RESUMEN
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
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2',5'-Oligoadenilato Sintetasa/genética , Interferón Tipo I/genética , Sitios de Carácter Cuantitativo/genética , Síndrome de Sjögren/genética , 2',5'-Oligoadenilato Sintetasa/biosíntesis , Alelos , Empalme Alternativo/genética , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Interferón Tipo I/metabolismo , Masculino , Síndrome de Sjögren/metabolismo , Síndrome de Sjögren/patología , Virosis/genética , Virosis/virologíaRESUMEN
Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , beta Carioferinas/genética , Enfermedades Autoinmunes/genética , Teorema de Bayes , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Regiones Promotoras GenéticasRESUMEN
INTRODUCTION: The aim of this study was to determine whether a single-nucleotide polymorphism (SNP; 1858CT, R620W) in the protein tyrosine phosphatase N22 (PTPN22) gene confers susceptibility to idiopathic inflammatory myopathy (IIM) in South Australian patients with IIM. METHODS: Genotyping was performed on stored DNA from 199 patients with histologically confirmed polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM), and then compared with 455 matched controls. Associations with the 8.1 ancestral haplotype (AH), and myositis-specific (MSA) and myositis-associated (MAA) autoantibodies were investigated. RESULTS: The PTPN22 R620W minor allele frequency was increased in IIM patients (50 of 398, 12.6%) compared with controls (75 of 910, 8.2%) (odds ratio 1.6, 95% confidence interval 1.1-2.3, P = 0.016). In IIM patients, there was no association between the R620W minor allele and detection of any MSA/MAA (P = 0.70), nor any evidence of epistasis with the 8.1 AH (P = 0.69). CONCLUSIONS: The PTPN22 R620W minor allele is associated with susceptibility to IIM in SA patients, independent of the 8.1 AH. Muscle Nerve, 2016 Muscle Nerve 55: 270-273, 2017.
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Predisposición Genética a la Enfermedad/genética , Miositis/genética , Polimorfismo de Nucleótido Simple/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Adulto , Australia , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. METHODS: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. RESULTS: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR(+) patients there was a trend toward increased malignancy (P = 0.15). CONCLUSIONS: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11. Muscle Nerve 52: 196-203, 2015.
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Autoanticuerpos/sangre , Estudios de Asociación Genética , Hidroximetilglutaril-CoA Reductasas/sangre , Miositis/sangre , Miositis/genética , Anciano , Estudios de Cohortes , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculares/sangre , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Miositis/diagnóstico , Necrosis , Sistema de RegistrosRESUMEN
Natural killer (NK) cell recognition of the nonclassical human leukocyte antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus can manipulate this central innate interaction through the provision of a "mimic" of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here, we analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore, functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94-NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors.
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Citomegalovirus/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Células Asesinas Naturales/inmunología , Polimorfismo Genético , Proteínas Virales/genética , Adulto , Secuencia de Aminoácidos , Sitios de Unión , Células Cultivadas , Citomegalovirus/inmunología , Citotoxicidad Inmunológica , Femenino , Trasplante de Células Madre Hematopoyéticas , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/fisiología , Humanos , Células Asesinas Naturales/metabolismo , Leucemia Mieloide Aguda/terapia , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Subfamília D de Receptores Similares a Lectina de las Células NK/metabolismo , Filogenia , Unión Proteica , Análisis de Secuencia de ADN , Proteínas Virales/química , Proteínas Virales/inmunología , Adulto Joven , Antígenos HLA-ERESUMEN
OBJECTIVES: Giant cell arteritis (GCA) is a systemic inflammatory vasculitis affecting the elderly. It primarily affects medium and large arteries of the head and neck and can cause stroke and blindness. The cause of GCA is unknown; however both genetic and environmental factors are likely to be involved. TLR4 is implicated in the pathogenesis of GCA, however previous studies, examining the association between GCA and two TLR4 single nucleotide polymorphisms (SNPs), have reported conflicting results. The aim of this study was to determine the association between GCA and range of SNPs spanning the TLR4 gene sequence. METHODS: A case-control genetic study was performed using DNA from Australian biopsy proven GCA patients (n=139) and population controls (n=130). Samples were genotyped for 8 SNPs tagging common variation across TLR4. These SNPs included rs4986790 (+896A/G, Asp299Gly) and rs4986791 (+1196C/T) which have been previously studied in GCA. Allelic and haplotypic variation was analysed by logistic regression assuming an additive genetic model. A random effects meta-analysis of the association between GCA and rs4986790 was performed utilising data from three previous studies. RESULTS: rs4986790 and rs4986791 are in strong linkage disequilbrium and tag one of the five common TLR4 haplotypes identified. No associations were observed between TLR4 SNPs and/or haplotypes and GCA. A meta-analysis, comprising 577 GCA patients and 1153 controls, did not confirm an association between GCA and rs4986790 (OR 1.29, 95% CI 0.86, 1.92, p=0.22). CONCLUSIONS: There is no evidence of an association between TLR4 polymorphism and susceptibility to GCA.
