Atopic dermatitis (AD) is a chronic inflammatory skin disorder with a doubled or tripled increasing prevalence during the past three decades in industrialized countries; 15–30% of children and 2–10% of adults are affected [
1
, 2
]. The clinical phenotype of AD is complex and the disease pathogenesis remains unclear so far [[3]
].Our previous GWAS provided confidential association evidence for rs7701890 within 5q22.1, rs2393903 within 10q21.2, rs6010620 within 20q13.33 [
[4]
]. In the present study, the association of these SNPs with subphenotype of AD was investigated.Study subjects were selected from our previous AD GWAS in the Chinese Han population from hospitals located in multiple cities in central and northern China [
[4]
]. Generally, 4538 cases and 13,412 controls being available for detailed clinical information in terms of gender, age, age onset, family history, concomitant diseases (asthma and allergic rhinitis) and disease severity were used in this study. All the samples were recruited with written consent. The study was approved by the Institutional Ethical Committee of Anhui Medical University and was conducted according to the Declaration of Helsinki principles.We compared the genotype distribution of rs7701890, rs2393903 and rs6010620 between cases and controls by using Chi squared test on 2 × 2 contingency table (Table 1). When the AA genotype was used as the reference for rs7701890, rs2393903 and rs6010620, for SNP rs7701890 (PGA = 2.00E−07, OR = 1.23); for SNP rs2393903 (PGG+GA = 1.21E−12, OR = 1.40); for SNP rs6010620 (PGG = 1.83E−07, OR = 1.40).
Table 1Distribution of genotypes of SNP rs2393903, rs6010620 and rs7701890 in patients and controls.
| SNP ID | Genotype | Cases (%) | Controls (%) | Pvalue | OR(95%CI) |
|---|---|---|---|---|---|
| rs2393903 | AA | 1105(25.1%) | 2481(29.4%) | NA | 1 |
| GA | 2235(50.7%) | 4196(49.8%) | 6.09E−05 | 1.20(1.10–1.30) | |
| GG | 1070(24.2%) | 1750(20.8%) | 2.21E−09 | 1.37(1.24–1.52) | |
| GA + GG | 3305(74.9%) | 5496(70.6%) | 1.21E−12 | 1.40(1.24–1.47) | |
| rs6010620 | AA | 2274(50.4%) | 7155(54.4%) | NA | 1 |
| GA | 1828(40.5%) | 5065(38.5%) | 4.73E−04 | 1.14(1.06–1.22) | |
| GG | 412(9.1%) | 930(7.1%) | 1.83E−07 | 1.40(1.23–1.58) | |
| GA + GG | 2240(49.6%) | 5995(45.6%) | 2.76E−06 | 1.175(1.10–1.26) | |
| rs7701890 | AA | 3246(71.6%) | 9749(75.6%) | NA | 1 |
| GA | 1194(26.3%) | 2915(22.6%) | 2.00E−07 | 1.23(1.14–1.33) | |
| GG | 95(2.1%) | 232(1.8%) | 9.30E−02 | 1.22(0.97–1.59) | |
| GA + GG | 1289(28.4%) | 3147(24.4%) | 2.76E−06 | 1.18(1.14–1.33) | |
For rs2393903, “Pvalue = 1.19E−08″ for genotype using a 3 × 2 contingency table.
For rs6010620, “Pvalue = 9.71E−08″ for genotype using a 3 × 2 contingency table.
For rs7701890, “Pvalue = 6.21E−07″ for genotype using a 3 × 2 contingency table.
We also observed SNPs rs2393903 and rs6010620 showed significant protective effect on clinical types of AD (Table 2) (AD with and without asthma for SNP rs2393903 Pgenotype = 0.02, PBonferroni = 0.012; OR = 0.73; familial and sporadic AD for SNP rs6010620 Pgenotype = 0.01, PBonferroni = 0.006; OR = 0.60). However, SNP rs7701890 showed no either risk or protective effect on any investigated subphenotype of AD in the current study (data no shown). There was also no other statistical significant association for any other clinical features of AD in terms of patients with and without allergic rhinitis, disease severity and family history atopic disease of asthma, allergic rhinitis and AD for SNPs rs2393903 and rs6010620 (PBonferroni > 0.05) (Table 2).
