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HLA-C*01:02 and HLA-A*02:07 Confer Risk Specific for Psoriatic Patients in Southern China

  • Author Footnotes
    6 These authors contributed equally to this work.
    Minglong Cai
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China

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

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, China

    Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China
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  • Author Footnotes
    6 These authors contributed equally to this work.
    He Huang
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China

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

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, China

    Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China
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  • Delin Ran
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Xiaodong Zheng
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Leilei Wen
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Zhengwei Zhu
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Lu Liu
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Chuanliang Zhang
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Xiaojie Hong
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Jiaqi Hong
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Wenjuan Wu
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Jie Ma
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Mingshun Wu
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Danfeng Qian
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China
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  • Yujun Sheng
    Correspondence
    Corresponding author
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China

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

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, China

    Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China
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  • Xuejun Zhang
    Correspondence
    Corresponding author
    Affiliations
    Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Institute of Dermatology, Anhui Medical University, Hefei, China

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

    State Key Laboratory Incubation Base of Dermatology, Anhui Medical University, Hefei, China

    Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China
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  • Author Footnotes
    6 These authors contributed equally to this work.
Open ArchivePublished:March 13, 2019DOI:https://doi.org/10.1016/j.jid.2019.02.027

      Abbreviations:

      MAF (minor allele frequency), PsN (the population of northern Han Chinese psoriasis patients), PsS (the population of southern Han Chinese psoriasis patients)
      To the Editor
      Psoriasis is a complex, multigenic, immune-mediated skin disease characterized by heterogeneity across diverse ancestries; its prevalence varies from 0.09% to 11.4%, depending on the population of origin (
      • Gibbs S.
      Skin disease and socioeconomic conditions in rural Africa: Tanzania.
      ,
      • Danielsen K.
      • Olsen A.O.
      • Wilsgaard T.
      • Furberg A.S.
      Is the prevalence of psoriasis increasing? A 30-year follow-up of a population-based cohort.
      ). In China, it is estimated that 0.47% of the population suffering from psoriasis (
      • Ding X.
      • Wang T.
      • Shen Y.
      • Wang X.
      • Zhou C.
      • Tian S.
      • et al.
      Prevalence of psoriasis in China: a population-based study in six cities.
      ), and the prevalence of psoriasis in northern China is higher than in southern China.
      Recent genome-wide association studies have identified more than 80 regions associated with psoriasis, and a large transethnic genome-wide association study meta-analysis showed different genetic architecture of psoriasis susceptibility among populations (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ,
      • Yin X.
      • Low H.Q.
      • Wang L.
      • Li Y.
      • Ellinghaus E.
      • Han J.
      • et al.
      Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.
      ).
      Studies on the genetic structure of population showed one-dimensional north-south stratification in Han Chinese and showed large differences in allele frequency between north and south Han Chinese populations (
      • Chen J.
      • Zheng H.
      • Bei J.-X.
      • Sun L.
      • Jia W-h
      • Li T.
      • et al.
      Genetic structure of the Han Chinese population revealed by genome-wide SNP variation.
      ,
      • Xu S.
      • Yin X.
      • Li S.
      • Jin W.
      • Lou H.
      • Yang L.
      • et al.
      Genomic dissection of population substructure of Han Chinese and its implication in association studies.
      ,
      • Zhou F.
      • Cao H.
      • Zuo X.
      • Zhang T.
      • Zhang X.
      • Liu X.
      • et al.
      Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.
      ). Genetic structural difference across two subpopulations may be the result of evolutionary adaptations, as a consequence of environmental influences, including the effects of seasonality and climate, agricultural distribution, or varying prevalence of infectious diseases (
      • Suo C.
      • Xu H.
      • Khor C.C.
      • Ong R.T.
      • Sim X.
      • Chen J.
      • et al.
      Natural positive selection and north-south genetic diversity in East Asia.
      ). To further uncover the distinct genetic architecture of psoriasis across two populations in China, we included a total of 8,150 psoriasis patients and 9,906 matched control individuals and classified them into north Han Chinese ancestry (3,657 cases vs. 5,257 controls) and south Han Chinese ancestry (4,493 cases vs. 4,649 controls). Major histocompatibility complex (MHC) targeted sequencing and stringent quality control have been described elsewhere (
      • Zhou F.
      • Cao H.
      • Zuo X.
      • Zhang T.
      • Zhang X.
      • Liu X.
      • et al.
      Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.
      ). Then, we calculated the heritabilities of psoriasis in northern China (PsN) and psoriasis in southern China (PsS) using the genome-wide complex trait analysis method (
      • Yang J.
      • Lee S.H.
      • Goddard M.E.
      • Visscher P.M.
      GCTA: a tool for genome-wide complex trait analysis..
      ) and performed a fine-mapping study to identify region-specific HLA associations in psoriasis.

