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Association analysis of allergic sensitization susceptibility loci with atopic dermatitis in Chinese population

  • Author Footnotes
    1 These authors contributed equally to this study.
    Jinping Gao
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Yuemei Ma
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Allergy and Department of Dermatology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Yujun Sheng
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Xianbo Zuo
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Wenjun Wang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Xiaodong Zheng
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Huayang Tang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Xianfa Tang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Fusheng Zhou
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Sen Yang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Xuejun Zhang
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Liangdan Sun
    Correspondence
    Corresponding author at: Institute of Dermatology & Department of Dermatology, the First Affiliated Hospital in Anhui Medical University, Hefei 230032, China.
    Affiliations
    Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China

    State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, Anhui 230032, China
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  • Author Footnotes
    1 These authors contributed equally to this study.
Published:September 28, 2015DOI:https://doi.org/10.1016/j.jdermsci.2015.09.009

      Abbreviations:

      AD (atopic dermatitis), GWAS (genome-wide association study), OR (odds ratio), CI (confidence interval), SCORAD (scoring of atopic dermatitis), C11orf30 (chromosome 11 open reading frame 30), SLC25A46 (solute carrier family 25 member 46)

      Keywords

      Atopic dermatitis is a chronically recurrent disorder involving disturbed skin barrier functions with inflammatory hypersensitivity. It was often accompanied with other atopic manifestations, elevated serum immunoglobulin E [
      • Bieber T.
      Atopic dermatitis.
      ]. The prevalence was about 10–20% in children and 1–3% in adults [
      • Niebuhr M.
      • Werfel T.
      Innate immunity, allergy and atopic dermatitis.
      ]. The etiology has not been fully elucidated which combined with genetic and environmental factors. Previous genetic studies had identified amount of susceptibility genes/loci that associated with AD [
      • Tamari M.
      • Hirota T.
      Genome-wide association studies of atopic dermatitis.
      ]. However, these findings did not fully explain the risk of AD, suggesting additional genetic factors remain need to be discovered. Recent meta-analysis had established several susceptibility loci for allergic sensitization [
      • Bonnelykke K.
      • Matheson M.C.
      • Pers T.H.
      • Granell R.
      • Strachan D.P.
      • Alves A.C.
      • et al.
      Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.
      ]. Due to the similar features between allergic sensitization and AD, they may share common genetic components in the etiology of these two diseases. In order to identify the overlapping susceptibility loci and enhance understanding their relationship, we performed the association analysis of allergic sensitization related loci with AD in Chinese population.
      A total of 2205 cases (1359 men and 846 women, mean age of 4.10 ± 1.41) and 2208 controls (1162 men and 1046 women, mean age of 25.01 ± 15.23) were enrolled. The diagnosis of AD according to standard criteria [
      • Brenninkmeijer E.E.
      • Schram M.E.
      • Leeflang M.M.
      • Bos J.D.
      • Spuls P.I.
      Diagnostic criteria for atopic dermatitis: a systematic review.
      ], demographic and clinical information, such as accompanying symptoms, serum IgE level, age of onset, SCORAD and family history were collected. The study was approved by the Ethical Committee and was conducted according to Declaration of Helsinki principles. We selected 8 SNPs (Table 1) in non-HLA region which reached the genome-wide significance threshold of P ≤ 5 × 10−8 [
      • Bonnelykke K.
      • Matheson M.C.
      • Pers T.H.
      • Granell R.
      • Strachan D.P.
      • Alves A.C.
      • et al.
      Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.
