RESUMEN
Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the GBA1 gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of formation and breakdown of glucocerebroside and glucosylsphingosine, resulting in the accumulation of these lipid substrates in the lysosome. This gives rise to the development of Gaucher cells, engorged macrophages with a characteristic wrinkled tissue paper appearance. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease, associated with varying degrees of severity. The visceral and hematologic manifestations of Gaucher disease respond well to both enzyme replacement therapy and substrate reduction therapy. However, these therapies do not improve the neuronopathic manifestations, as they cannot cross the blood-brain barrier. There is now an established precedent for treating lysosomal storage disorders with gene therapy strategies, as many have the potential to cross into the brain. The range of the gene therapies being employed is broad, but this review aimed to discuss the progress, advances, and challenges in developing viral gene therapy as a treatment for Gaucher disease.
Asunto(s)
Enfermedad de Gaucher , Humanos , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/terapia , Glucosilceramidasa/genética , Glucosilceramidasa/uso terapéutico , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Macrófagos/metabolismoRESUMEN
Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in GBA1, characterized by glucocerebrosidase dysfunction and glucocerebroside and glucosylsphingosine accumulation. Since phenotypes of murine models of GD often differ from those in patients, the careful characterization of Gba1 mutant mice is necessary to establish their ability to model GD. We performed side-by-side comparative biochemical and pathologic analyses of four murine Gba1 models with genotypes L444P/L444P (p.L483P/p.L483P), L444P/null, D409H/D409H (p.D448H/p.D448H) and D409H/null, along with matched wildtype mice, all with the same genetic background and cage conditions. All mutant mice exhibited significantly lower glucocerebrosidase activity (p < 0.0001) and higher glucosylsphingosine levels than wildtype, with the lowest glucocerebrosidase and the highest glucosylsphingosine levels in mice carrying a null allele. Although glucocerebrosidase activity in L444P and D409H mice was similar, D409H mice showed more lipid accumulation. No Gaucher or storage-like cells were detected in any of the Gba1 mutant mice. Quantification of neuroinflammation, dopaminergic neuronal loss, alpha-synuclein levels and motor behavior revealed no significant findings, even in aged animals. Thus, while the models may have utility for testing the effect of different therapies on enzymatic activity, they did not recapitulate the pathological phenotype of patients with GD, and better models are needed.
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Enfermedad de Gaucher , Psicosina/análogos & derivados , Ratones , Humanos , Animales , Anciano , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/patología , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Modelos Animales de Enfermedad , Encéfalo/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , MutaciónRESUMEN
BACKGROUND: Genome editing using CRISPR/Cas9 has become a powerful tool in zebrafish to generate targeted gene knockouts models. However, its use for targeted knock-in remains challenging due to inefficient homology directed repair (HDR) pathway in zebrafish, highlighting the need for efficient and cost-effective screening methods. RESULTS: Here, we present our fluorescent PCR and capillary electrophoresis based screening approach for knock-in using a single-stranded oligodeoxynucleotide donor (ssODN) as a repair template for the targeted insertion of epitope tags, or single nucleotide changes to recapitulate pathogenic human alleles. For the insertion of epitope tags, we took advantage of the expected change in size of the PCR product. For point mutations, we combined fluorescent PCR with restriction fragment length polymorphism (RFLP) analysis to distinguish the fish with the knock-in allele. As a proof-of-principle, we present our data on the generation of fish lines with insertion of a FLAG tag at the tcnba locus, an HA tag at the gata2b locus, and a point mutation observed in Gaucher disease patients in the gba gene. Despite the low number of germline transmitting founders (1-5%), combining our screening methods with prioritization of founder fish by fin biopsies allowed us to establish stable knock-in lines by screening 12 or less fish per gene. CONCLUSIONS: We have established a robust pipeline for the generation of zebrafish models with precise integration of small DNA sequences and point mutations at the desired sites in the genome. Our screening method is very efficient and easy to implement as it is PCR-based and only requires access to a capillary sequencer.
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Mutación Puntual , Pez Cebra , Humanos , Animales , Pez Cebra/genética , Epítopos , InvestigaciónRESUMEN
Parkinson disease, the second most common movement disorder, is a complex neurodegenerative disorder hallmarked by the accumulation of alpha-synuclein, a neural-specific small protein associated with neuronal synapses. Mutations in the glucocerebrosidase gene (GBA1), implicated in the rare, autosomal recessive lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease. Insights into the inverse relationship between glucocerebrosidase and alpha-synuclein have led to new therapeutic approaches for the treatment of Gaucher disease and GBA1-associated Parkinson disease. Unlike the current drugs used to treat Gaucher disease, which are highly expensive and do not cross the blood-brain-barrier, new small molecules therapies, including competitive and non-competitive chaperones that enhance glucocerebrosidase levels are being developed to overcome these limitations. Some of these include iminosugars, ambroxol, other competitive glucocerebrosidase inhibitors, and non-inhibitory chaperones or activators that do not compete for the active site. These drugs, which have been shown in different disease models to increase glucocerebrosidase activity, could have potential as a therapy for Gaucher disease and GBA1- associated Parkinson disease. Some have been demonstrated to reduce α-synuclein levels in pre-clinical studies using cell-based or animal models of GBA1-associated Parkinson disease, and may also have utility for idiopathic Parkinson disease.
