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1.
J Autoimmun ; : 102349, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31629629

RESUMO

BACKGROUND: Genome-wide association studies have identified over 120 risk loci for psoriasis. However, most of the variations are located in non-coding region with high frequency and small effect size. Pathogenetic variants are rarely reported except HLA-C*0602 with the odds ratio being approximately 4.0 in Chinese population. Although rare variations still account for a small proportion of phenotypic variances in complex diseases, their effect on phenotypes is large. Recently, more and more studies focus on the low-frequency functional variants and have achieved a certain amount of success. METHOD: Whole genome sequencing and sanger sequencing was performed on 8 MZ twin pairs discordant for psoriasis to scan and verified the de novo mutations (DNMs). Additionally, 665 individuals with about 20 years' medical history versus 2054 healthy controls and two published large population studies which had about 8 years' medical history (including 10,727 cases versus 10,582 controls) were applied to validate the enrichment of rare damaging mutations in two DNMs genes. Besides, to verify the pathogenicity of candidate DNM in C3, RNA-sequencing for CD4+, CD8+ T cells of twins and lesion, non-lesion skin of psoriasis patients were carried out. Meanwhile, the enzyme-linked immunosorbent assay kit was used to detect the level of C3, C3b in the supernatant of peripheral blood. RESULT: A total of 27 DNMs between co-twins were identified. We found six of eight twins carry HLA-C∗0602 allele which have large effects on psoriasis. And it is interesting that a missense mutation in SPRED1 and a splice region mutation in C3 are found in the psoriasis individuals in the other two MZ twin pairs without carrying HLA-C*0602 allele. In the replication stage, we found 2 loss-of-function (LOF) variants of C3 only in 665 cases with about 20 years' medical history and gene-wise analysis in 665 cases and 2054 controls showed that the rare missense mutations in C3 were enriched in cases (OR = 1.91, P = 0.0028). We further scanned the LOF mutations of C3 in two published studies (about 8 years' medical history), and found one LOF mutation in the case without carrying HLA-C*0602. In the individual with DNM in C3, RNA sequencing showed the expression level of C3 in skin was significant higher than healthy samples in public database (TPM fold change = 1.40, P = 0.000181) and ELISA showed protein C3 in peripheral blood was higher (~2.2-fold difference) than the other samples of twins without DNM in C3. CONCLUSION: To the best of our knowledge, this is the first report that DNM in C3 is the likely pathological mutations, and it provided a better understanding of the genetic etiology of psoriasis and additional treatments for this disease.

2.
J Proteomics ; 205: 103420, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229693

RESUMO

Lysine 2-hydroxyisobutyrylation is a newly discovered posttranslational modification. Although this modification is an important type of protein acylation, its role in psoriasis remains unstudied. We compared lesional and nonlesional psoriasis skin samples from 45 psoriasis patients. The result showed that this highly conserved modification was found in large quantities in both normal and diseased dermal tissues. However, there were a number of clear and significant differences between normal and diseased skin tissue. By comparing, lysine 2-hydroxyisobutyrylation was upregulated at 94 sites in 72 proteins and downregulated at 51 sites in 44 proteins in lesional skin. In particular, the sites with the most significant downregulation of lysine 2-hydroxyisobutyrylation were found in S100A9 (ratio = 0.140, p-value = .000371), while the most upregulated site was found in tenascin (ratio = 3.082, p-value = .0307). Loci associated with psoriasis, including FUBP1, SERPINB2 and S100A9, also exhibited significant regulation. Analyses of proteome data revealed that SERPINB2 and S100A9 were differentially expressed proteins. And bioinformatics analysis suggest that the P13K-Akt signaling pathway was more enriched with lysine 2-hydroxyisobutyrylation in lesional psoriasis skin. Our study revealed that lysine 2-hydroxyisobutyrylation is broadly present in psoriasis skin, suggesting that this modification plays a role in psoriasis pathogenesis. SIGNIFICANCE: A newly discovered protein posttranslational modification, lysine 2-hydroxyisobutyrylation, has been found to occur in a wide variety of organisms and to participate in some important metabolic processes. In this study, lysine 2-hydroxyisobutyrylation in lesional psoriasis skin and nonlesional psoriasis skin was quantified and compared for the first time. We found a number of differentially modified proteins and sites in our comparisons. Interestingly, some of the identified proteins and pathways with significantly different modifications, such as S100A9 and the PI3K-Akt signaling pathway, have been previously reported to be associated with psoriasis. We hope that this research will provide new insights into psoriasis.