      ], and genotyped by Sequenom Mass Array system. P-values, ORs and 95% CIs were estimated using PLINK 1.07 software. The level of associated significance was assigned at P < 0.006 (0.05/8) after Bonferroni correction. The genetic statistical power for SNPs was estimated using CaTS-Power Calculator.
      Table 1The results of 8 SNPs replicated in Han Chinese AD cases and controls.
      SNPChrAllelesNearest geneMAFP valueOR (95% CI)Statistical power
      ControlsCase
      rs100563405q22.1G/TSLC25A460.1440.1663.00E-031.188 (1.058-1.335)89%
      rs215521911q13.5G/TC11orf300.440.4094.00E-030.884 (0.812-0.962)79%
      rs174545844q27G/AIL2/ADAD10.120.1311.08E-011.110 (0.978-1.260)27%
      rs98658183q28G/ALPP0.2970.3111.56E-011.068 (0.975-1.170)17%
      rs44108718q24.21T/CMYC/PVT10.3430.3562.29E-011.055 (0.967-1.152)11%
      rs105951312q13.3G/ASTAT60.0740.074.67E-010.941 (0.800-1.108)3%
      rs176164344p14T/CTLR1/6/100.3530.3596.14E-011.023 (0.937-1.116)2%
      rs37711752q12.1A/TIL1RL1/IL18R10.0860.0879.61E-010.996 (0.859-1.156)1%
      We only found rs10056340 (P= 0.003, OR = 1.19) and rs2155219 (P= 0.004, OR = 0.88) significantly associated with AD (Table 1). For rs10056340, risk allele G was the minor allele in Han population, which was higher in AD than controls (16.6% vs. 14.4%). Compared to the additive model (P= 0.006, OR = 1.12), the dominant model provided best fit for rs10056340 associated with AD in genetic model analysis (P= 0.002, OR = 1.24) (Table A.1). OR of the G allele for rs2155219 was 0.88 (95% CI: 0.81–0.96), which suggested a protective effect relative to the T allele with regards to susceptibility to AD. Genetic model analysis showed rs2155219 was suited to the additive model (P= 0.004) compared to the recessive and dominant model (Table A.1) in AD. When TT genotype was used as reference, the combined genotype GG + GT were associated with a higher risk of AD (Table A.1). The other 6 SNPs did not reached the statistical significance, which might result from low statistical power (1 ∼ 27%) (Table 1).
      We also performed a stratified analysis to determine which subtype of AD was associated with these two SNPs. For rs10056340, there was no significant results for each of the subtype of AD in case-only analysis, except for the genotype test showed a marginally association with age onset (P = 0.057) (Table A.2). The risk allele of rs10056340 SNP was significantly associated with early age onset of disease, high SCORAD and with xeroderma syndrome (Table A.2). However, as for the rs2155219, there was a potential difference between the high and low IgE level in the case only analysis (P = 0.035) (Table 2). Besides, SNP rs2155219 was significantly associated with high and low level of IgE phenotypes in sub-phenotype-control analyses.
      Table 2Associations between rs2155219 and AD in subphenotype control- and case-only analyses.
      GenotypePgenotype valueAllelePsubgroup vs controlsCombined genotypesPcombined valueOR (95% CI)
      TTGTGGTGTTGG+GT
      Age at onset
      ≤1 years655(34.6)933(49.2)307(16.2)4.22E-012243(59.2)1547(40.8)5.00E-03655(34.6)1240(65.4)6.70E-010.95(0.73-1.23)
      >1 years104(35.9)132(45.5)54(18.6)340(58.6)240(41.4)2.50E-01104(35.9)186(64.1)
      AD with diseases
      Yes323(36.0)426(47.4)149(16.6)5.98E-011072(59.7)724(40.3)8.00E-03323(36.0)575(64.0)3.70E-011.09(0.98-1.30)
      No423(34.1)615(49.6)203(16.4)1461(58.9)1021(41.1)2.50E-02423(34.1)818(65.9)
      IgE level
      High115(40.1)137(47.7)35(12.2)3.50E-02367(63.9)207(36.1)1.00E-04115(40.1)172(59.9)4.00E-021.31(1.01-1.68)
      Low635(33.9)915(48.8)324(17.3)2185(58.3)1563(41.7)3.00E-02635(33.9)1239(66.1)
      AD with xeroderma
      Yes550(34.3)780(48.7)273(17.0)7.20E-011880(58.2)1348(41.8)2.60E-02550(34.3)1053(65.7)5.70E-010.94(0.77-1.16)
      No189(35.7)258(48.7)83(15.7)636(60.0)424(40.0)1.00E-02189(35.7)341(64.3)
      SCORAD
      <25149(32.8)224(49.3)81(17.8)2.70E-01522(57.5)386(42.5)5.80E-01149(32.8)305(67.2)3.00E-010.89(0.71-1.11)
      ≥25581(35.4)794(48.4)264(16.1)1956(59.7)1322(40.3)1.60E-03581(35.4)1058(64.6)
      Familial history
      Positive87(32.8)128(48.3)50(18.9)4.67E-01302(57.0)228(43.0)6.40E-0187(32.8)178(67.2)6.20E-010.93(0.71-1.23)
      Negative672(34.4)973(49.7)311(15.9)2317(59.2)1595(40.8)2.40E-03672(34.4)1284(65.6)
      AD with Keratosis pilaris
      Yes111(38.7)133(46.3)43(15.0)2.95E-01355(61.8)219(38.2)7.30E-03111(38.7)176(61.3)1.30E-011.22(0.94-1.58)
      No620(34.1)890(48.9)309(17.0)2130(58.5)1508(41.5)2.60E-02620(34.1)1199(65.9)
      AD with ichthyosis
      Yes97(30.7)164(51.9)55(17.4)2.57E-01358(56.6)274(43.4)7.50E-0197(30.7)219(69.3)1.00E-010.81(0.62-1.04)