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Arteritis de Células Gigantes , Arterias Temporales/patología , Receptor Toll-Like 4/genética , Anciano , Australia/epidemiología , Biopsia , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Arteritis de Células Gigantes/epidemiología , Arteritis de Células Gigantes/genética , Arteritis de Células Gigantes/patología , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Estadística como AsuntoRESUMEN
INTRODUCTION: Necrotizing myopathy (NM) is distinguished from idiopathic inflammatory myositis (IIM) by dominance of myofiber necrosis, lack of mononuclear inflammatory infiltrates, and presence of antibodies to signal recognition particle (SRP). METHODS: The clinical features of 64 cases of NM were determined. Measurement of autoantibodies was undertaken on stored sera from 23 patients with NM. The incidence of malignancy was determined from the South Australian Cancer Registry. RESULTS: NM patients showed male predominance (61%), more frequent myalgias, and higher creatine kinase (CK) levels compared with IIM patients. Patients with NM had a high incidence of systemic lupus erythematosus (SLE) (21%), hypertension (11 of 17, 65%), and diabetes mellitus (3 of 13, 23%). No patient had antibodies to SRP. NM patients showed no altered risk for malignancy compared with the South Australian population (P = 0.86). CONCLUSIONS: NM is associated with SLE, hypertension, and diabetes mellitus. Comprehensive assessment of cardiovascular risk is indicated in NM, which raises the possibility of targeted interventions.
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Autoanticuerpos/sangre , Miositis/sangre , Miositis/inmunología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Forma MM de la Creatina-Quinasa/sangre , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hipertensión/epidemiología , Lupus Eritematoso Sistémico/epidemiología , Masculino , Persona de Mediana Edad , Miositis/epidemiología , Sistemas en Línea , Australia del Sur/epidemiología , Adulto JovenRESUMEN
The aim of this study was to determine the HLA and autoantibody associations of patients with histologically confirmed idiopathic inflammatory myositis (IIM). Serum and DNA were archived from South Australian patients with biopsy-proven dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). HLA typing for Class I and II alleles was performed by serology and DNA-based technology, respectively, for 133 myositis patients and 166 Caucasian population-based controls. Myositis-specific and myositis-associated autoantibodies were detected by line immunoblot. All alleles of the 8.1AH were associated with myositis susceptibility. The B8-DR3 haplotype fragment conferred the strongest susceptibility (OR 2.9, 95% CI 1.8-4.6), and the B-DR region of other ancestral haplotypes was associated with myositis subgroups. Autoantibodies were present in 42/130 (32%) IIM patients and were more frequent in DM (11/17, 65%) than PM (23/70, 33%) or IBM (8/43, 19%), P = 0.002. Autoantibodies were associated with DRB1 03 (P = 0.0005) but also with DRB1 04 (P = 0.004). The frequency of autoantibodies in the three myositis subgroups mirrored the frequency of DR4. Polyarthralgia (±synovitis) was more common in DM/PM (30/76, 39%) than IBM (3/32, 9%), P = 0.004, and there was a strong ordinal association between the prevalence of autoantibodies and polyarthralgia ± synovitis (proportional OR = 5.5, 95% CI 2.3-13.7, P = 0.0004). The central MHC region confers the strongest susceptibility for IIM and also modulates disease phenotype. Our findings reveal a novel association of autoantibodies with DR4 and with arthralgia/synovitis in IIM and raise the possibility of a genetically (DR4) determined citrullination of myositis autoantigens expressed in muscle and synovium.