3.
J Invest Dermatol ; 139(11): 2302-2312.e14, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31078570

RESUMO

Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases.

4.
Ann Rheum Dis ; 78(6): 773-780, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30936065

RESUMO

OBJECTIVE: The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC. METHODS: We first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case-control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants. RESULTS: HLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10-36, OR=2.29). DRß1:37N had an independent protective effect (p=5.81×10-16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRß1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility. CONCLUSIONS: We provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.

5.
Hepatology ; 70(1): 294-307, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30854688

RESUMO

Anti-nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome-wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single-nucleotide polymorphisms rs492899 (P = 3.27 × 10-22 ; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34-3.66) and rs1794280 (P = 5.78 × 10-28 ; OR, 3.89; 95% CI, 3.05-4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti-sp100-positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA-DRß1-Asn77/Arg74, DRß1-Ser37, and DPß1-Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10-9 ; OR, 2.97; 95% CI, 2.06-4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

6.
Arch Dermatol Res ; 311(4): 277-285, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826962

RESUMO

To verify whether PsA-associated HLA alleles proposed in other populations are also related to PsA in Chinese Han population, a study of PsA susceptible alleles in the HLA-A, HLA-B, HLA-C and HLA-DRB1 alleles was presented for Chinese Han population. Genotyping was performed by Illumina Miseq platform (Illumina, USA). 50 subtypes and 77 subtypes of HLA-A, HLA-B, HLA-C and HLA-DRB1 with minor allele frequency (MAF) > 1% were genotyped from two-digit and four-digit resolution analysis in 111 PsA and 207 HCs (healthy controls) collected from Chinese Han population, respectively. Data handling, quality control and association analysis were performed using SPSS 25.0 software. In risk estimate, by mean of Bonferroni correction, a newfound four-digit allele HLA-A*01:01 [P = 5.5 × 10-4, OR 3.35 (1.69-6.66)], four-digit allele HLA-C*06:02 [P = 8.5 × 10-7, OR 3.80 (2.23-6.47)] and six two-digit alleles HLA-A*01 [P = 5.2 × 10-5, OR 3.43 (1.89-6.23)], HLA-B*13 [P = 4.0 × 10-6, OR 2.65 (1.76-4.01)], HLA-B*27 [P = 7.5 × 10-4, OR 5.84 (2.09-16.29)], HLA-B*57 [P = 5.8 × 10-5, OR 20.10 (4.65-86.83)], HLA-C*03 [P = 2.1 × 10-4, OR 0.40 (0.25-0.65)], HLA-C*06 [P = 1.9 × 10-12, OR 4.48 (2.95-6.81)] showed statistical significance by the univariate binary logistic regression analysis. Besides, in the binary logistic regression analysis with multiple variables, when the two alleles HLA-A*01:01 and HLA-C*06:02 were considered as covariates, HLA-A*01:01 [P = 2.7 × 10-3,OR 2.95 (1.46-5.98)] also showed significant association for PsA as risk factor, but may be not the main risk factor [HLA-C*06:02, P = 3.0 × 10-6, OR 3.68 (2.13-6.37)]. When all the above two-digit alleles were included as covariates, HLA-A*01 [P = 4.8 × 10-2, OR 2.00 (1.01-3.94)], HLA-B*13 [P = 4.2 × 10-5, OR 2.62 (1.65-4.16)], HLA-B*27 [P = 1.7 × 10-4, OR 7.62 (2.64-21.96)], HLA-B*57 [P = 2.97 × 10-4, OR 15.90 (3.55-71.18)], HLA-C*06 [P = 6.1 × 10-5, OR 2.70 (1.66-4.40)] showed significant for PsA as risk factors, HLA-C*03 [OR 0.65 (0.39-1.09), P = 0.10] showed no association with PsA. In conclusion, we assessed HLA-A, HLA-B, HLA-C and HLA-DRB1 alleles in PsA cohort of Chinese Han population, found HLA-A*01:01 and HLA-A*01 may be the susceptible genes associated with PsA, and also confirmed the association of four loci with PsA in Chinese Han population. These findings may extend the susceptibility HLA alleles of PsA and help in developing possible genetic markers to predict PsA.


