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Genetic variants rs2393903 at 10q21.2 and rs6010620 at 20q13.33 are associated with clinical features of atopic dermatitis in the Chinese Han population

  • Author Footnotes
    1 These authors contributed equally to this work.
    Ping Li
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Baoyu Wu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Birong Guo
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Xin Zhang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Yang Li
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Hui Cheng
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Yantao Ding
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Jianbo Wang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Xianbo Zuo
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Xiangfeng Yuan
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Fangfang Qian
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Yujuan Zhai
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Jing Wang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Liangdan Sun
    Correspondence
    Corresponding authors at: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Sen Yang
    Correspondence
    Corresponding authors at: Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
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  • Xuejun Zhang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China

    Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, Anhui, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
      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 [
      • Taylor B.
      • Wadsworth J.
      • Wadsworth M.
      • Peckham C.
      Changes in the reported prevalence of childhood eczema since the 1939–45 war.
      ,
      • Williams H.
      • Flohr C.
      How epidemiology has challenged 3 prevailing concepts about atopic dermatitis.
      ]. The clinical phenotype of AD is complex and the disease pathogenesis remains unclear so far [
      • Williams H.
      • Stewart A.
      • von Mutius E.
      • Cookson W.
      • Anderson H.R.
      Is eczema really on the increase worldwide?.
      ].
      Our previous GWAS provided confidential association evidence for rs7701890 within 5q22.1, rs2393903 within 10q21.2, rs6010620 within 20q13.33 [
      • Sun L.D.
      • Xiao F.L.
      • Li Y.
      • Zhou W.M.
      • Tang H.Y.
      • Tang X.F.
      • et al.
      Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.
      ]. 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 [
      • Sun L.D.
      • Xiao F.L.
      • Li Y.
      • Zhou W.M.
      • Tang H.Y.
      • Tang X.F.
      • et al.
      Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.
      ]. 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 IDGenotypeCases (%)Controls (%)PvalueOR(95%CI)
      rs2393903AA1105(25.1%)2481(29.4%)NA1
      GA2235(50.7%)4196(49.8%)6.09E−051.20(1.10–1.30)
      GG1070(24.2%)1750(20.8%)2.21E−091.37(1.24–1.52)
      GA + GG3305(74.9%)5496(70.6%)1.21E−121.40(1.24–1.47)
      rs6010620AA2274(50.4%)7155(54.4%)NA1
      GA1828(40.5%)5065(38.5%)4.73E−041.14(1.06–1.22)
      GG412(9.1%)930(7.1%)1.83E−071.40(1.23–1.58)
      GA + GG2240(49.6%)5995(45.6%)2.76E−061.175(1.10–1.26)
      rs7701890AA3246(71.6%)9749(75.6%)NA1
      GA1194(26.3%)2915(22.6%)2.00E−071.23(1.14–1.33)
      GG95(2.1%)232(1.8%)9.30E−021.22(0.97–1.59)
      GA + GG1289(28.4%)3147(24.4%)2.76E−061.18(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.
      PhenotypeGenotypePvalue
      Pvalue for genotype using a 3×2 contingency table.
      Combined genotypesPcombinedOR(95%CI)
      AA (%)GA (%)GG (%)AA (%)GA + GG (%)
      rs2393903
      Family history of atopic disease
       AD positive174(25.1%)325(47.0%)193(27.9%)0.04174(25.1%)499(74.9%)0.021.24(1.03–1.49)
