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2.
bioRxiv ; 2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-39071447

RESUMO

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.

4.
Nat Commun ; 13(1): 4287, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896530

RESUMO

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.


Assuntos
Estudo de Associação Genômica Ampla , Síndrome de Sjogren , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren/genética
7.
RMD Open ; 7(3)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34907023

RESUMO

OBJECTIVES: Fatigue is common and severe in primary Sjögren's syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. METHODS: Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed. RESULTS: Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10-8). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. RTP4 expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified. CONCLUSION: Genetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.


Assuntos
Síndrome de Sjogren , Alelos , Estudos de Coortes , Fadiga/epidemiologia , Fadiga/genética , Estudo de Associação Genômica Ampla , Humanos , Serina Proteases Associadas a Proteína de Ligação a Manose , Síndrome de Sjogren/complicações , Síndrome de Sjogren/genética
8.
Front Immunol ; 12: 702037, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335613

RESUMO

Primary Sjögren's syndrome (pSS) is an autoimmune inflammatory disease with profound clinical heterogeneity, where excessive activation of the type I interferon (IFN) system is considered one of the key mechanisms in disease pathogenesis. Here we present a DNA methylation-based IFN system activation score (DNAm IFN score) and investigate its potential associations with sub-phenotypes of pSS. The study comprised 100 Swedish patients with pSS and 587 Swedish controls. For replication, 48 patients with pSS from Stavanger, Norway, were included. IFN scores were calculated from DNA methylation levels at the IFN-induced genes RSAD2, IFIT1 and IFI44L. A high DNAm IFN score, defined as > meancontrols +2SDcontrols (IFN score >4.4), was observed in 59% of pSS patients and in 4% of controls (p=1.3x10-35). Patients with a high DNAm IFN score were on average seven years younger at symptom onset (p=0.017) and at diagnosis (p=3x10-3). The DNAm IFN score levels were significantly higher in pSS positive for both SSA and SSB antibodies compared to SSA/SSB negative patients (pdiscovery=1.9x10-8, preplication=7.8x10-4). In patients positive for both SSA subtypes Ro52 and Ro60, an increased score was identified compared to single positive patients (p=0.022). Analyzing the discovery and replication cohorts together, elevated DNAm IFN scores were observed in pSS with hypergammaglobulinemia (p=2x10-8) and low C4 (p=1.5x10-3) compared to patients without these manifestations. Patients < 70 years with ongoing lymphoma at DNA sampling or lymphoma at follow-up (n=7), presented an increased DNAm IFN score compared to pSS without lymphoma (p=0.025). In conclusion, the DNAm-based IFN score is a promising alternative to mRNA-based scores for identification of patients with activation of the IFN system and may be applied for patient stratification guiding treatment decisions, monitoring and inclusion in clinical trials.


Assuntos
Metilação de DNA/imunologia , Interferon Tipo I/imunologia , Síndrome de Sjogren/imunologia , Feminino , Humanos , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/imunologia
9.
Rheumatology (Oxford) ; 60(2): 837-848, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32889544

RESUMO

OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. CONCLUSION: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.


Assuntos
Autoanticorpos/sangue , Cadeias alfa de HLA-DQ/genética , Síndrome de Sjogren , Idade de Início , Autoimunidade/genética , Correlação de Dados , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Síndrome de Sjogren/classificação , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/fisiopatologia , Suécia/epidemiologia
10.
Tidsskr Nor Laegeforen ; 139(8)2019 May 07.
Artigo em Norueguês | MEDLINE | ID: mdl-31062556

RESUMO

BACKGROUND: Uveitis and acute renal failure can be seen in various immune-mediated systemic diseases. Here we present a case of a young man with a rare inflammatory oculorenal syndrome. CASE REPORT: A man in his thirties was admitted with a constellation of fatigue, flank pain, weight loss and bilateral acute anterior uveitis. Laboratory tests showed anaemia, leukocytosis with eosinophilia, as well as elevated creatinine and C-reactive protein, and urine analyses demonstrated mild proteinuria. Work-up excluded sarcoidosis, Sjögren's syndrome, systemic lupus erythematosus, ANCA-associated vasculitides, Behçet disease, spondyloarthritis and infection. Renal biopsy showed severe tubulointerstitial nephritis. INTERPRETATION: Following exclusion of the abovementioned disorders, a diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome was made. TINU syndrome is a rare inflammatory disorder which can be diagnosed in patients presenting with uveitis and tubulointerstitial nephritis after exclusion of other causes of similar oculorenal involvement.


Assuntos
Nefrite Intersticial/diagnóstico , Uveíte/diagnóstico , Adulto , Humanos , Masculino , Nefrite Intersticial/tratamento farmacológico , Nefrite Intersticial/patologia , Uveíte/tratamento farmacológico , Uveíte/patologia
12.
Ann Rheum Dis ; 73(6): 1253-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23606706

RESUMO

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune rheumatic disease mainly characterised by focal mononuclear cell infiltration in the salivary and lacrimal glands, and by the symptoms xerostomia and keratoconjunctivitis sicca. Germinal centre-like structures (GC) are found in the minor salivary glands of approximately 25% of patients. In this study, we aimed to assess genetic variations in pSS patients with GC-like formations (GC+) compared with patients without such formations (GC-). METHODS: Minor salivary gland biopsies from Swedish and Norwegian pSS patients (n=320) were evaluated for GC-like formations, identifying 76 GC+ and 244 GC- patients. A panel of 1536 single-nucleotide polymorphisms (SNPs) in 107 genes was genotyped. Minor allele frequencies in GC+ and GC- patients were compared using Fisher's exact test, and associations were considered significant when p<4.7×10(-4) and suggestive when p<0.01. RESULTS: In this case-only analysis, we identified two SNPs in CCL11 (eotaxin) associated with GC-like structures (p<4.7×10(-4), OR 0.45 and 0.41, respectively). A haplotype of the two minor alleles was associated with GC status with p=2.6×10(-4), OR 0.40. Suggestive associations (p<0.01) were found in SNPs in the B cell activation and/or GC-formation related genes AICDA, BANK1 and BCL2. Furthermore, SNPs in IL17A, ICA1, PKN1 and SNPs in the NF-κB pathway genes CARD8, IKBKE and TANK were found suggestively associated with GC-like structures. CONCLUSIONS: Our findings suggest that genetic variations may explain why ectopic GC-like structures are present in some pSS patients, and support the hypothesis that GC+ and GC- patients represent distinct disease phenotypes.


Assuntos
Centro Germinativo/patologia , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/genética , Xerostomia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Autoantígenos/genética , Biópsia , Proteínas Adaptadoras de Sinalização CARD/genética , Quimiocina CCL11/genética , Citidina Desaminase/genética , Feminino , Frequência do Gene , Genes bcl-2/genética , Haplótipos , Humanos , Quinase I-kappa B/genética , Interleucina-17/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteína Quinase C/genética , Síndrome de Sjogren/complicações , Síndrome de Sjogren/patologia , Xerostomia/etiologia , Xerostomia/patologia
13.
Ann Rheum Dis ; 71(6): 981-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22294627

RESUMO

OBJECTIVES: Lymphotoxin ß (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. METHODS: 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. RESULTS: Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. CONCLUSIONS: A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.


Assuntos
Linfotoxina-alfa/genética , Linfotoxina-beta/genética , Síndrome de Sjogren/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Linfotoxina-alfa/imunologia , Linfotoxina-beta/imunologia , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Glândulas Salivares/imunologia , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/imunologia , Suécia/epidemiologia , Fator de Necrose Tumoral alfa/imunologia , População Branca/genética , População Branca/estatística & dados numéricos
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