Table 2Distribution of genotypes of rs2393903 and rs6010620 polymorphisms in clinical features of AD.
| Phenotype | Genotype | Pvalue | Combined genotypes | Pcombined | OR(95%CI) | |||
|---|---|---|---|---|---|---|---|---|
| AA (%) | GA (%) | GG (%) | AA (%) | GA + GG (%) | ||||
| rs2393903 | ||||||||
| Family history of atopic disease | ||||||||
| AD positive | 174(25.1%) | 325(47.0%) | 193(27.9%) | 0.04 | 174(25.1%) | 499(74.9%) | 0.02 | 1.24(1.03–1.49) |
| AD negative | 909(24.8%) | 1880(51.4%) | 869(23.8%) | 909(24.8%) | 2789(75.2%) | |||
| Asthma positive | 149(21.0%) | 383(54.0%) | 177(25.0%) | 0.03 | 149(21.0%) | 532(79.0%) | 0.70 | 1.04(0.86–1.25) |
| Asthma negative | 936(25.7%) | 1822(50.0%) | 885(24.3%) | 936(25.7%) | 2758(74.3%) | |||
| Allergic rhinitis positive | 512(24.9%) | 1032(50.2%) | 512(24.9%) | 0.75 | 512(24.9%) | 1544(75.1%) | 0.47 | 1.05(0.92–1.21) |
| Allergic rhinitis negative | 573(25.0%) | 1173(51.1%) | 550(23.9%) | 573(25.0%) | 1746(75.0%) | |||
| Disease severity | ||||||||
| Mild 0–14 | 212(24.5%) | 427(49.2%) | 228(26.3%) | 0.49 | 212(24.5%) | 639(75.5%) | 0.31 | |
| Moderate 15–40 | 721(24.8%) | 1490(51.3%) | 691(23.9%) | 721(24.8%) | 2211(75.2%) | |||
| Severity > 40 | 168(26.7%) | 311(49.4%) | 150(23.8%) | 168(26.7%) | 482(73.2%) | |||
| AD with asthma | 157(26.1%) | 325(54.1%) | 119(19.8%) | 0.02 | 157(26.1%) | 482(73.9%) | 0.004 | 0.73(0.59–0.91) |
| AD without asthma | 924(24.7%) | 1874(50.1%) | 941(25.2%) | 924(24.7%) | 2798(75.3%) | |||
| AD with allergic rhinitis | 337(23.5%) | 746(52.1%) | 349(24.4%) | 0.29 | 337(23.5%) | 1083(76.5%) | 0.93 | 0.99(0.86–1.15) |
| AD without allergic rhinitis | 743(25.6%) | 1452(49.9%) | 712(24.5%) | 743(25.6%) | 2195(74.4%) | |||
| rs6010620 | ||||||||
| Family history of atopic disease | ||||||||
| AD positive | 368(51.9%) | 298(42.0%) | 43(6.1%) | 0.01 | 368(51.9%) | 666(48.1%) | 0.002 | 0.60(0.43–0.83) |
| AD negative | 1874(50.0%) | 1508(40.3%) | 363(9.7%) | 1874(50.0%) | 3382(50.0%) | |||
| Asthma positive | 357(50.0%) | 288(40.3%) | 69(9.7%) | 0.87 | 357(50.0%) | 645(50.0%) | 0.59 | 1.08(0.82–1.41) |
| Asthma negative | 1886(50.4%) | 1518(40.6%) | 338(9.0%) | 1886(50.4%) | 3404(49.6%) | |||
| Allergic rhinitis positive | 1040(49.4%) | 863(40.9%) | 204(9.7%) | 0.35 | 1040(49.4%) | 1903(50.6%) | 0.25 | 1.13(0.92–1.38) |
| Allergic rhinitis negative | 1202(51.2%) | 943(40.1%) | 204(8.7%) | 1202(51.2%) | 2145(48.8%) | |||
| Disease severity | ||||||||
| Mild 0–14 | 452(51.1%) | 347(39.3%) | 85(9.6%) | 0.91 | 452(51.1%) | 799(48.9%) | 0.81 | |
| Moderate 15–40 | 1495(50.3%) | 1207(40.6%) | 270(9.1%) | 1495(50.3%) | 2702(49.7%) | |||
| Severity > 40 | 323(49.9%) | 268(41.4%) | 56(8.7%) | 323(49.9%) | 591(50.1%) | |||
| AD with asthma | 303(49.0%) | 267(43.1%) | 49(7.9%) | 0.26 | 303(49.0%) | 570(51.0%) | 0.24 | 0.83(0.61–1.13) |
| AD without asthma | 1932(50.5%) | 1533(40.1%) | 359(9.4%) | 1932(50.5%) | 3465(49.5%) | |||
| AD with allergic rhinitis | 728(49.7%) | 600(40.9%) | 138(9.4%) | 0.82 | 728(49.7%) | 1328(50.3%) | 0.71 | 1.04(0.84–1.29) |
| AD without allergic rhinitis | 1506(50.6%) | 1200(40.3%) | 270(9.1%) | 1506(50.6%) | 2706(49.4%) | |||
Bold values indicate Pvalue < 0.05/2 = 0.025.