       AD negative909(24.8%)1880(51.4%)869(23.8%)909(24.8%)2789(75.2%)
       Asthma positive149(21.0%)383(54.0%)177(25.0%)0.03149(21.0%)532(79.0%)0.701.04(0.86–1.25)
       Asthma negative936(25.7%)1822(50.0%)885(24.3%)936(25.7%)2758(74.3%)
       Allergic rhinitis positive512(24.9%)1032(50.2%)512(24.9%)0.75512(24.9%)1544(75.1%)0.471.05(0.92–1.21)
       Allergic rhinitis negative573(25.0%)1173(51.1%)550(23.9%)573(25.0%)1746(75.0%)
      Disease severity
       Mild 0–14212(24.5%)427(49.2%)228(26.3%)0.49212(24.5%)639(75.5%)0.31
       Moderate 15–40721(24.8%)1490(51.3%)691(23.9%)721(24.8%)2211(75.2%)
       Severity > 40168(26.7%)311(49.4%)150(23.8%)168(26.7%)482(73.2%)
      AD with asthma157(26.1%)325(54.1%)119(19.8%)0.02157(26.1%)482(73.9%)0.0040.73(0.59–0.91)
       AD without asthma924(24.7%)1874(50.1%)941(25.2%)924(24.7%)2798(75.3%)
       AD with allergic rhinitis337(23.5%)746(52.1%)349(24.4%)0.29337(23.5%)1083(76.5%)0.930.99(0.86–1.15)
       AD without allergic rhinitis743(25.6%)1452(49.9%)712(24.5%)743(25.6%)2195(74.4%)
      rs6010620
      Family history of atopic disease
      AD positive368(51.9%)298(42.0%)43(6.1%)0.01368(51.9%)666(48.1%)0.0020.60(0.43–0.83)
       AD negative1874(50.0%)1508(40.3%)363(9.7%)1874(50.0%)3382(50.0%)
       Asthma positive357(50.0%)288(40.3%)69(9.7%)0.87357(50.0%)645(50.0%)0.591.08(0.82–1.41)
       Asthma negative1886(50.4%)1518(40.6%)338(9.0%)1886(50.4%)3404(49.6%)
       Allergic rhinitis positive1040(49.4%)863(40.9%)204(9.7%)0.351040(49.4%)1903(50.6%)0.251.13(0.92–1.38)
       Allergic rhinitis negative1202(51.2%)943(40.1%)204(8.7%)1202(51.2%)2145(48.8%)
      Disease severity
       Mild 0–14452(51.1%)347(39.3%)85(9.6%)0.91452(51.1%)799(48.9%)0.81
       Moderate 15–401495(50.3%)1207(40.6%)270(9.1%)1495(50.3%)2702(49.7%)
       Severity > 40323(49.9%)268(41.4%)56(8.7%)323(49.9%)591(50.1%)
       AD with asthma303(49.0%)267(43.1%)49(7.9%)0.26303(49.0%)570(51.0%)0.240.83(0.61–1.13)
       AD without asthma1932(50.5%)1533(40.1%)359(9.4%)1932(50.5%)3465(49.5%)
       AD with allergic rhinitis728(49.7%)600(40.9%)138(9.4%)0.82728(49.7%)1328(50.3%)0.711.04(0.84–1.29)
       AD without allergic rhinitis1506(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 [
      • Oh D.Y.
      • Schumann R.R.
      • Hamann L.
      • Neumann K.
      • Worm M.
      • Heine G.
      Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis.
      ], filaggrin polymorphism P478S conferring susceptibility to the development of AD and modified by IgE levels [
      • Wang I.J.
      • Lin T.J.
      • Kuo C.F.
      • Lin S.L.
      • Lee Y.L.
      • Chen P.C.
      Filaggrin polymorphism P478S, IgE level, and atopic phenotypes.
      ]. 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 [
      • Barrett J.C.
      • Hansoul S.
      • Nicolae D.L.
      • Cho J.H.
      • Duerr R.H.
      • Rioux J.D.
      • et al.
      Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.
      ]. 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) [
      • Sun L.D.
      • Xiao F.L.
      • Li Y.
      • Zhou W.M.
      • Tang H.Y.
      • Tang X.F.
      • et al.
      Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.
      ]. 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 [
      • Li R.
      • Zhang H.
      • Yu W.
      • Chen Y.
      • Gui B.
      • Liang J.
      • et al.
      ZIP: a novel transcription repressor, represses EGFR oncogene and suppresses breast carcinogenesis.
      ]. 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 [
      • Mascia F.
      • Mariani V.
      • Girolomoni G.
      • Pastore S.
      Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation.
      ]. 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.

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