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The HLA-DQB1*03:01 Is Associated with Bullous Pemphigoid in the Han Chinese Population

  • Yonghu Sun
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Hong Liu
    Correspondence
    Corresponding author
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Zhenzhen Wang
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Xi’an Fu
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Chuan Wang
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Zihao Mi
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Lele Sun
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Fangfang Bao
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Gongqi Yu
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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  • Guizhi Zhou
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong, China
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  • Furen Zhang
    Correspondence
    Corresponding author
    Affiliations
    Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong, China

    Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China

    National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China
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Open ArchivePublished:February 26, 2018DOI:https://doi.org/10.1016/j.jid.2018.02.021

      Abbreviations:

      BP (bullous pemphigoid), OR (odds ratio)
      To the Editor
      Bullous pemphigoid (BP) is a potentially fatal subepidermal blistering autoimmune disease that characteristically affects elderly patients who present with large tense bullae on the entire skin and frequently on the extremities (
      • Nousari H.C.
      • Anhalt G.J.
      Pemphigus and bullous pemphigoid.
      ,
      • Sami N.
      • Yeh S.W.
      • Ahmed A.R.
      Blistering diseases in the elderly: diagnosis and treatment.
      ). Subepidermal blisters with inflammation are the hallmark of BP histology. Direct immunofluorescence of perilesional skin shows linear deposits of the C3 and IgG. Two hemidesmosomal antigens have been identified, one protein of approximately 230 kDa associated with the intracellular plaque (BPAG1, also known as BP230) (
      • Stanley J.R.
      • Hawley-Nelson P.
      • Yuspa S.H.
      • Shevach E.M.
      • Katz S.I.
      Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia.
      ), and the other protein of approximately 180 kDa associated with transmembrane glycoprotein (BPAG2, also known as BP180) (
      • Diaz L.A.
      • Ratrie 3rd, H.
      • Saunders W.S.
      • Futamura S.
      • Squiquera H.L.
      • Anhalt G.J.
      • et al.
      Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome.
      ). Antibodies against both BPAG1 and BPAG2, as measured by ELISA, have been used for the diagnosis of BP (
      • Roussel A.
      • Benichou J.
      • Randriamanantany Z.A.
      • Gilbert D.
      • Drenovska K.
      • Houivet E.
      • et al.
      Enzyme-linked immunosorbent assay for the combination of bullous pemphigoid antigens 1 and 2 in the diagnosis of bullous pemphigoid.
      ).
      Although the heritability has not been well understood, genetic studies have revealed that persons with certain HLA alleles have higher risk of specific autoimmune blistering disease than persons without these alleles. Currently, the genetic data of BP are sparse and inconsistent. Various association results were reported for BP in different studies, such as the association of DQB1*03:01 with BP in Caucasians (
      • Delgado J.C.
      • Turbay D.
      • Yunis E.J.
      • Yunis J.J.
      • Morton E.D.
      • Bhol K.
      • et al.
      A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid.
      ) and Iranians (
      • Esmaili N.
      • Mortazavi H.
      • Chams-Davatchi C.
      • Daneshpazhooh M.
      • Damavandi M.R.
      • Aryanian Z.
      • et al.
      Association between HLA-DQB1*03:01 and Bullous pemphigoid in Iranian patients.
      ), and the association of DQB1*03:02/DRB1*11:01/DRB1*04:03 in Japanese BP (
      • Okazaki A.
      • Miyagawa S.
      • Yamashina Y.
      • Kitamura W.
      • Shirai T.
      Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid.
      ). Associations between HLA-DQB1*0301 have been reported frequently for the clinical variants of BP, including mucous membrane pemphigoid of oral and ocular mucosae (
      • Chan L.S.
      • Hammerberg C.
      • Cooper K.D.
      Significantly increased occurrence of HLA-DQB1*0301 allele in patients with ocular cicatricial pemphigoid.
      ,
      • Setterfield J.
      • Theron J.
      • Vaughan R.W.
      • Welsh K.I.
      • Mallon E.
      • Wojnarowska F.
      • et al.
      Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production.
      ). In a recent genetic investigation of 25 Chinese BP patients and 57 controls (
      • Gao X.H.
      • Winsey S.
      • Li G.
      • Barnardo M.
