kim HK, Jang TW, Jung MH, Park HW, Lee JE, Shin ES, et al. Association between genetic variations of the transforming growth factor β receptor type III and asthma in a Korean population. Exp Mol Med. 2010; 42:420–427.

13. Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet. 2004; 74:106–120.

14. Bell PA, Chaturvedi S, Gelfand CA, Huang CY, Kochersperger M, Kopla R, et al. SNPstream UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques. 2002; Suppl. 70–72. 7476–77.

15. Denomme GA, Van Oene M. High-throughput multiplex single-nucleotide polymorphism analysis for red cell and platelet antigen genotypes. Transfusion. 2005; 45:660–666.

16. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002; 70:425–434.

17. Lake SL, Lyon H, Tantisira K, Silverman EK, Weiss ST, Laird NM, et al. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered. 2003; 55:56–65.

18. Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol. 2009; 129:543–552.

19. Esparza-Gordillo J, Weidinger S, Fölster-Holst R, Bauerfeind A, Ruschendorf F, Patone G, et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet. 2009; 41:596–601.

20. Sun LD, Xiao FL, Li Y, Zhou WM, Tang HY, Tang XF, et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet. 2011; 43:690–694.

21. Paternoster L, Standl M, Chen CM, Ramasamy A, Bønnelykke K, Duijts L, et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet. 2011; 44:187–192.

22. Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Sakashita M, et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet. 2012; 44:1222–1226.

23. Kim HT, Lee JY, Han BG, Kimm K, Oh B, Shin HD, et al. Association analysis of sphingomyelinase 2 polymorphisms for the extrinsic type of atopic dermatitis in Koreans. J Dermatol Sci. 2007; 46:143–146.

24. Kim E, Lee JE, Namkung JH, Park JH, Kim S, Shin ES, et al. Association of the single-nucleotide polymorphism and haplotype of the interleukin 18 gene with atopic dermatitis in Koreans. Clin Exp Allergy. 2007; 37:865–871.

25. Namkung JH, Lee JE, Kim E, Cho HJ, Kim S, Shin ES, et al. IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in Koreans. Allergy. 2007; 62:934–942.

26. Kim E, Lee JE, Namkung JH, Kim PS, Kim S, Shin ES, et al. Single nucleotide polymorphisms and the haplotype in the DEFB1 gene are associated with atopic dermatitis in a Korean population. J Dermatol Sci. 2009; 54:25–30.

27. Namkung JH, Lee JE, Kim E, Kim S, Kim S, Shin ES, et al. Association of single nucleotide polymorphisms in the IL-12 (IL-12A and B) and IL-12 receptor (IL-12Rbeta1 and beta2) genes and gene-gene interactions with atopic dermatitis in Koreans. J Dermatol Sci. 2010; 57:199–206.

28. Namkung JH, Lee JE, Kim E, Byun JY, Kim S, Shin ES, et al. Hint for association of single nucleotide polymorphisms and haplotype in SPINK5 gene with atopic dermatitis in Koreans. Exp Dermatol. 2010; 19:1048–1053.

29. Namkung JH, Lee JE, Kim E, Park GT, Yang HS, Jang HY, et al. An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population. J Dermatol Sci. 2011; 62:16–21.

30. Namkung JH, Lee JE, Kim E, Kim HJ, Seo EY, Jang HY, et al. Association of polymorphisms in genes encoding IL-4, IL-13 and their receptors with atopic dermatitis in a Korean population. Exp Dermatol. 2011; 20:915–919.

31. Park MK, Kim HK, Lee JW, Yoo KH, Park KY, Seo SJ, et al. Identification of filaggrin gene polymorphisms in Korean atopic dermatitis patients. Korean J Dermatol. 2010; 62:Suppl 2. 151–152.

32. Park KY, Park MK, Kim EJ, Lee MK, Seo SJ. FCεRI gene promoter polymorphisms and total IgE levels in susceptibility to atopic dermatitis in Korea. J Korean Med Sci. 2011; 26:870–874.

33. Shin HD, Park BL, Kim LH, Kim JS, Kim JW. Interleukin-10 haplotype associated with total serum IgE in atopic dermatitis patients. Allergy. 2005; 60:1146–1151.