Assuntos
Artrite Psoriásica/genética , Genótipo , Antígeno HLA-A1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Risco , Adulto Jovem
7.
Epigenomics ; 11(4): 455-467, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30785334

RESUMO

AIM: A genomic region on 5q33.3 lies between and encompasses the IL12B and PTTG1 genes, and contains many potential psoriasis causal variants. We aimed to further examine the influence of variants in and around this region. MATERIALS & METHODS: We used least absolute shrinkage and selection operator (LASSO)-based regression analysis to assess independent contributions of 2171 variants to psoriasis susceptibility and tested them for association with different clinical psoriasis subtypes. RESULTS: We found that ADRA1B gene variants contribute to psoriasis in Chinese population. ADRA1B gene variants have a stronger association with moderate-to-severe disease group and an earlier age at onset of psoriasis than IL-12B and PTTG1 variants. CONCLUSION: The association of variants in the ADRA1B gene with psoriasis could explain why variants in the IL-12B, ADRA1B and PTTG1 gene regions are associated with psoriasis.

8.
Clin Epigenetics ; 10(1): 160, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587242

RESUMO

BACKGROUND: Psoriasis (Ps) is a common chronic inflammatory skin disease. The keratinocytes of psoriatic skin defy normal apoptosis and exhibit active cell proliferation. Aberrant DNA methylation (DNAm) has been suggested relevant through regulating the expression of Ps susceptibility genes. However, it is unclear whether the biological age inferred from DNA methylome is affected. RESULTS: To address the above issue, we applied a recently developed methylation clock model to our Chinese Han population dataset, which includes DNAm data of 114 involved psoriatic skin tissues (PP) and 41 uninvolved psoriatic skin tissues (PN) from Ps patients, and 62 normal skin tissues (NN) from health controls. We first confirmed the applicability of the clock in PN and NN. We then showed that PP samples have largely unchanged DNAm age, and that no association was observed between available clinical features and DNAm age acceleration. Examination of genome-wide CpGs yielded age-associated CpGs with concordant age-association coefficients among the three groups, which was also supported by an external dataset. We also interestingly observed two clock CpGs differentially methylated between PP and PN. CONCLUSIONS: Overall, our results suggest no significant alteration in DNAm age in PN and PP. Therefore, the increase in keratinocyte proliferation and alteration in DNAm caused by Ps may not affect the biological age of psoriatic skin tissue.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigenômica/métodos , Psoríase/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
J Invest Dermatol ; 138(11): 2307-2314, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29857070

RESUMO

To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10-8, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.

10.
Hum Genomics ; 12(1): 27, 2018 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-29784039

RESUMO

BACKGROUND: Mutations in keratin proteins have been vastly associated with a wide array of genodermatoses; however, mutations of keratins in psoriasis have not been fully investigated. The main aim of the current research was to identify the mutation in K14, K10, K16, and K17 genes in two stages of psoriasis patients. METHODS: Ninety-six psoriatic skin biopsies were collected. mRNA transcript of K14, K10, K16, and K17 was prepared, amplified, and sequenced. Sanger sequences of all keratins were further validated for mutational analysis using Mutation Surveyor and Alamut Visual. Then, in silico analysis of protein stability and protein and gene expression of all keratins was performed and validated. RESULTS: Out of 44 mutations, about 75% of keratins are highly pathogenic and deleterious. Remaining 25% mutations are less pathogenic and tolerated in nature. In these 33 deleterious mutations were immensely found to decrease keratin protein stability. We also found a correlation between keratin and Psoriasis Area and Severity Index score which added that alteration in keratin gene in skin causes severity of psoriasis. CONCLUSIONS: We strongly concluded that acanthosis and abnormal terminal differentiation was mainly due to the mutation in epidermal keratins. In turn, disease severity and relapsing of psoriasis are mainly due to the mutation of hyperproliferative keratins. These novel keratin mutations in psoriatic epidermis might be one of the causative factors for psoriasis.