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Autoanticuerpos/análisis , Dermatomiositis/inmunología , Antígeno HLA-DR4/inmunología , Miositis por Cuerpos de Inclusión/inmunología , Sinovitis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Dermatomiositis/genética , Dermatomiositis/patología , Femenino , Antígeno HLA-DR4/genética , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/patología , Sinovitis/genética , Sinovitis/patología , Adulto JovenRESUMEN
OBJECTIVE: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies. METHODS: The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing. We examined X and Y single-nucleotide polymorphism heterogeneity to determine the number of X chromosomes. For statistical comparisons, we used χ2 analyses with calculation of 95% confidence intervals. RESULTS: Three of seventy men with SSc had 47,XXY (P = 0.0001 compared with control men). Among the 435 women with SSc, none had 47,XXX. Among 709 men with polymyositis or dermatomyositis (PM/DM), seven had 47,XXY (P = 0.0016), whereas among the 1783 women with PM/DM, two had 47,XXX. Of 147 men with inclusion body myositis (IBM), six had 47,XXY, and 1 of the 114 women with IBM had 47,XXX. For each of these myositis disease groups, the excess 47,XXY and/or 47,XXX was significantly higher compared with in controls as well as the known birth rate of Klinefelter syndrome or 47,XXX. CONCLUSION: Klinefelter syndrome (47,XXY) is associated with SSc and idiopathic inflammatory myopathies, similar to other autoimmune diseases with type 1 interferon pathogenesis, namely, systemic lupus erythematosus and Sjögren syndrome.
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BACKGROUND: Zn (Zn) is an essential trace element with important roles in protein structure and function. Labile Zn is the fraction available for regulatory functions through it loose binding to albumin. As Zn deprivation reduces labile Zn levels and leads to an immune compromised state, we investigated labile Zn levels in the context of systemic autoimmune disease. METHODS: Cross sectional case control study in patients with Systemic Lupus Erythematosus (SLE; n= 45), primary Sjögren's Syndrome (n= 53) and healthy controls (HC; n= 27). Serum labile Zn levels were measured by an in-house assay using the UV-excitable fluorophore zinquin ethyl ester. Associations between labile Zn levels and SLE manifestations were investigated by nonparametric methods. RESULTS: None of the SLE or pSS patients was found to be Zn deficient. Labile Zn levels were significantly higher in SLE (31.7 mcg/dl) than in pSS patients (22.3 mcg/dl) and HC (19.7 mcg/dl) (p<0.001). Labile Zn levels did not associate with demographics, disease activity scores, or inflammatory cytokine levels, but correlated inversely with lymphocyte counts (Rs -0.37, p<0.01), antidsDNA, anticardiolipin (Rs -0.29, p=0.01), anti-rib P antibody levels (Rs -0.24, p=0.02) and with circulating NK-cell numbers in SLE patients (Rs .27, p= 0.02). CONCLUSIONS: There is no evidence of Zn deficiency in patients with pSS or SLE. Labile Zn levels are unexpectedly high in SLE patients, independent of cytokine levels and may play a role in immune modulation through increased NK numbers and autoantibody containment.