RESUMEN
Stuttering is a common neurodevelopmental disorder that has been associated with mutations in genes involved in intracellular trafficking. However, the cellular mechanisms leading to stuttering remain unknown. Engineering a mutation in N-acetylglucosamine-1-phosphate transferase subunits α and ß (GNPTAB) found in humans who stutter into the mouse Gnptab gene resulted in deficits in the flow of ultrasonic vocalizations similar to speech deficits of humans who stutter. Here we show that other human stuttering mutations introduced into this mouse gene, Gnptab Ser321Gly and Ala455Ser, produce the same vocalization deficit in 8-day-old pup isolation calls and do not affect other nonvocal behaviors. Immunohistochemistry showed a marked decrease in staining of astrocytes, particularly in the corpus callosum of the Gnptab Ser321Gly homozygote mice compared to wild-type littermates, while the staining of cerebellar Purkinje cells, oligodendrocytes, microglial cells, and dopaminergic neurons was not significantly different. Diffusion tensor imaging also detected deficits in the corpus callosum of the Gnptab Ser321Gly mice. Using a range of cell type-specific Cre-drivers and a Gnptab conditional knockout line, we found that only astrocyte-specific Gnptab-deficient mice displayed a similar vocalization deficit. These data suggest that vocalization defects in mice carrying human stuttering mutations in Gnptab derive from abnormalities in astrocytes, particularly in the corpus callosum, and provide support for hypotheses that focus on deficits in interhemispheric communication in stuttering.
Asunto(s)
Astrocitos/metabolismo , Cuerpo Calloso/metabolismo , Mutación , Tartamudeo/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Vocalización Animal , Animales , Recuento de Células , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Transgénicos , Fenotipo , Hidrolasas Diéster Fosfóricas/sangreRESUMEN
The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (ε-ß4-µ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as "AP-4 deficiency syndrome". In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the ε subunit of AP-4. We find that AP-4 ε KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the µ4 subunit of AP-4 and in various neuronal types in AP-4 ε KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 ε KO neurons. These findings indicate that the AP-4 ε KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.
Asunto(s)
Complejo 4 de Proteína Adaptadora/deficiencia , Complejo 4 de Proteína Adaptadora/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas de la Membrana/metabolismo , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Complejo 4 de Proteína Adaptadora/química , Subunidades del Complejo de Proteínas Adaptadoras/química , Subunidades del Complejo de Proteínas Adaptadoras/deficiencia , Subunidades del Complejo de Proteínas Adaptadoras/genética , Animales , Axones/metabolismo , Conducta Animal/fisiología , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Proteína Huntingtina/química , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Neuronas/metabolismo , Agregado de Proteínas/genética , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismo , Receptores de Glutamato/metabolismo , Paraplejía Espástica Hereditaria/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Red trans-Golgi/metabolismoRESUMEN
A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general "cellular housekeeping" genes is unknown. To address this question, we asked whether a missense mutation associated with human stuttering causes vocal or other abnormalities in mice. We compared vocalizations from mice engineered to carry a mutation in the Gnptab (N-acetylglucosamine-1-phosphotransferase subunits alpha/beta) gene with wild-type littermates. We found significant differences in the vocalizations of pups with the human Gnptab stuttering mutation compared to littermate controls. Specifically, we found that mice with the mutation emitted fewer vocalizations per unit time and had longer pauses between vocalizations and that the entropy of the temporal sequence was significantly reduced. Furthermore, Gnptab missense mice were similar to wild-type mice on an extensive battery of non-vocal behaviors. We then used the same language-agnostic metrics for auditory signal analysis of human speech. We analyzed speech from people who stutter with mutations in this pathway and compared it to control speech and found abnormalities similar to those found in the mouse vocalizations. These data show that mutations in the lysosomal enzyme-targeting pathway produce highly specific effects in mouse pup vocalizations and establish the mouse as an attractive model for studying this disorder.