11.
Cell Immunol ; 331: 16-21, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29748001

RESUMO

This study was aimed to investigate whether NFKB1 participates in the pathogenesis of psoriasis by mediating Th1/Th17 cells. In this study, expression of NFKB1 was assessed in skin tissues from psoriasis patients and the healthy controls through Western blot and Immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the serum levels of IFN-γ, IL-17 (IL-17A) and IL-17RA. The imiquimod-induced psoriasis mouse model was employed to examine the role of NFKB1 in psoriasis via the assessment of psoriasis area and severity index (PASI), including erythema, thickness and scales. The effects of NFKB1 on Th1/Th17 cells in were examined by flow cytometry. In vitro co-culture of Th1/Th17 cells isolated from different mice with HaCat cells was conducted to elucidate the effect of Th1/Th17 cells-mediated by NFKB1 on HaCat cells by MTT, wound healing and transwell invasion assay, respectively. The results showed that NF-κB p105/p50 expression in skin tissues was significantly increased in psoriasis (n = 21) compared to the healthy controls (n = 16), as well as levels of serum INF-γ and IL-17. Additionally, NF-κB p105/p50 expression in lesional skin tissues was much higher than that in non-lesional skin tissues of the same patients. In the psoriasis mouse model, NFKB1 overexpression significantly elevated the scores of erythema, thickness and scales. Besides, NFKB1 up-regulated the level of NF-κB p105/p50, INF-γ, T-bet, IL-17 and RORγt, as well as Th1/Th17 cells in skin tissues of psoriasis mice. Finally, in vitro assay confirmed that the activation of Th1 and Th17 mediated by NFKB1 in psoriasis promoted the proliferation, migration and invasion of keratinocytes. These findings suggest a critical role for NFKB1 in the regulation of Th1 and Th17 in psoriasis.

12.
Front Med ; 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29623515

RESUMO

Psoriasis (Ps) is an inflammatory skin disease caused by genetic and environmental factors. Previous studies on DNA methylation (DNAm) found genetic markers that are closely associated with Ps, and evidence has shown that DNAm mediates genetic risk in Ps. In this study, Consensus Clustering was used to analyze DNAm data, and 114 Ps patients were divided into three subclassifications. Investigation of the clinical characteristics and copy number variations (CNVs) of DEFB4, IL22, and LCE3C in the three subclassifications revealed no significant differences in gender ratio and in Ps area and severity index (PASI) score. The proportion of late-onset ( ⩾ 40 years) Ps patients was significantly higher in type I than in types II and III (P = 0.035). Type III contained the smallest proportion of smokers and the largest proportion of non-smoking Ps patients (P = 0.086). The CNVs of DEFB4 and LCE3C showed no significant differences but the CNV of IL22 significantly differed among the three subclassifications (P = 0.044). This study is the first to profile Ps subclassifications based on DNAm data in the Chinese Han population. These results are useful in the treatment and management of Ps from the molecular and genetic perspectives.

13.
Exp Cell Res ; 365(1): 138-144, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29501569

RESUMO

OBJECTIVE: This study was aimed to explore the effect of Bach2 on B cells in systemic lupus erythematosus (SLE), as well as the underlying mechanisms. METHODS: Expression of Bach2, phosphorylated-Bach2 (p-Bach2), Akt, p-Akt and BCR-ABL (p210) in B cells isolated from SLE patients and the healthy persons were assessed by Western blot. Immunofluorescence staining was performed to assess the localization of Bach2 in B cells. Enzyme-linked immunosorbent assay (ELISA) was employed to detect IgG produced by B cells. Cell counting kit-8 (CCK-8) and Annexin-V FITC/PI double staining assay were adopted to evaluate cell proliferation and apoptosis in B cells, respectively. RESULTS: Compared to the healthy controls, Bach2, p-Akt and p210 were significantly decreased, while nuclear translocation of Bach2, IgG, CD40 and CD86 obviously up-regulated in B cells from SLE patients. Bach2 significantly inhibited the proliferation, promoted apoptosis of B cells from SLE patients, whereas BCR-ABL dramatically reversed cell changes induced by Bach2. Besides, BCR-ABL also inhibited nuclear translocation of Bach2 in B cells from SLE patients. Further, LY294002 treatment had no effect on decreased expression of Bach2 induced by BCR-ABL, but significantly eliminated BCR-ABL-induced phosphorylation of Bach2 and restored reduced nuclear translocation of Bach2 induced by BCR-ABL in B cells from SLE. CONCLUSIONS: Bach2 may play a suppressive role in B cells from SLE, and BCR-ABL may inhibit the nuclear translocation of Bach2 via serine phosphorylation through the PI3K pathway.