* Pvalue for genotype using a 3 × 2 contingency table.
This study might help to investigate whether there are phenotype specific genetic factors for AD, which should give us new insights into the etiology and pathogenesis of AD. Currently, few relationships between AD subphenotypes and individual risk alleles have been reported such as association of the toll-like receptor 2 A-16934T promoter polymorphism with severe AD [
[5]
], filaggrin polymorphism P478S conferring susceptibility to the development of AD and modified by IgE levels [[6]
]. These studies implied that AD is an extremely heterogeneous disease and will advance our understanding on the etiology of AD.In the current study, we found that 10q21.2 (rs2393903 is located in intron of ZNF365) and 20q13.33 (rs6010620 is located in intron of RTEL1) showed protective effect for AD without asthma and sporadic AD, respectively. At 10q21.2, the association signal refers to a single gene ZNF365, which encodes the zinc finger protein 365. Disruption of normal ZNF365 function causes mitotic failure, possibly because of centrosome defects or incomplete cytokinesis. ZNF365 has also been associated with Crohn's disease [
[7]
]. Thus, our results strengthen the hypothesis of joint barrier disease genes and further functional study on ZNF365 will help us to explore its potential role in the pathogenesis of AD without asthma.At 20q13.33, multiple genes were implicated. Expression quantitative trait loci analysis suggested that the risk-associated SNP rs6010620 might be associated with TNFRSF6B and ZGPAT expression (P = 0.024 and P = 0.039, respectively) [
[4]
]. TNFRSF6B has a critical role in adaptive immune responses, which acts on T-cell, dendritic cell and macrophage responses. ZGPAT is involved in the epidermal growth factor receptor (EGFR) pathway [[8]
]. EGFR is overexpressed in lesional skin of individuals with AD, and blocking EGFR induces dysregulated chemokine expression in keratinocytes and leads to enhanced skin inflammation [[9]
]. Taken together, these results indicate that TNFRSF6B and ZGPAT are plausible candidate genes for AD and therefore predispose to sporadic AD. However, further studies will be required to investigate their underlying role in the development of sporadic AD.In summary, our study not only implied that AD is an extremely heterogeneous disease with various features, but also indicated that 10q21.2 and 20q13.33 showed protective effect on AD without asthma and sporadic AD. It further suggested that these two loci might contribute to different subphenotypes of AD and showed that complex genetic factors are involved in the disease mechanisms. Therefore, understanding the relationships between AD genotype and phenotype of the disease might help to further elucidate the pathogenesis of AD and seek better clinical evaluation and therapy.
Acknowledgements
This study was funded by General Program of National Natural Science Foundation of China (31171224, 31000528), Program for New Century Excellent Talents in University (NCET-11-0889), Science and Technological Foundation of Anhui Province for Outstanding Youth (1108085J10) and Pre-project of State Key Basic Research Program 973 of China (No. 2012CB722404). We thank all study participants and all the volunteers who have so willingly participated in this study, thus make this study possible.
References
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- How epidemiology has challenged 3 prevailing concepts about atopic dermatitis.J Allergy Clin Immunol. 2006; 118: 209-213
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- Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.Nat Genet. 2011; 43: 690-694
- Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis.Allergy. 2009; 64: 1608-1615
- Filaggrin polymorphism P478S, IgE level, and atopic phenotypes.Br J Dermatol. 2011; 164: 791-796
- Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.Nat Genet. 2008; 40: 955-962
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Article info
Publication history
Published online: July 08, 2013
Received:
July 20,
2012
Identification
Copyright
© 2013 Published by Elsevier Inc.
