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Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE 总被引:17,自引:0,他引:17 下载免费PDF全文
Kyogoku C Langefeld CD Ortmann WA Lee A Selby S Carlton VE Chang M Ramos P Baechler EC Batliwalla FM Novitzke J Williams AH Gillett C Rodine P Graham RR Ardlie KG Gaffney PM Moser KL Petri M Begovich AB Gregersen PK Behrens TW 《American journal of human genetics》2004,75(3):504-507
We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. 相似文献
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Rheumatic heart disease (RHD) or acute rheumatic fever (ARF) develops as a consequence of an exaggerated immune response
to Group A beta haemolytic streptococci causing pharyngitis. The molecular mimicry appears between human cardiac myosin and
M protein of group A streptococcal membranes. The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22)
gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility
to several autoimmune diseases such as SLE and RA. The objective of this study was to investigate whether PTPN22 R620W polymorphism
confers susceptibility to RHD in Turkish population. PTPN 22 R620W (rs2476601, A/G) polymorphism was genotyped by PCR-RFLP
in 121 patients with RHD who fulfilling the revised classification criteria of Jones, and 160 healthy control (HC), and also
137 SLE as a diseased–control. The frequency of GG and AG genotypes were found to be 94% (114), 6% (7) in RHD, respectively
and 96% (153) and 4% (7) in HC, respectively. The homozygous AA genotype was not present in RHD and HC. There was no statistically
significant difference between RHD and HC according to the frequency of AG heterozygote genotype (P = 0.831; OR = 1.13; 95% CI 0.37–3.46). The frequency of the rare allele A was also very similar in RHD patients and HC (3,
2% respectively). A similar result was also found between SLE and HC. Our results demonstrated that the PTPN22 R620W polymorphism
is not associated with RHD nor with SLE in Turkish population. 相似文献
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Edoardo Fiorillo Valeria Orrú Stephanie M. Stanford Yingge Liu Mogjiborahman Salek Novella Rapini Aaron D. Schenone Patrizia Saccucci Lucia G. Delogu Federica Angelini Maria Luisa Manca Bitti Christian Schmedt Andrew C. Chan Oreste Acuto Nunzio Bottini 《The Journal of biological chemistry》2010,285(34):26506-26518
A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling. 相似文献
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The PTPN22-1858C>T (R620W) functional polymorphism is associated with generalized vitiligo in the Romanian population 总被引:1,自引:0,他引:1
Generalized vitiligo is an autoimmune disorder of the skin in which autoimmune-mediated destruction of melanocytes leads to depigmented patches of skin and overlying hair. The 1858C>T (R620W) functional polymorphism of the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (Lyp), has been associated with susceptibility to a number of autoimmune disorders, including generalized vitiligo. The aim of this study was to test genetic association of the PTPN22 1858C>T variant and generalized vitiligo in a Romanian case-control cohort. We observed significant association of generalized vitiligo with the 1858T risk allele of PTPN22 [P = 0.0138; OR = 2.92 (1.21-7.03)], with significantly different distribution of PTPN22 1858C>T genotypes in cases versus controls [P = 0.036; OR = 2.69 (1.07-6.80)]. Our results provide evidence that the PTPN22 1858T allele contributes to risk of generalized vitiligo in European Caucasian populations, and underscores the importance of a genetically mediated autoimmune mechanism in the pathogenesis of vitiligo. 相似文献
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Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes 总被引:14,自引:0,他引:14 下载免费PDF全文
Criswell LA Pfeiffer KA Lum RF Gonzales B Novitzke J Kern M Moser KL Begovich AB Carlton VE Li W Lee AT Ortmann W Behrens TW Gregersen PK 《American journal of human genetics》2005,76(4):561-571
Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes. 相似文献
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The PTPN22 gene, located on chromosome 1p13, encoding lymphoid protein tyrosine phosphatase (LYP), plays a crucial role in the negative
control of T lymphocyte activation. Since the age-related change in T-cell signal transduction may be one of the most important
causes of cell-mediated immune response decline with ageing, we performed a population-based association study to test whether
the PTPN22 1858C>T (R620W) functional polymorphism affects the ability to survive to old age and to reach even exceptional life expectancy.