15.
Gene ; 648: 76-81, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29355683

RESUMO

Vitiligo is an immune-related disease with patchy depigmentation of skin and hair caused by selective destruction of melanocytes. In recent decades, many studies have shown the association between vitiligo and HLA genes; however, the results of Han Chinese are scarce. In this study, we performed a fine-mapping analysis of the MHC region in 2818 Han Chinese subjects through a widely used HLA imputation method with a newly built large-scale Han-MHC reference panel. Three new four-digit HLA alleles (HLA-DQB1 ∗ 02:02, HLA-DQA1 ∗ 02:01 and HLA-DPB1 ∗ 17:01) were identified to be associated with the risk of vitiligo, and four previously reported alleles were confirmed. Further conditional analysis revealed that two important variants, HLA-DQß1 amino acid position 135 (OR = 1.79, P = 1.87 × 10-11) and HLA-B amino acid positions 45-46 (OR = 1.44, P = 5.61 × 10-11), conferred most of the MHC associations. Three-dimension ribbon models showed that the former is located within the ß2 domain of the HLA-DQß1 molecule, and the latter lies in the α1 domain of the HLA-B molecule, while both are involved in specific antigen presenting process. Finally, we summarized all significant signals in the MHC region to clarify their complex relationships, and 8.60% of phenotypic variance could be explained based on all reported variants in Han Chinese so far. Our findings highlight the complex genetic architecture of the MHC region for vitiligo in Han Chinese population and expand our understanding of the roles of HLA coding variants in the etiology of vitiligo.


Assuntos
Predisposição Genética para Doença/genética , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , Vitiligo/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Mapeamento Cromossômico/métodos , Frequência do Gene , Predisposição Genética para Doença/etnologia , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Fatores de Risco , Vitiligo/etnologia
16.
Ann Rheum Dis ; 77(3): 417, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29233832

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS: We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS: We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (pmeta <5.00×10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10-5) in ex vivo experiments. CONCLUSIONS: This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE.

17.
J Invest Dermatol ; 138(5): 1078-1087, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29258893

RESUMO

Psoriasis is an autoimmune disease characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes. LIM-domain only protein 4 (LMO4) is a transcription factor coregulator that promotes the assembly of multiprotein complexes to regulate mammary epithelium and keratinocyte differentiation and proliferation during embryogenesis. In this study, LMO4 has been found to be abundantly expressed in psoriatic epidermis. LMO4 expression is increased in human keratinocytes induced to differentiate by calcium ex vivo, and LMO4 overexpression induces spontaneous differentiation and growth acceleration of human keratinocytes in the absence of calcium. IL-23, a cytokine highly expressed in psoriatic skin lesions, induces differentiation and promotes proliferation of human keratinocytes. The IL-23-mediated effects are accompanied by an increase in LMO4 expression mediated by signal transducer and activator of transcription 3 through an IL-23/acutely transforming retrovirus AKT8 in rodent T-cell lymphoma/signal transducer and activator of transcription 3 pathway in keratinocytes. Knockdown of LMO4 effectively inhibits differentiation and growth of keratinocytes both ex vivo and in IL-23-injected ears of mice. LMO4 appears to mediate IL-23-related responses in psoriatic keratinocytes and is a potential therapeutic target in psoriasis.

18.
J Dermatol Sci ; 89(3): 258-262, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29248402

RESUMO

BACKGROUND: Bullous pemphigoid (BP) is one of the most common autoimmune skin diseases. Associations of genes, especially human leukocyte antigen (HLA)-DQ alleles, with BP indicate that genetic predisposition contributes to the disease. OBJECTIVES: To evaluate the association of HLA class I and HLA class II alleles with susceptibility to BP in the northern Chinese Han population. METHODS: We performed genotype for HLA-A, -B, -C, -G, -DPA1, -DPB1, -DQA1, -DQB1 and -DRB1 loci in 105 patients with BP by Sanger sequence-based typing (SBT) method. These data were compared with a local control cohort of 420 age- and sex-matched cases. RESULTS: Among the HLA alleles described herein, the susceptibility alleles associated with a high prevalence of BP were A*11:01 (OR = 1.9 Pc = 0.017); B*37:01 (OR = 8, Pc = 1.811 × 10-6); G*01:01 (OR = 3.61, Pc = 2.839 × 10-15) and G*01:06 (OR = 2.22, Pc = 0.025); DQA1*01:05 (OR = 4.87, Pc = 5.822 × 10-5), DQA1*05:05 (OR = 2.64, Pc = 9.114 × 10-4), and DQA1*05:08 (OR = 10.2, Pc = 0.016); DQB1*03:01 (OR = 1.69, Pc = 0.048) and DQB1*05:01 (OR = 3.42, Pc = 7.28 × 10-6); and DRB1*10:01 (OR = 6.85, Pc = 2.63 × 10-6). To the contrary, HLA-DQA1*01:02 (OR = 0.46, Pc = 8.603 × 10-4) and DQA1*01:03 (OR = 0.38, Pc = 0.048); DQB1*02:02 (OR = 0.28, Pc = 0.016); and DRB1*07:01 (OR = 0.26, Pc = 0.004) had significant associations with protection against BP. In addition, the frequency of haplotype HLA-DRB1*13-DQA1*05-DQB1*03 (OR = 12.32, Pc = 0.026) in BP patients was significantly higher than those in controls. CONCLUSION: Our data demonstrated that the alleles and haplotypes found in this study may be important differential genetic markers for susceptibility to or protection against BP in individuals of northern Chinese Han population.