      • Zhu X.J.
      • Chen H.D.
      • et al.
      HLA-DR and DQ polymorphisms in bullous pemphigoid from northern China.
      ), only lower frequencies of DRB1*08 (DR8) and DRB1*08/DQB1*06 (DR8/DQ6) haplotypes were observed in BP patients compared to controls (P < 0.05), which suggested ethnic differences may influence the genetic susceptibility to BP. Furthermore, other studies have reported that DQB1*03:01 was restricted to a different phenotype, involving the response of CD4+ T cells to BPAG2 (
      • Büdinger L.
      • Borradori L.
      • Yee C.
      • Eming R.
      • Ferencik S.
      • Grosse-Wilde H.
      • et al.
      Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls.
      ), or was only associated with male BP patients (
      • Banfield C.C.
      • Wojnarowska F.
      • Allen J.
      • George S.
      • Venning V.A.
      • Welsh K.I.
      The association of HLA-DQ7 with bullous pemphigoid is restricted to men.
      ). Aiming to discover genetic risk factors for BP and to fine-map the associations within the extended major histocompatibility complex region, we conducted a genetic association analysis study by using a next-generation sequence-based HLA typing method in a sample of 575 pemphigoid patients and 976 healthy controls of Chinese descent.
      All of the BP cases were recruited from Shandong Provincial Institute of Dermatology and Venereology from 2006 to the present. The diagnosis of BP was based on the combination of clinical data and a predominantly subepidermal blistering picture, the linear deposition of IgG or C3 along the base membrane zone by direct immunofluorescence microscopy, and/or serological ELISA tests using commercially available BP180- and BP230-specific serological kits (Medical & Biological Laboratories, Nagoya, Japan). Direct immunofluorescence microscopy of salt split skin or seronegative results of circulating autoantibodies against type VII collagen by ELISA (Medical & Biological Laboratories) were employed to exclude the diagnosis of epidermolysis bullosa acquisita.
      Basic characteristics of all 575 BP patients are shown in Table 1. There were 327 (56.9%) male and 248 (43.1%) female patients. Mean age at onset of BP was 69 years, ranging from 0 to 97 years without gender bias. Three infant BP patients, who were less than 1 year old and reported as case series previously (
      • Yang B.
      • Wu M.
      • Yan X.
      • Bao F.
      • Yue Z.
      • Pei Z.
      • et al.
      Childhood bullous pemphigoid: a report of three cases in China.
      ), were also included in the study. The study was approved by the Institutional Review Board of Shandong Provincial Institute of Dermatology and Venereology and all the subjects or their parents gave written informed consent.
      Table 1Basic characteristics and histological features of all the bullous pemphigoid patients and controls
      CategoryPatientsControls
      Gender, n (%)
       Male327 (56.9)596 (61.1)
       Female248 (43.1)380 (38.9)
      Total, n575976
      Age, y, mean (range)
       Male68.9 (0–93)61.9 (23–82)
       Female69.0 (0–97)61.4 (22–91)
      All69.0 (0–97)61.7 (22–91)
      Antigen, n (%)
       BP180-positive465 (94.7)NA
       BP230-positive267 (54.4)NA
       BP180-positive and BP230-negative224 (45.6)NA
       BP230-positive and BP180-negative26 (5.3)NA
       BP180- and BP230-positive241 (49.1)NA
      Total, n491NA
      Histology, n (%)
       IgA352 (62.4)NA
       IgM188 (33.3)NA
       IgG379 (67.2)NA
       C3564 (100)NA
      Total, n564NA
      Combination of antibodies, n (%)
       C3-IgG-IgA-IgM168 (29.8)NA
       C3-IgG-IgA154 (27.3)NA
       C3-IgG-IgM7 (1.2)NA
       C3-IgA-IgM8 (1.4)NA
       C3-IgG50 (8.9)NA
       C3-IgA22 (3.9)NA
       C3-IgM5 (0.9)NA
       C3150 (26.6)NA
       Total564NA
      Abbreviation: NA, not available.