892 unrelated healthy individuals (age range 8–106 years, 403 males and 489 females) from central Italy were studied. For
both gender, the frequency of PTPN22*T1858 carriers does not differ significantly in nona/centenarians and in octogenarians respect to young group. Allele and
genotype frequencies of age groups were compared to those reported in previously published studied carried out on control
individuals with Italic ancestry (N = 1393), further confirming results obtained from our sample population. Overall, our
study suggests that PTPN22*T1858 allele is not negatively selected at oldest ages and we speculate that its increased ability to protect individuals
against development of infectious diseases may counteract its deleterious effect on immune system leading to autoimmunity. 相似文献
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Kouhpayeh HR Hashemi M Hashemi SA Moazeni-Roodi A Naderi M Sharifi-Mood B Taheri M Mohammadi M Ghavami S 《Genetics and molecular research : GMR》2012,11(2):1075-1081
The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, which encodes an intracellular lymphoid-specific phosphatase, is considered an important regulator of T-cell activation. We investigated a possible association between the PTPN22 C1858T (R620W) polymorphism and pulmonary tuberculosis in an Iranian population. Single nucleotide polymorphisms of PTPN22 C1858T (rs2476601) were genotyped in 172 pulmonary tuberculosis cases and 204 normal subjects from Zaheden, Iran. Frequencies of genotypes CC, CT and TT of the PTPN22 C1858T polymorphism were 98.3, 1.7 and 0% in the pulmonary tuberculosis patients, and 96.1, 3.9 and 0% in the control group, respectively (P = 0.239). The frequency of the minor (T) allele was 0.8% in pulmonary tuberculosis patients and 2.0% in controls. Significant differences were not observed in genotype or allele frequencies of PTPN22 C1858T in the comparison between pulmonary tuberculosis patients and healthy subjects in our Iranian population sample. 相似文献
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Wan Taib WR Smyth DJ Merriman ME Dalbeth N Gow PJ Harrison AA Highton J Jones PB Stamp L Steer S Todd JA Merriman TR 《PloS one》2010,5(10):e13544
Objectives
The Trp620 allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype ‘5’, haplotype group ‘6–10’ and susceptibility haplotype ‘4’, suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility.Methods
A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.Results
The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10−5). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85).Conclusions
We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant. 相似文献11.
Chelsea L. Deschamps Kimberly E. Connors Matthias S. Klein Virginia L. Johnsen Jane Shearer Hans J. Vogel Joseph M. Devaney Heather Gordish-Dressman Gina M. Many Whitney Barfield Eric P. Hoffman William E. Kraus Dustin S. Hittel 《PloS one》2015,10(6)
Homozygosity for a premature stop codon (X) in the ACTN3 “sprinter” gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs 43.2 ±1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 ± 2 vs 105 ± mmHg, p = 0.027) and diastolic (69 ± 3 vs 59 ± 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene. 相似文献
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《PloS one》2013,8(8)
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10−9, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10−5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG. 相似文献
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Association of SLC22A4 Gene Polymorphism with Rheumatoid Arthritis in the Chinese Population 下载免费PDF全文
Tian‐li Ren Zhi‐jun Han Cheng‐jian Yang Yuan‐xing Hang De‐yu Fang Ke Wang Xue Zhu Xiao‐jing Ji Fan‐fan Zhou 《Journal of biochemical and molecular toxicology》2014,28(5):206-210
Rheumatoid arthritis (RA) is a chronic inflammatory disease with complex genetic factors. Single‐nucleotide polymorphisms (SNPs) in the SLC22A4 gene have been previously reported to be associated with RA in Japanese but not European populations. This study further investigated the association of SLC22A4 polymorphisms, in particular slc2F1/slc2F2, with RA in the Chinese population, the largest Asian population. A total of 160 human subjects with 95 RA patients and 65 healthy controls were genotyped for slc2F1‐G/A and slc2F2‐C/T polymorphisms. The results showed that there was a significant difference in the genotype distribution of these two polymorphisms between the two groups. In addition, the presence of slc2F1 A allele and slc2F2 T allele carries a 1.93‐fold and 2.14‐fold increased risk for anticyclic citrullinated peptide (CCP) positivity, respectively. Overall, this study provided evidence that SLC22A4 gene polymorphisms played important roles in the etiology of RA in the largest Asian population, the Chinese population. 相似文献
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Fabio Coppedè Roberta Ricciardi Maria Denaro Anna De Rosa Carlo Provenzano Emanuela Bartoccioni Angelo Baggiani Marco Lucchi Alfredo Mussi Lucia Migliore 《PloS one》2013,8(11)