      HLA associations with PsS and PsN susceptibility

      We observed that HLA alleles collectively explained a higher heritability of PsN (20.2%) than PsS (17.1%), which implies that there is different genetic architecture between PsN and PsS susceptibility. To further explain this result, we performed a stratification analysis to search for psoriatic region-specific risk alleles using stepwise analysis. We identified HLA-C*06:02 (P = 1.00 × 10–604,), HLA-C*07:04 (P = 3.12 × 10–25), B-Y67C (P = 1.21 × 10–23), B-Y116S (P = 7.71 × 10–18), and HLA-DPB1*05:01 (P = 1.21 × 10–10) were independently associated with PsN (see Supplementary Figure S1 and Supplementary Table S1 online). HLA-C*06:02 (P = 1.00 × 10–604), HLA-C*07:04 (P = 9.55 × 10–19), HLA-C*01:02 (P = 2.45 × 10–7), B-Y67C (P = 3.00 × 10–39), B-Q32L (P = 1.62 × 10–12), HLA-A*02:07 (corresponding to A-Y99C, P = 2.49 × 10–11), and DPB1-F35L (P = 2.30 × 10–7) were independently associated with PsS (see Supplementary Figure S2 and Supplementary Table S2 online). Most of these loci were consistent with those of our previous association study in the overall Han Chinese population (
      • Zhou F.
      • Cao H.
      • Zuo X.
      • Zhang T.
      • Zhang X.
      • Liu X.
      • et al.
      Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.
      ). HLA-C*06:02, HLA-C*07:04, and B-Y67C are shared, independent of psoriasis risk variants, across the two subpopulations. Moreover, HLA-C*06:02 and HLA-C*07:04 showed similarities in peptide binding preference (
      • Pavlos R.
      • McKinnon E.J.
      • Ostrov D.A.
      • Peters B.
      • Buus S.
      • Koelle D.
      • et al.
      Shared peptide binding of HLA class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles.
      ), and B-Y67C was located at functional pockets of the HLA-B molecule (
      • Zhou F.
      • Cao H.
      • Zuo X.
      • Zhang T.
      • Zhang X.
      • Liu X.
      • et al.
      Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.
      ), which suggest that these markers confer susceptibility to psoriasis in the Han Chinese population, because they are related to the disease itself and not to geographic location. However, other independent HLA variants (HLA-C*01:02, HLA-A*02:07, B-Y116S, and B-Q32L) showed region-specific associations with psoriasis.

      HLA associations with geographic location in the Han Chinese psoriasis population

      To further confirm the region-specific susceptibility loci, we directly comparing the PsN group with the PsS group and validated two independent region-specific risk loci for HLA-C*01:02 (Figure 1, Table 1) (P = 3.24 × 10–19) and HLA-A*02:07 (P = 4.11 × 10–8). HLA-C*01:02 and HLA-A*02:07 were independently associated with PsS (P = 2.45 × 10–7 and P = 2.49 × 10–11, respectively) and not with PsN (P = 0.003 and P = 0.024, respectively). We also identified that A-L180X and A-F33T were significantly associated with geographic locations, but they were not associated with psoriasis. DPB1-F35, a synonymous variant with high linkage to DPB1-F35L (r2 = 0.83) and DBP1*05:01 (r2 = 0.63), was found to meet the significance threshold in PsN-PsS analysis. The frequencies among these three variations were significantly higher in southern than in northern Han Chinese (see Supplementary Table S3 online). Therefore, we speculate that a signal marker within HLA-DPB1 is independently associated with psoriasis and contributes a higher risk to the PsS than the PsN population.
      Figure thumbnail gr1
      Figure 1A Manhattan plot of the stepwise conditional association for geographic location in the MHC region. Stepwise analysis of HLA-C, HLA-A, and HLA-DPB1 in PsN versus PsS. For each plot, the horizontal axis shows genomic position, and the vertical axis shows negative log10-transformed P values for association. The dashed horizontal line corresponds to the significance threshold of P = 1.87 × 10−6. MHC, major histocompatibility complex; SNP, single nucleotide polymorphism.
      Table 1Association of HLA variants with geographic location in Chinese psoriasis population
      HLA VariantFrequencyPsN vs PsS
      Freq_PsNFreq_PsSOR (95% CI)P
      HLA-C Alleles
      HLA-C*01:020.0820.1270.61 (0.54–0.68)3.24 × 10–19
      HLA-A Alleles
      A-L156X0.2230.2740.77 (0.71–0.83)1.06 × 10–11
      A-F9T0.0740.0880.71 (0.63–0.81)6.74 × 10–8
      A-Y99C0.0530.0830.6546 (0.56–0.76)4.11 × 10–8
      HLA-DPB1 Alleles
      DPB1-F350.4260.4840.84 (0.79–0.90)6.28 × 10–7
      Abbreviations: CI, confidence interval; Freq_PsN, allele frequency in psoriatic patients from northern China; Freq_PsS: Allele frequency in psoriatic patients from southern China; OR, odds ratio.