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Lupus Eritematoso Sistémico/sangre , Síndrome de Sjögren/sangre , Zinc/sangre , Adulto , Anciano , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The clinical significance of curvilinear bodies (CB) seen in association with hydroxychloroquine (HCQ) therapy is uncertain. Patients with CB on muscle biopsy performed between 2006 and the present were identified, and their clinical features including body mass index and cumulative HCQ dose were recorded. A control group of 16 patients with idiopathic inflammatory myositis (IIM) on HCQ at time of biopsy but without evidence of CB was identified. Nineteen patients with CB were identified; details were available for 18. Among patients with CB, 7/18 also had IIM. Seven out of ten patients with CB who did not have IIM or MHCI/II expression had proximal weakness; 7/11 had raised serum creatinine kinase (CK) levels. There was no difference in body weight (p = 0.47), body mass index (p = 0.93), cumulative HCQ dose (p = 0.52) or cumulative dose adjusted for body weight (p = 0.39) or body mass index (p = 0.32) between patients with CB and controls. Patients with CB had lower median CK levels than controls (p = 0.034). Weakness was present in 12/17 patients and 12/16 controls (p = 1.0). Concurrent proton-pump inhibitors were co-prescribed in 12/18 (67 %) patients with CB and in 6/16 (38 %) controls (p = 0.17). Development of CB does not appear to be related to cumulative HCQ dose or body weight. Patients with CB frequently have muscle weakness in the absence of MHC1 expression suggesting a role for non-immune mechanisms of muscle injury. A high proportion of patients with CB are co-prescribed proton-pump inhibitors raising the possibility that co-prescription of both agents may disrupt lysosomal function and adversely affect muscle function.
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Antirreumáticos/efectos adversos , Hidroxicloroquina/efectos adversos , Debilidad Muscular/inducido químicamente , Músculo Esquelético/patología , Miositis/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Bases de Datos Factuales , Humanos , Hidroxicloroquina/uso terapéutico , Debilidad Muscular/patología , Miositis/patologíaRESUMEN
INTRODUCTION: The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population. METHODS: We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls. RESULTS: A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10(-10)) in anti-centromere antibody (ACA) positive cases. CONCLUSIONS: This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.
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Endodesoxirribonucleasas/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Esclerodermia Sistémica/genética , Autoanticuerpos/inmunología , Centrómero/inmunología , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Pleiotropía Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Proyectos Piloto , Esclerodermia Sistémica/inmunologíaRESUMEN
Low copy number (CN) of the FCGR3B gene reduces FCGR3B membrane expression on neutrophils and results in clearance of a smaller amount of immune complex. We investigated FCGR3B CN in relation to the clinical phenotype in a Caucasian SLE cohort (n = 107). FCGR3B CN was determined by three different qPCR parameter estimations (Ct-, Cy0, and cpD1) and confirmed by the FCGR2C/FCGR2A paralog ratio test. Clinical and serological data were then analyzed for their association with FCGR3B CN. Low FCGR3B CN (<2) was more frequent in SLE patients than in healthy controls (n = 162) (20% versus 6%, OR 4.15, P = 0.003) and associated with higher disease activity scores (SLEDAI 10.4 versus 6.1, P = 0.03), lupus nephritis (LN) (25 versus 5%, P = 0.03), and increased levels of antibodies against dsDNA (81 versus 37 IU, P = 0.03), C1q (22 versus 6 IU, P = 0.003), and ribosomal P (10 versus 5 IU, P = 0.01). No such associations were seen with antibodies against extractable nuclear antigens or high FCGR3B CN (>2). In multivariate analyses, LN was independently associated with anti-C1q-Ab levels (P = 0.03) and low FCGR3B CN (P = 0.09). We conclude that the susceptibility for LN in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies.
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Objective. To determine the relationship between FCGR3B gene copy number variation (CNV) and biopsy proven giant cell arteritis (GCA). Methods. FCGR3B CNV was determined in 139 Australian biopsy proven GCA patients and 162 population matched controls, using a duplex qPCR assay and RNase P as the reference gene. Copy number was determined using Copy Caller software (v.1.0, Applied Biosystems, USA). CNV genotypes were classified into 3 groups (<2, 2, 3+) for analysis purposes, and analysis was performed using logistic regression. Results. All GCA patients had a positive temporal artery biopsy, and the most common presenting symptoms were visual disturbance and temporal headache. The mean age of patients at biopsy was 74 years (range 51-94) and 88/139 (63%) were female. The frequency of low (<2) FCGR3B copy number was comparable between GCA patients (9/139 = 6.5%) and controls (10/162 = 6.2%), as was the frequency of high (3+) FCGR3B copy number (15/130 (10.8%) in GCA patients versus 13/162 (8.0%) in controls). Overall there was no evidence that FCGR3B CNV frequencies differed between GCA patients and controls (χ (2) = 0.75, df = 2, P = 0.69). Conclusion. FCGR3B CNV is not associated with GCA; however, replicate studies are required.