Assuntos
Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Penfigoide Bolhoso/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China/etnologia , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
19.
PLoS One ; 12(10): e0186067, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29020033

RESUMO

Researchers have learned that nearly all conditions and diseases have a genetic component. With the benefit of technological advances, many single-nucleotide polymorphisms (SNPs) have been found to be associated with the risk of complex disorders by using genome wide association studies (GWASs). Disease-associated SNPs are sometimes shared by healthy controls and cannot clearly distinguish affected individuals from unaffected ones. The combined effects of multiple independent SNPs contribute to the disease process, but revealing the relationship between genotype and phenotype based on the combinations remains a great challenge. In this study, by considering the disease prevalence rate, we conducted an exhaustive process to identify whether a genotype combination pattern would have a decisive effect on complex disorders. Based on genotype data for 68 reported SNPs in 8,372 psoriasis patients and 8,510 healthy controls, we found that putative causal genotype combination patterns (CGCPs) were only present in psoriasis patients, not in healthy subjects. These results suggested that psoriasis might be contributed by combined genotypes, complementing the traditional modest susceptibility of a single variant in a single gene for a complex disease. This work is the first systematic study to analyze genotype combinations based on the reported susceptibility genes, considering each individual among the cases and controls from the Chinese population, and could potentially advance disease-gene mapping and precision medicine due to the causality relationship between the candidate CGCPs and complex diseases.


Assuntos
Algoritmos , Predisposição Genética para Doença , Psoríase/genética , Adulto , Alelos , Cromossomos Humanos/genética , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Inquéritos e Questionários
20.
Mol Med Rep ; 16(4): 4811-4816, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28765912

RESUMO

Mutation of genes encoding the enzymes of the mevalonate pathway cause a variety of diseases, including skin disorders. Mutation of four genes in this pathway, including mevalonate kinase, phosphomevalonate kinase, mevalonate diphosphate decarboxylase and farnesyl diphosphate synthase, have demonstrated to be responsible for porokeratosis (PK). However, the pathogenesis of PK remains unclear. In the present study, specific enzyme inhibitors of the mevalonate pathway, including pravastatin (PRA), alendronate (ALD), farnesyl transferase inhibitor (FTI­277) and geranylgeranyl transferase inhibitor (GGTI­298), were used to investigate the effect on differentiation of keratinocytes (KCs). Western blotting demonstrated that PRA, ALD, FTI­277 or GGTI­298 alone, or in combination, inhibited the expression level of calcium­induced differentiation maker involucrin (INV) in KCs. ALD and PRA induced greater inhibition of INV compared with FTI­277 and GGTI­298 treatment. These inhibitors additionally influenced the expression levels of keratin1. Mechanistic studies revealed that treatment of cells with inhibitors decreased the expression levels of p53 and Notch1, and regulated activation of the mitogen activated protein kinase and phosphoinositide­3­kinase/protein kinase B signaling pathways. The results of the present study suggested that regulation of the mevalonate pathway may be necessary for differentiation of KCs, and the pathogenesis of disseminated superficial actinic PK.


Assuntos
Cálcio/metabolismo , Diferenciação Celular , Queratinócitos/citologia , Queratinócitos/metabolismo , Redes e Vias Metabólicas , Ácido Mevalônico/metabolismo , Biomarcadores , Diferenciação Celular/genética , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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