      HLA-C*01:02 and HLA-A*02:07 are psoriasis-associated alleles specific to PsS

      It makes sense that C*01:02 and A*02:07 showed PsS-specific risk loci, because their frequencies are much higher in southern Han Chinese than those in northern Han Chinese (see Supplementary Table S3). In addition, HLA-A*02 and HLA-C*01 have very similar peptide binding motifs (
      • Andersen M.H.
      • Sondergaard I.
      • Zeuthen J.
      • Elliott T.
      • Haurum J.S.
      An assay for peptide binding to HLA-Cw∗0102.
      ), suggesting that specific autoantigen peptides presented by HLA-A*02:07 and HLA-C*01:02 could share a common structure and be involved in the pathogenesis of PsS. HLA-A*02:07 was reported to be associated with psoriasis in Japanese, and A-Y99C was located at functional pockets of the HLA-A molecule (
      • Hirata J.
      • Hirota T.
      • Ozeki T.
      • Kanai M.
      • Sudo T.
      • Tanaka T.
      • et al.
      Variants at HLA-A, HLA-C, and HLA-DQB1 confer risk of psoriasis vulgaris in Japanese.
      ). Our previous study, in which samples were enrolled mainly from individuals in southern China, also showed that HLA-A*02:07 was associated with psoriasis in Han Chinese (
      • Yin X.
      • Low H.Q.
      • Wang L.
      • Li Y.
      • Ellinghaus E.
      • Han J.
      • et al.
      Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.
      ). Moreover, we noted that the A*02:07-C*01:02-B*46:01 haplotype with a frequency of greater than 5% was reported in Han Chinese from the Zhejiang and Yunnan provinces, located in southern China (
      • Chen N.
      • Wang W.
      • Wang F.
      • Dong L.
      • Zhao S.
      • Zhang W.
      • et al.
      The distributions of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 allele and haplotype at high-resolution level in Zhejiang Han population of China.
      ,
      • Shen Y.
      • Cao D.
      • Li Y.
      • Kulski J.K.
      • Shi L.
      • Jiang H.
      • et al.
      Distribution of HLA-A, -B, and -C alleles and HLA/KIR combinations in Han population in China.
      ). In our data set, the frequency of A*02:07-C*01:02-B*46:01 in healthy southern Han Chinese was significantly higher than in healthy northern Han Chinese (5.2% and 3.1%, respectively; P = 3.85 × 10–7).

      Limitations and future directions

      We did not identify any independent PsN-specific risk variants in HLA, despite a higher heritability. Possible reasons for this might be as follows. First, considering the statistical power, we removed variants with a minor allele frequency (MAF) of less than 1% for association analysis, although we used all sequencing data to calculate the heritability of psoriasis. There is a possibility that very-low-frequency variants (MAF < 1%) that confer risk for PsN were missed. Second, we did not have sufficient power (<80%) to detect low-frequency variants (MAF < 5%) with odds ratios of less than 1.6. Therefore, variants with MAF between 1% and 5% have a small effect and were also lost. In addition, statistical power of association analysis in PsN was slightly lower than PsS because of relatively small sample size and unbalanced distribution for northern Han Chinese. Large studies with sequencing data would clarify this in the future.

      Study approval

      All participating individuals provided written informed consent and were recruited according to the protocols approved by the institutional ethics committee of the First Affiliated Hospital of Anhui Medical University.

      Data availability

      The raw sequencing data from samples evaluated in the Han-MHC project and Psoriasis Association Analysis have been deposited in the Sequence Read Archive with the accession number SRA205317. The constructed Han-MHC database is available through the GigaScience database at https://doi.org/10.5524/100156.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      This study was supported financially by the National Natural Science Foundation of China ( 81872527 , 81130031 , 81803117 ) and the Natural Science Foundation of Anhui Province ( 1808085QH284 ).
      We are grateful to all participants, their families, and healthy control individuals who donated blood samples in this study.