      Direct immunofluorescence microscopy of perilesional skin biopsies showed linear deposits of C3 at the base membrane zone in all BP patients (100%), while 379 BP patients (67.2%) showed IgG deposits or weak deposits. In addition, 352 BP patients and 188 BP patients showed IgA (62.4%) and IgM deposits (33.3%) or weak deposits at the base membrane zone, respectively. Eight combined deposit patterns were identified in BP patients. The three most common observed patterns were, C3+-IgG+-IgA+-IgM+ (29.8%), C3+-IgG+-IgA+-IgM (27.3%), and C3+-IgG-IgA-IgM (26.6%), which together accounted for 83.7% of all BP patients. The rarest pattern was C3+-IgG-IgA-IgM+, which was found in only five BP patients (0.9%).
      The positive rates of anti-BP180 and anti-BP230 were also assessed by ELISA tests. As expected, more BP patients showed anti-BP180–positive (94.7%) than anti-BP230–positive (54.4%). Dual-positivity for both antibodies occurred in 241 BP patients (49.1%), while 250 BP patients were single-positive (224 for anti-BP180–positive alone and 26 for anti-BP230–positive alone).
      To investigate the associations within the major histocompatibility complex region, we conducted high coverage next-generation sequence-based HLA typing analysis on five classical HLA alleles—HLA-A, -B, -C, -DRB1, and -DQB1. Consequently, the whole genomic region of class I major histocompatibility complex alleles and the polymorphic region (exon 2, 3, and 4) of class II major histocompatibility complex alleles were amplified and then sequenced by using illumina Miseq platform (Illumina Inc, San Diego, CA). A mean coverage of 622.8x for HLA across all the samples was identified (511.3x for -A, 472.1x for -B, 434.9 for -C, 736.2x for -DRB1, and 885.8x for -DQB1). The high-resolution classical HLA alleles were subsequently called with default settings by the software NGSengine (GenDX, Utrecht, The Netherlands). After stringent quality control (three patients failed this step), 572 BP patients and 976 healthy controls were involved in the subsequent analysis.
      Classical HLA alleles were defined as a series of binary markers (present/absent). We applied the logistic regression framework to test each of these binary markers for association. The most significant risk association for BP was demonstrated to be DQB1*03:01 (P = 1.27 × 10–7; odds ratio [OR] = 1.582; 95% confidence interval = 1.334–1.875; Table 2). DQB1*03:03 (P = 6.11 × 10–7; OR = 0.552; 95% confidence interval = 0.437–0.697) was identified as the most significant protective allele for BP, while DQB1*06:01 (P = 1.18 × 10–5; OR = 0.478; 95% confidence interval = 0.344–0.665) was identified as a second significant protective allele. These three classical alleles were independent from each other, and conditioning on the effect of them could eliminate all the other associations. The significance level was estimated at 1.86 × 10–4, with 269 classical alleles were involved in the association analysis.
      Table 2Significant association results and stratified analysis by gender and antibody
      AlleleF_AF_UP-ValueORL95U95
       HLA_DQB1_03010.2850.21.27E-071.5821.3341.875
       HLA_DQB1_03030.0950.166.11E-070.5520.4370.697
       HLA_DQB1_06010.0430.0851.18E-050.4780.3440.665
      AlleleF_MaleF_FemaleP-ValueORL95U95
       Stratified by gender
      HLA_DQB1_03010.2830.2878.69E-010.9780.7511.274
      HLA_DQB1_03030.0910.1015.38E-010.8790.5831.325
      HLA_DQB1_06010.0450.047.27E-011.1120.6132.017
      AlleleF_BPAG2F_BPAG1F_UP-Value_1OR_1L95_1U95_1P-Value_2OR_2L95_2U95_2
       Stratified by antibody
      HLA_DQB1_03010.2930.2560.27.99E-081.6381.3681.9615.65E-031.3711.0961.716
      HLA_DQB1_03030.0970.1070.168.10E-060.5650.440.7262.45E-030.6310.4670.852
      HLA_DQB1_06010.0450.0430.0851.53E-040.5080.3580.7211.26E-030.4860.3110.76
      Abbreviations: F_A, allele frequency in affected cases; F_BPAG2, allele frequency in BPAG2-positive patients; F_BPAG1, allele frequency in BPAG1-positive patients; F_Female, allele frequency in female patients; F_Male, allele frequency in male patients; F_U, allele frequency in unaffected controls; OR, odds ratio.
      Associations tests first stratified by gender were reported in a previous publication (
      • Banfield C.C.