RESUMEN
Two single-nucleotide polymorphisms (SNPs) in SLC22A4 encoding an organic cation/zwitterion transporter protein, rs2073838 (commonly called slc2F1) and rs3792876 (slc2F2), had been associated with susceptibility to rheumatoid arthritis (RA) in two Japanese and one recent Chinese studies but not in other two Japanese and six Caucasian studies. In this study, the two SNPs were genotyped for 2313 Korean participants and their associations with RA susceptibility and severity were examined. SNP association with RA susceptibility was tested among 1304 RA patients and 1009 healthy controls, and association with joint erosion among 1063 erosive and 241 non-erosive RA patients. Meta-analysis for RA susceptibility association was additionally performed using 10 previous studies and the current one. The two SNPs were almost perfectly correlated with each other (r(2 )= 0.98), and therefore only slc2F1 was tested for association. RA susceptibility association was not found in Koreans (p = 0.93), but still significant in meta-analysis of six Asian studies including this Korean study (p = 0.00036, odds ratio = 1.1) or all 11 studies additionally including five Caucasian studies (p = 0.00021, odds ratio = 1.1). In contrast, an association was found for RA severity in Koreans. The minor allele A was marginally associated with 1.5-fold increased risk of joint erosion among RA patients afflicted for ≤11 years (p = 0.025) or ≤7 years (p = 0.029), though not among patients with longer-standing RA. Accordingly, SLC22A4 was associated with joint erosion in not-very-longstanding RA, although RA susceptibility association was weak and its clinical significance was uncertain.
Asunto(s)
Artritis Reumatoide/genética , Artritis Reumatoide/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Articulaciones/patología , Proteínas de Transporte de Catión Orgánico/genética , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Oportunidad Relativa , Simportadores , Adulto JovenRESUMEN
A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.
Asunto(s)
Encéfalo/metabolismo , Factores de Transcripción Forkhead/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Tartamudeo/genética , Tartamudeo/metabolismo , Adulto , Brasil , Niño , Preescolar , Femenino , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Humanos , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/metabolismo , Análisis por Micromatrices , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/metabolismo , América del Norte , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Población Blanca/genética , Adulto JovenRESUMEN
OBJECTIVE: To investigate whether a human X chromosome locus of IRAK1 and MECP2 is associated with susceptibility to rheumatoid arthritis (RA), an autoimmune disease that predominantly affects women. METHODS: A total of 2,334 unrelated Korean participants (including 1,318 patients with RA) were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) and 3 additional SNPs in an Xq28 region harboring MECP2 and IRAK1. Twenty-nine additional neighboring SNPs were imputed using the Korean HapMap Project data. All 37 SNPs were statistically tested for association with RA susceptibility, and 2 SNPs associated with RA were examined for their functional effects. RESULTS: RA susceptibility was associated with multiple SNPs in a 79-kb linkage disequilibrium block harboring both MECP2 and IRAK1. The most significant association was for MECP2 SNP rs1734792 (P = 0.00089), but 2 nonsynonymous IRAK1 SNPs, rs1059702 (P = 0.0034) and rs1059703 (P = 0.0042), which were in strong linkage disequilibrium with the MECP2 SNP (D' = 0.87 and 0.91, respectively) affected IRAK1 protein activity. The major haplotype of the 2 nonsynonymous SNPs was associated with a 1.7-fold increase in RA susceptibility versus the minor haplotype (P = 0.0082), and with increased IRAK1 activity, which was demonstrated by a 1.7-fold increase in the intracellular activity of transcription factor NF-κB. CONCLUSION: Our findings indicate that RA susceptibility is associated with multiple SNPs in MECP2 and IRAK1, but high linkage disequilibrium between them does not allow for further localization. Therefore, both genes remain candidates. Nevertheless, the major haplotype of the 2 nonsynonymous IRAK1 SNPs encoding for pPhe196Ser and pSer532Leu confers enhanced IRAK1 activity and, consequently, enhanced susceptibility to RA, as compared to the minor haplotype.