      Author Contributions

      MC: lead: writing (original draft preparation), visualization; equal: conceptualization, data curation, formal analysis; supporting: writing (review and editing). HH: lead: writing (review and editing); equal: conceptualization, data curation; supporting: writing (original draft preparation), DR: equal: conceptualization, data curation. XZ: equal: data curation, formal analysis. LW: equal: data curation; supporting: writing (review and editing). ZZ: equal: data curation; supporting: visualization. LL: equal: conceptualization; supporting: data curation. CZ: equal: data curation; supporting: writing (review and editing. XH: equal: writing (review and editing); supporting: visualization. JH: equal: writing (review and editing); supporting: visualization. WW: equal: formal analysis; supporting: writing (review and editing). JM: equal: conceptualization; supporting: data curation. MW: equal: data curation; supporting: visualization. DQ: equal: data curation; supporting: methodology. YS: lead: conceptualization, methodology; equal: funding acquisition, supervision, writing (original draft preparation), writing (review and editing. XZ: lead: funding acquisition; equal: conceptualization, methodology, supervision, writing (original draft preparation), writing (review and editing). All authors read and approved the final manuscript.

      Supplementary Materials

      Sample selection

      A total of 8,150 psoriasis patients (patients with psoriatic arthritis were not included) and 9,906 matched control individuals of Han Chinese ethnicity were recruited through collaboration with multiple medical institutions in China. All selected patients had disease diagnosed by at least two dermatologists, and all control individuals were healthy, without psoriasis, autoimmune diseases, systemic diseases, or a family history of genetic diseases (including first-, second- and third-degree relatives). We classified participants into northern Han Chinese ancestry (3,657 patients and 5,257 control individuals) and southern Han Chinese ancestry (4,493 patients and 4,649 control individuals), using the Huai River–Qin Mountains as the dividing line. All participating individuals provided written informed consent and were recruited according to the protocols approved by the institutional ethics committee of the First Affiliated Hospital of Anhui Medical University.

      MHC targeted sequencing and statistical quality control

      The samples enrolled for analysis including 8,150 patient samples and 9,906 control samples for which HLA sequences were generated and stringent quality control were conducted in our previous MHC targeted sequencing research (
      • Zhou F.
      • Cao H.
      • Zuo X.
      • Zhang T.
      • Zhang X.
      • Liu X.
      • et al.
      Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.
      ). In addition to this, we excluded variants with MAF less than 1%, Hardy-Weinberg equilibrium of P less than 10–4, or with a call rate of less than 99%. Finally, we obtained a total of 26,775 markers including single nucleotide polymorphisms, classic alleles, and amino acid residues.

      Statistical power calculation

      The statistical power of our study was evaluated by Power and Sample Size software, version 3.1.2 (www.power-analysis.com/). Type I error was set to 1.87 × 10–6 (after Bonferroni correction, P = 0.05/26,775). We had a power of greater than 80% for detecting MAF greater than 2.5%, and odds ratio of the effect allele was equal to 2, but we did not have sufficient power (<80%) to detect low-frequency variants (MAF <0.5%) even if the odds ratio was greater than 3.5.

      Heritability of psoriasis conferred by MHC locus

      Using genome-wide complex trait analysis (
      • Yang J.
      • Lee S.H.
      • Goddard M.E.
      • Visscher P.M.
      GCTA: a tool for genome-wide complex trait analysis.
      ,
      • Yang J.
      • Bakshi A.
      • Zhu Z.
      • Hemani G.
      • Vinkhuyzen A.A.
      • Lee S.H.
      • et al.
      Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index.
      ), we calculated the heritability of PsS and PsN conferred by MHC region with the assumption of a disease prevalence of 0.47%.