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Sjögren's syndrome is a common autoimmune disease (affecting â¼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10(-114)), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10(-19)), STAT4 (Pmeta = 6.80 × 10(-15)), IL12A (Pmeta = 1.17 × 10(-10)), FAM167A-BLK (Pmeta = 4.97 × 10(-10)), DDX6-CXCR5 (Pmeta = 1.10 × 10(-8)) and TNIP1 (Pmeta = 3.30 × 10(-8)). We also observed suggestive associations (Pmeta < 5 × 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.
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Inmunidad Adaptativa/genética , Sitios Genéticos/genética , Inmunidad Innata/genética , Síndrome de Sjögren/genética , Síndrome de Sjögren/inmunología , Estudios de Asociación Genética , Variación Genética , Antígenos de Histocompatibilidad Clase II/inmunología , HumanosRESUMEN
OBJECTIVE: Immune complexes play an important role in the pathogenesis of primary Sjögren's syndrome (pSS). Crosslinking of the neutrophil-specific Fc-γ receptor 3b (FCGR3B) facilitates immune complex clearance, and copy number variation (CNV) of the FCGR3B gene is known to reduce the uptake, and potentially clearance, of circulating immune complexes. Our objective was to determine whether FCGR3B CNV is a risk factor for pSS. METHODS: This was a cross-sectional study of patients with established pSS (n = 174) and population-matched controls (n = 162). FCGR3B CNV was determined by a quantitative real-time polymerase chain reaction assay, using genomic DNA as template and Taqman chemistry. Reactions were performed as a duplex, with RNAse P as the reference gene. Clinical and serological data were analyzed for their association with FCGR3B copy number (CN). RESULTS: Low FCGR3B CN (< 2 copies) was a risk factor for pSS in this cohort (p = 0.016), and combined results from this and a previous study yielded an overall OR of 2.3 (95% CI 1.3, 3.9, p = 0.003). Among patients with pSS in our cohort, low FCGR3B CN was not associated with anti-Ro ± La autoantibodies, but was associated with lower rheumatoid factor titers (p = 0.001) and serum IgG levels (p = 0.031). CONCLUSION: We confirmed that, similarly to other systemic autoimmune diseases, FCGR3B CN is a genetic susceptibility factor for pSS. As in rheumatoid arthritis, the mechanism does not appear to be related to seropositivity for characteristic autoantibodies.
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Dosificación de Gen/genética , Predisposición Genética a la Enfermedad/genética , Receptores de IgG/genética , Síndrome de Sjögren/genética , Autoanticuerpos/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Estudios Transversales , Femenino , Proteínas Ligadas a GPI/genética , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Factor Reumatoide/sangre , Factor Rho/inmunología , Factores de Riesgo , Síndrome de Sjögren/sangreRESUMEN
Behçet's disease (BD) is an immune-mediated systemic vasculitis associated with HLAB51. Other gene associations are likely and may provide further insight into the pathogenesis of this disease. Fc-gamma receptors play an important role in regulating immune function. Copy number variation (CNV) of the Fc-gamma receptor 3B (FCGR3B) gene is associated with other inflammatory conditions and may also play a role in BD. The aim of this study was to determine whether CNV of the FCGR3B gene is associated with BD or its clinical features. FCGR3B copy number was determined for 187 Iranian patients and 178 ethnicity-matched controls using quantitative real-time PCR. The genotype frequencies were comparable in both BD patients and controls. The odds ratio for low copy number (<2CN) was 0.6 (P = 0.16) and the odds ratio for high copy number (>2CN) was 0.75 (P = 0.50). There was no association found between high or low CN of the FCGR3B gene and BD or its clinical features in this Iranian population. We are the first to report this finding which, when looked at in the context of other genetic studies, gives us further insight into the complex pathogenesis of BD.