      • Wojnarowska F.
      • Allen J.
      • George S.
      • Venning V.A.
      • Welsh K.I.
      The association of HLA-DQ7 with bullous pemphigoid is restricted to men.
      ), but no significant results were observed (P > 0.05 for all the three markers). We then stratified the BP patients into BPAG1-positive and BPAG2-positive groups and conducted association analysis comparing them to the healthy controls. The two protective alleles, DQB1*03:03 and DQB1*06:01, showed similar ORs and P values for both antibody groups. However, DQB1*03:01 showed a significant difference between the BPAG1 and BPAG2 groups. Although both groups were significantly associated, the risk effect for the BPAG2 group (P = 7.99 × 10–8; OR = 1.638) was stronger than the BPAG1 group (P = 5.65 × 10–3; OR = 1.371).
      Finally, we evaluated the effectiveness of DQB1*03:01 for risk prediction. DQB1*03:01 was presented in 49.65% of the patients (284 of 572), but only 35.25% of the healthy controls (344 of 976). For BP, it suggests that the presence of DQB1*03:01 has a sensitivity of 49.65% and a specificity of 64.75% as a risk predictor, with an area under the curve of 0.573 for disease prediction. On the basis of the estimated prevalence of the BP (2/100,000), we calculated the predictive value of the classical HLA allele for BP. DQB1*03:01 would have a negative predictive value of 99.99%, which meant that nearly all the negative samples represented true-negative samples, but a positive predictive value of 0.0028% was caused by the rare prevalence of disease.
      Although the nature of the trigger remains unresolved in most of the autoimmune blistering diseases, a strong association between HLA and the particular autoimmune blistering disease has been established for several dozens of years. In this study, we confirmed DQB1*03:01 as the only significant risk association for BP in the Chinese population, while DQB1*03:03 and DQB1*06:01 were demonstrated to be significant protective associations. The risk effect of DQB1*03:01 was much weaker than that found in the Caucasian mucous membrane pemphigoid patients, in which 75.8% patients carried the risk allele (
      • Setterfield J.
      • Theron J.
      • Vaughan R.W.
      • Welsh K.I.
      • Mallon E.
      • Wojnarowska F.
      • et al.
      Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production.
      ). After we stratified the patients into BPAG1-positive and BPAG2-positive groups, we observed increased allele frequency for DQB1*03:01 in the BPAG2-positive group. Although the DQB1*03:01 association was still nominally significant in the BPAG1-positive group, these findings would suggest that DQB1*03:01 is more restricted to BPAG2 antigen presenting.
      DQB1*03:01 has been reported to be associated with multiple diseases, such as cutaneous melanoma (
      • Lee J.E.
      • Reveille J.D.
      • Ross M.I.
      • Platsoucas C.D.
      HLA-DQB1*0301 association with increased cutaneous melanoma risk.
      ) and familial generalized vitiligo (
      • Fain P.R.
      • Babu S.R.
      • Bennett D.C.
      • Spritz R.A.
      HLA class II haplotype DRB1*04-DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset.
      ). Although its precise effect in the pathogenesis is unclear, it has been hypothesized that the HLA allele may play a pivotal role in the recognition of antigenic peptides by T cells (
      • Hassan I.
      • Ahmad F.
      Structural diversity of class I MHC-like molecules and its implications in binding specificities.
      ).
      In conclusion, this study represents, to our knowledge, the largest genetic study of BP, as well as the first HLA analysis by using next-generation sequence-based HLA typing methods in BP. Through this investigation, the associations of HLA-DQB1*03:01, -DQB1*03:03, and DQB1*06:01 have been identified in Chinese Han BP patients, which advances our understanding of the genetics of BP susceptibility and offers molecular insight into the pathophysiological mechanisms underlying BP in the Chinese Han population.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We thank all of the participants involved in this study. This work was funded by grants from the National Natural Science Foundation of China (816201008025, 81472868, 81472869, 81502736), the Natural Science Foundation of Shandong Province (JQ201616,2014ZRC03128), the Key Research and Development Program of Shandong Province (2016ZDJS07A06), the Innovation Project of Shandong Academy of Medical Sciences, and the Shandong Provincial Advanced Taishan Scholar Construction Project.

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