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Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Quinasas Asociadas a Receptores de Interleucina-1/genética , Proteína 2 de Unión a Metil-CpG/genética , Adulto , Anciano , Artritis Reumatoide/epidemiología , Linfocitos B/citología , Linfocitos B/fisiología , Estudios de Casos y Controles , Línea Celular Transformada , Cromosomas Humanos X/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , República de Corea/epidemiologíaRESUMEN
INTRODUCTION: Anti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status. METHODS: All 2,317 unrelated Korean subjects including 1,313 patients with RA and 1,004 unaffected controls were genotyped for three nonsynonymous (padi4_89, padi4_90, and padi4_92) and one synonymous (padi4_104) single-nucleotide polymorphisms (SNPs) in PADI4 and for HLA-DRB1 by direct DNA sequence analysis. Odds ratios (OR) were calculated by multivariate logistic regression. Interaction was evaluated by attributable proportions (AP), with 95% confidence intervals (CI). RESULTS: A functional haplotype of the three fully correlated nonsynonymous SNPs in PADI4 was significantly associated with susceptibility to not only anti-CCP-positive (adjusted OR 1.73, 95% CI 1.34 to 2.23) but also -negative RA (adjusted OR 1.75, 95% CI 1.15 to 2.68). A strong association with both non-erosive (adjusted OR 1.62, 95% CI 1.29 to 2.05) and erosive RA (adjusted OR 1.62, 95% CI 1.14 to 2.31) was observed for PADI4 haplotype. Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92). Theses interactions were also observed for both non-erosive (AP 0.48, 95% CI 0.25 to 0.72) and erosive RA (AP 0.46, 95% CI 0.14 to 0.78). In contrast, no interaction was observed between smoking and PADI4 polymorphisms. CONCLUSIONS: A haplotype of nonsynonymous SNPs in PADI4 contributes to development of RA regardless of anti-CCP or erosive joint status. The homozygous PADI4 haplotype contribution is affected by gene-gene interactions with HLA-DRB1 SE alleles.
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Anticuerpos Antiidiotipos/sangre , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Epítopos/genética , Haplotipos/genética , Hidrolasas/genética , Articulaciones/patología , Péptidos Cíclicos/inmunología , Adulto , Alelos , Artritis Reumatoide/etnología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Genotipo , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Humanos , Articulaciones/inmunología , Corea (Geográfico) , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Arginina Deiminasa Proteína-Tipo 4 , Desiminasas de la Arginina ProteicaAsunto(s)
Antígenos CD/genética , Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Inmunológicos/genética , Artritis Reumatoide/etnología , Estudios de Casos y Controles , Femenino , Humanos , Japón , Corea (Geográfico) , Desequilibrio de Ligamiento/genética , Lupus Eritematoso Sistémico/etnología , Masculino , Familia de Moléculas Señalizadoras de la Activación LinfocitariaRESUMEN
OBJECTIVE: Recent genome-wide association scans and replication studies of European populations have disclosed several single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA) susceptibility. The aim of this study was to evaluate the RA-associated loci by genotyping previously reported SNPs and additional tag SNPs in a Korean population. METHODS: A total of 1,316 unrelated RA patients and 1,006 controls were genotyped for 12 SNPs identified in genome-wide scans and for 12 additional tag SNPs in IL2RB, OLIG3-TNFAIP3, PTPN22, and TRAF1-C5, and the findings were statistically compared. RESULTS: None of the SNPs tested was associated with RA susceptibility, except rs7021206 in TRAF1 intron 3 (P = 0.0032) and, among the SNPs previously reported, rs6457617 in HLA (P = 4.6 x 10(-35)). The association of rs7021206 was positive in patients who were seropositive for rheumatoid factor (P = 0.0051) or for anti-cyclic citrullinated peptide autoantibodies (P = 0.0062). However, Korean patients were negative for the association of rs3761847 in the TRAF1-C5 intergenic region previously reported in Caucasians. Linkage disequilibrium between rs3761847 and rs7021206 was not as high in Koreans (r(2) = 0.37) as in Caucasians (r(2) = 0.67), which explains the lack of association of rs3761847 in Koreans. Accordingly, RA susceptibility was localized to an extended haplotype marked by rs7021206 rather than rs3761847, and SNPs highly correlated with rs7021206 (r(2) > or = 0.81) extended from rs1953126 in the PHF19-TRAF1 intergenic region to rs2900180 in the TRAF1-C5 intergenic region, spanning 66 kb. CONCLUSION: Our results demonstrate that within and around TRAF1, excluding PHF19 and C5, SNPs highly correlated with rs7021206, but not those correlated with rs3761847, are associated with RA in both Asians and Caucasians and are possibly correlated with causative variations.
Asunto(s)
Artritis Reumatoide/genética , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Factor 1 Asociado a Receptor de TNF/genética , Población Blanca/genética , Adulto , Estudios de Casos y Controles , Femenino , Genotipo , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Haplotipos/genética , Humanos , Corea (Geográfico) , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are rheumatoid arthritis (RA)-specific serologic markers. RA susceptibility has been associated with HLA-DRB1 shared epitope (SE) alleles and single-nucleotide polymorphism (SNP) haplotypes in the peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti-CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA. METHODS: Three nonsynonymous SNPs in PADI4 (padi4_89, padi4_90, and padi4_92) and SE alleles were genotyped, and serum anti-CCP levels were measured, in 311 patients with nonerosive or erosive RA. The relationships between anti-CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically. RESULTS: Anti-CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti-CCP-positive patients with RA with a disease duration of