      Statistical analyses

      Analysis of all variants were performed with logistic regression, assuming an additive effect of the allele dosages in the log-odds scale. We included sex, family history, and age at onset as covariates to correct for population stratification. HLA associations with three binary psoriasis susceptibility characteristics defined by region were analyzed as follows: i) associations between HLA alleles with psoriasis susceptibility in northern China (PsN vs control individuals from northern China), ii) associations between HLA alleles with psoriasis susceptibility in southern China (PsS vs control individuals from southern China), iii) directly comparing psoriasis patients in northern China with patients in southern China (PsN vs PsS). For stepwise conditional analysis, we continuously included the identified marker as a covariant to find additional associated variants with independent effect. This was repeated in a forward stepwise approach until no variation exceeded the predefined significance threshold after Bonferroni correction (P < 1.87 × 10–6). Logistic regression and stepwise conditional analysis were conducted by PLINK, version 1.9 (
      • Chang C.C.
      • Chow C.C.
      • Tellier L.C.
      • Vattikuti S.
      • Purcell S.M.
      • Lee J.J.
      Second-generation PLINK: rising to the challenge of larger and richer datasets.
      ).
      Figure thumbnail fx1
      Supplementary Figure S1A Manhattan plot of the stepwise conditional association for PsN in the MHC region. Stepwise analysis of HLA-C, HLA-B, and HLA-DPB1 in PsN versus control individuals. For each plot, the horizontal axis shows the genomic position, and the vertical axis shows negative log10-transformed P-values for association. The dashed horizontal line corresponds to the significance threshold of P = 1.87 × 10−6. MHC, major histocompatibility complex; PsN, psoriatic patients from northern China; SNP, single nucleotide polymorphism.
      Figure thumbnail fx2
      Supplementary Figure S2A Manhattan plot of the stepwise conditional association for PsS in the MHC region. Stepwise analysis of HLA-C, HLA-B, HLA-A, and HLA-DPB1 in PsS versus control individuals. For each plot, the horizontal axis shows genomic position and the vertical axis shows negative log10-transformed P-values for association. The dashed horizontal line corresponds to the significance threshold of P = 1.87 × 10−6. MHC, major histocompatibility complex; PsS, psoriatic patients from southern China.
      Supplementary Table S1Association of HLA variants with psoriasis in northern China
      HLA VariantFrequencyPsN vs NC
      Freq_PsNFreq_NCOR (95% CI)P
      HLA-C Alleles
      HLA-C*06:020.4540.12712.31 (11.11–13.63)1.00 × 10–501
      HLA-C*07:040.0190.0124.383 (3.32–5.80)3.12 × 10–25
      HLA-B Alleles
      B-Y67C0.0900.0862.04(1.77–2.34)1.21 × 10–23
      B-Y116S0.3010.2951.45 (1.33–1.58)7.71 × 10–18
      HLA-DPB1 Alleles
      HLA-DPB1*05:010.3430.3451.31 (1.20–1.42)1.21 × 10–10
      Abbreviations: CI, confidence interval; Freq_PsN, allele frequency in psoriatic patients from northern China; NC, control individuals from northern China; OR, odds ratio.
      Supplementary Table S2Association of HLA variants with psoriasis in southern China
      HLA variantFrequencyPsS vs SC
      Freq_PsSFreq_SCOR (95% CI)P
      HLA-C Alleles
      HLA-C*06:020.4230.09216.52 (14.88–18.33)1.00 × 10–604
      HLA-C*07:040.0130.0084.24 (3.08–5.84)9.55 × 10–19
      HLA-C*01:020.1270.1681.32 (1.19–1.46)2.45 × 10–07
      HLA-B Alleles
      B-Y67C0.0950.0892.43 (2.13–2.77)3.00 × 10–39
      B-Q32L0.1340.2340.69 (0.62–0.76)1.62 × 10–12
      HLA-A Alleles
      HLA-A*02:07
      Equivalent to A-Y99C in the Han Chinese population.
      0.0830.0871.67 (1.44–1.94)2.49 × 10–11
      HLA-DPB1 Alleles
      DPB1-F35L0.4370.471.231 (1.14–1.33)2.30 × 10–07
      Abbreviations: CI, confidence interval; Freq_PsN, allele frequency in psoriatic patients from northern China; SC, control individuals from southern China; OR, odds ratio.
      1 Equivalent to A-Y99C in the Han Chinese population.
      Supplementary Table S3Allele frequencies between the northern Han Chinese and southern Han Chinese populations
      HLA AllelesAllele Frequency in Northern ChineseAllele Frequency in Southern Chinese
      Freq_PsNFreq_NCFreq_PsSFreq_SC
      HLA-C*01:020.081620.11250.12710.1683
      HLA-C*06:020.45430.12710.42330.09163
      HLA-C*07:040.018460.01170.013240.008496
      A-F33T0.074240.12450.088250.1347
      A-Y123C0.052780.056970.082680.08658
      A-L180X0.22310.32450.2740.4099
      B-Y140S0.30120.29520.33080.3612
      B-Y91C0.089960.08560.09470.08948
      B-Q56L0.13850.22690.13350.2337
      BTNL2:T165I0.059890.064590.056660.06528
      DPB1-F640.4260.45560.48350.5228
      DPB1*05:010.3430.34470.37280.3864
      DPB1-F64L0.38980.4080.4370.47
      Bold type indicates alleles that showed region-specific risk for psoriasis in southern China.
      Abbreviations: Freq_NC, allele frequency in control individuals from northern China; Freq_PsN, allele frequency in psoriatic patients from northern China; Freq_PsS, allele frequency in psoriatic patients from southern China; Freq_SC, allele frequency in control individuals from southern China.

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