      No635(35.5)859(48.0)297(16.6)2129(59.4)1453(40.6)2.60E-03635(35.5)1156(64.5)
      AD with Palm disease
      Yes171(38.4)204(45.8)70(15.7)1.84E-01546(61.3)344(38.7)3.30E-03171(38.4)274(61.6)6.60E-021.22(0.99-1.52)
      No561(33.8)819(49.3)282(17.0)1941(58.4)1383(41.6)4.30E-02561(33.8)1101(66.2)
      The main effort is to reveal shared susceptibility loci between these two diseases in Chinese population, an alternative approach is to take susceptibility loci of closely related physiological mechanism phenotype to replicate in AD. Through this method, we confirmed that rs2155219 at 11q13.5 and rs10056340 at 5q22.1 were the overlapping susceptibility loci in AD and allergic sensitization. Both of these two SNPs were not contained in our GWAS data of AD. Although the 11q13.5 locus has been identified in allergic sensitization and atopic disease [
      • Esparza-Gordillo J.
      • Weidinger S.
      • Folster-Holst R.
      • Bauerfeind A.
      • Ruschendorf F.
      • Patone G.
      • et al.
      A common variant on chromosome 11q13 is associated with atopic dermatitis.
      ,
      • Ramasamy A.
      • Curjuric I.
      • Coin L.J.
      • Kumar A.
      • McArdle W.L.
      • Imboden M.
      • et al.
      A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order.
      ], it was first confirmed in Chinese population. In previous study [
      • 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.
      ], we identified SNP rs7936562 at 11q13.5 (Pcombined = 2.98 × 10−4, OR = 0.91) only with suggestive evidence. The SNP rs2155219 (P = 0.004 after correction) showed moderate correlated with rs7936562 (D′ = 0.86, r2 = 0.58), which further support the role of 11q13.5 in AD. In 5q22.1 region, although SNP rs10056340 was only weakly correlated with the 4 SNPs in Chinese population (D′ = 0.69, r2 = 0.30 for rs7701890; D′ = 0.70, r2 = 0.28 for rs10067777; D′ = 0.73, r2 = 0.34 for rs13360927; D′ = 0.73, r2 = 0.34 for rs13361382 based HapMap data in CHB), we could not be sure whether this SNP represented independent risk variant associated with AD in current findings. Bioinformatics analysis of rs10056340 by HaploReg v3 showed that this SNP was located within a strong enhancer in epidermal keratinocytes. Continue in-depth studies are warranted to investigate whether there are multiple independent risk variants within 5q22.1 region.
      For rs2155219, located at 35 kb 3′ of C11orf30 gene which regulated chromatin states in endothelial cells, B-lymphocyte, lung fibroblasts and encoded the EMSY protein, bind the epithelium-derived cancer [
      • Hughes-Davies L.
      • Huntsman D.
      • Ruas M.
      • Fuks F.
      • Bye J.
      • Chin S.F.
      • et al.
      EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.
      ]. The potential involvement of C11orf30 in multiple inflammatory and malignant epithelial diseases strongly suggests its role in epithelial immunity, growth or differentiation. SNP rs10056340, located at 89 kb of SLC25A46 gene at 5q22.1, regulated chromatin states in epithelial cells and epidermal keratinocytes, and encoded mitochondrial carrier proteins [
      • Palmieri F.
      The mitochondrial transporter family (SLC25): physiological and pathological implications.
      ]. Genotype–phenotype analysis help to clarify whether these 2 loci were associated with specific disease sub-phenotypes. Our findings only indicated that the level of IgE might be related to rs2155219 at 11q13.5, and its biological implications might be involved in generating different AD phenotypes. In conclusion, the 11q13.5 and 5q22.1 have pleiotropic effects of importance in the development of allergic related diseases, which shared between these two disease in Han Chinese population. Further fine mapping and gene functional studies are warranted to identify and characterize the causal gene(s) within these loci.

      Conflict of interest

      The authors declare no conflict of interests.

      Acknowledgements

      We thank the individuals and their families who participated in this project. This study was funded by the key Program of National Natural Science Foundation of China (31171224, 81172838), Youth Project (81222022) of National Natural Science Foundation of China and Natural Science Foundation of Anhui Province (1508085JGD05).
      URLs. CaTS-Power Calculator, <http://csg.sph.umich.edu//abecasis/CaTS/>.

      Appendix A. Supplementary data

      The following are Supplementary data to this article:

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