Increasing evidence suggests a contribution of epigenetic processes in promoting cancer and autoimmunity. Myasthenia gravis (MG) is an autoimmune disease mediated, in approximately 80% of the patients, by antibodies against the nicotinic acetylcholine receptor (AChR+). Moreover, epithelial tumours (thymomas) are present in about 10-20% of the patients, and there is indication that changes in DNA methylation might contribute to the risk and progression of thymomas. However, the role of epigenetics in MG is still not completely clarified. In the present study we investigated if a common polymorphism (-579G>T: rs1569686) in the promoter of the DNMT3B gene coding for the DNA methyltransferase 3B, an enzyme that mediates DNA methylation, increases the risk to develop MG or MG-associated thymomas. The study polymorphism was selected based on recent reports and a literature meta-analysis suggesting association with increased risk of various types of cancer. We screened 324 AChR+ MG patients (140 males and 184 females, mean age 56.0 ± 16.5 years) and 735 healthy matched controls (294 males and 441 females, mean age 57.3 ± 15.6 years). 94 of the total MG patients had a thymoma. While there was no association with the whole cohort of MG patients, we found a statistically significant association of the DNMT3B
-579T allele (OR = 1.51; 95% CI=1.1-2.1, P = 0.01) and the TT homozygous genotype (OR = 2.59; 95% CI=1.4-4.9, P = 0.006) with the risk of thymoma. No association was observed in MG patients without thymoma, even after stratification into clinical subtypes. Present results suggest that the DNMT3B
-579T allele might contribute to the risk of developing thymoma in MG patients, particularly in homozygous TT subjects. 相似文献
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Butt C Peddle L Greenwood C Hamilton S Gladman D Rahman P 《Arthritis research & therapy》2006,8(1):R27
Recent studies have implicated PTPN22 and tp53 in susceptibility to several autoimmune diseases, including rheumatoid arthritis, suggesting that these genes are important in maintaining immune homeostasis. Because autoimmune diseases may share similar susceptibility loci, investigation of these genes in psoriatic arthritis (PsA) is of potential relevance. As a result we investigated known coding polymorphisms in PTPN22 and tp53 in a homogenous Caucasian PsA cohort from Newfoundland, Canada and an admixed Caucasian PsA cohort from Toronto, Canada. We observed a moderate association of the R620W variant of PTPN22 with PsA in the Toronto population only. Because of the conflicting findings reported regarding the association of PTPN22 with PsA, further studies in other PsA populations are warranted. 相似文献
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Michael F Seldin Omar K Alkhairy Annette T Lee Janine A Lamb Jon Sussman Ritva Pirskanen-Matell Fredrik Piehl Jan J G M Verschuuren Anna Kostera-Pruszczyk Piotr Szczudlik David McKee Angelina H Maniaol Hanne F Harbo Benedicte A Lie Arthur Melms Henri-Jean Garchon Nicholas Willcox Peter K Gregersen Lennart Hammarstrom 《Molecular medicine (Cambridge, Mass.)》2015,21(1):769-781
To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti–acetylcholine receptor [AChR] antibody positive; onset age ≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10−7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10−10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10−6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10−12) versus 2.82 in EOMG (P = 3.86 × 10−45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG. 相似文献
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豚鼠Cavia porcellus的隐性黄毛色表型是由编码黑素皮质激素受体1(MC1R)的extension基因座位的等位基因e控制。本研究对野生型和黄毛色豚鼠MC1R基因位点所在区域进行PCR扩增与测序发现,在黄毛色豚鼠中存在1个2 760 bp的基因组缺失,该缺失涵盖了MC1R基因的整个编码区。采用三引物扩增体系对豚鼠MC1R基因缺失突变进行群体基因分型,在随机选择的58只野生型个体中,36只为EE纯合子,22只为Ee杂合子,而31只黄毛色个体均为ee纯合子;在15只测交后代中,8只黄毛色个体均为ee纯合子,而7只野生型个体均为Ee杂合子。基因分型结果表明,MC1R基因2 760 bp的缺失与隐性黄毛色完全相关。本研究为进一步探究MC1R基因在哺乳动物毛色遗传机制中的作用以及豚鼠的分子标记辅助育种提供了理论依据。 相似文献
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Chrysiis Michaloglou Waltraut Lehmann Typhaine Martin Clara Delaunay Andreas Hueber Louise Barys Honglin Niu Eric Billy Markus Wartmann Moriko Ito Christopher J. Wilson Mary Ellen Digan Andreas Bauer Hans Voshol Gerhard Christofori William R. Sellers Francesco Hofmann Tobias Schmelzle 《PloS one》2013,8(4)
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Maine CJ Hamilton-Williams EE Cheung J Stanford SM Bottini N Wicker LS Sherman LA 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(11):5267-5275
PTPN22 encodes a tyrosine phosphatase that inhibits Src-family kinases responsible for Ag receptor signaling in lymphocytes and is strongly linked with susceptibility to a number of autoimmune diseases. As strength of TCR signal is critical to the thymic selection of regulatory T cells (Tregs), we examined the effect of murine PTPN22 deficiency on Treg development and function. In the thymus, numbers of pre-Tregs and Tregs increased inversely with the level of PTPN22. This increase in Tregs persisted in the periphery and could play a key part in the reduced severity observed in the PTPN22-deficient mice of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This could explain the lack of association of certain autoimmune conditions with PTPN22 risk alleles. 相似文献