Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1832526 (PCC)
 5,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-cyclic citrullinated peptide antibodies (anti-CCP) are a new diagnostic marker for rheumatoid arthritis (RA), which shows a specificity of 97% and a sensitivity of 81% in the second generation assay. About 61% of RA patients express HLA-DRB1*0401. In a cohort of patients with RA we investigated whether the expression of anti-CCP correlates with the carriage of certain genes on the HLA-DRB1 locus. Our data reveal a highly significant association between anti-CCP and HLA-DR4, and a weaker but still significant association with HLA-DR1. HLA-DRB1*0401 is not a prerequisite for anti-CCP production, but if HLA-DRB1*0401 was present, 90% of our RA patients were anti-CCP positive.
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PMID:HLA-DRB1 and anti-cyclic citrullinated peptide antibody production in rheumatoid arthritis. 1597 Jun 40

Recent progress in defining the role of genetic factors in rheumatoid arthritis (RA) has been remarkable. Anticyclic citrullinated peptide (anti-CCP) antibody-positive disease appears to be immunogenetically distinct from anti-CCP-negative disease, with the former subgroup primarily responsible for association and linkage with the HLA-DRB1 shared epitope (SE). There is preliminary evidence that non-HLA genes contribute differentially to anti-CCP-positive and negative disease. The phenotypic differences evident in anti-CCP-positive and negative disease suggest a need to reclassify RA based on the presence or absence of this autoantibody. Some recent work also suggests marked interactions between cigarette smoking, anti-CCP antibodies, and the SE, though these relationships may vary across populations. Lastly, a recent single nucleotide polymorphism-based genome-wide linkage analysis of multicase RA families revealed novel genomic regions that likely contain genes that predispose to RA or more specific phenotypes.
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PMID:Recent advances in the genetics of rheumatoid arthritis. 1697 14

Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA--the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele--in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. "Interaction" was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP-positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP-positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.
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PMID:Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. 1743 41

Polymorphisms of the peptidylarginine deiminase 4 (PADI4) gene encoding for the isoenzyme that converts arginyl into citrullyl residues have been shown to contribute to susceptibility to rheumatoid arthritis (RA), depending on the population studied. We aimed at determining whether PADI4 single nucleotide polymorphisms (SNPs) are associated with RA in a Hungarian population. The relationship between anticyclic citrullinated peptide (anti-CCP) production and HLA-DRB1 alleles encoding the shared epitope (SE) was also investigated. DNA samples were obtained from RA (n = 261) patients and from control donors (n = 120). HLA-DRB1 genotyping was carried out by polymerase chain reaction (PCR) with sequence-specific priming. PAD4_92 G/C and PAD4_104 T/C SNPs were genotyped using real-time PCR allele discrimination. Autoantibodies against CCP were detected by ELISA. All healthy controls tested anti-CCP negative, whereas 171 (66%) RA patients were anti-CCP positive. No significant difference in allele or genotype frequencies were found between RA patients and controls for any of the PADI4 SNPs. Anti-CCP seropositivity was unrelated to these two SNPs. No association was found between any of the PADI4 SNPs and HLA-DRB1 subtypes. Presence of the HLA-RB1 SE alleles was significantly associated with anti-CCP seropositivity; HLA-DRB1*0401 and HLA-DRB1*1001 carriers showed the strongest association. In conclusion, our data suggest that polymorphisms of the PADI4 gene are not associated with rheumatoid arthritis and are unlikely to be responsible for the presence of anti-CCP autoantibodies in a white Hungarian population. HLA-DRB1 SE alleles, however, may significantly contribute to the genetic determination of anti-CCP production in Hungarian patients with RA.
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PMID:Genetic background of anticyclic citrullinated peptide autoantibody production in Hungarian patients with rheumatoid arthritis. 1791 17

Recent evidence suggests that additional risk loci for RA are present in the major histocompatibility complex (MHC), independent of the class II HLA-DRB1 locus. We have now tested a total of 1,769 SNPs across 7.5Mb of the MHC located from 6p22.2 (26.03 Mb) to 6p21.32 (33.59 Mb) derived from the Illumina 550K Beadchip (Illumina, San Diego, CA, USA). For an initial analysis in the whole dataset (869 RA CCP + cases, 1,193 controls), the strongest association signal was observed in markers near the HLA-DRB1 locus, with additional evidence for association extending out into the Class I HLA region. To avoid confounding that may arise due to linkage disequilibrium with DRB1 alleles, we analyzed a subset of the data by matching cases and controls by DRB1 genotype (both alleles matched 1:1), yielding a set of 372 cases with 372 controls. This analysis revealed the presence of at least two regions of association with RA in the Class I region, independent of DRB1 genotype. SNP alleles found on the conserved A1-B8-DR3 (8.1) haplotype show the strongest evidence of positive association (P ~ 0.00005) clustered in the region around the HLA-C locus. In addition, we identified risk alleles that are not present on the 8.1 haplotype, with maximal association signals (P ~ 0.001-0.0027) located near the ZNF311 locus. This latter association is enriched in DRB1*0404 individuals. Finally, several additional association signals were found in the extreme centromeric portion of the MHC, in regions containing the DOB1, TAP2, DPB1, and COL11A2 genes. These data emphasize that further analysis of the MHC is likely to reveal genetic risk factors for rheumatoid arthritis that are independent of the DRB1 shared epitope alleles.
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PMID:Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus. 1830 76

The objective of the present study was to evaluate the contribution of the shared epitope (SE), the rheumatoid arthritis (RA) protection model, and the occurrence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in RA patients from a genetically diverse population. One hundred and forty Brazilian RA patients and 161 matched controls were typed for HLA-DRB1 alleles using amplified DNA hybridized with sequence-specific oligonucleotide probes or primers. Patients were stratified according to the presence or absence of SE (DRB1*0401, *0404, *0405, *0101, *1001, and *1402), of the DERAA alleles (DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304), and X (all other alleles). Anti-CCP antibodies were measured by ELISA. The combined frequency of SE-positive alleles was significantly greater (76.4 vs 23.6%, P < 0.0001) than the controls. The SE/SE and SE/X genotypes were over-represented (P < 0.0001, OR = 6.02) and DERAA/X was under-represented in RA patients (P < 0.001, OR = 0.49), whereas the frequencies of the SE/DERAA, X/X and X/DERAA genotypes were not significantly different from controls. The frequency of anti-CCP antibodies was higher in SE-positive patients than in SE-negative patients (64.6 vs 44.7%, P = 0.03; OR = 2.25). Although the Brazilian population is highly miscegenated, the results of this study support the findings observed in most genetically homogeneous populations with RA; however, they are not mutually exclusive but rather complementary. The participation of DRB1-DERAA alleles in protection against RA was also observed (OR = 0.4; 95%CI = 0.23-0.68).
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PMID:A majority of Brazilian patients with rheumatoid arthritis HLA-DRB1 alleles carry both the HLA-DRB1 shared epitope and anti-citrunillated peptide antibodies. 1856 Jun 74

Rheumatoid arthritis (RA) progresses more rapidly in some patients than in others and diverse factors influence radiographic progression in a specific population. Thus, we searched for variables that are associated with an early appearance of substantial joint damage in patients with RA by using radiographic assessments. A cohort of 157 consecutively enrolled Colombian RA patients was followed for an average of 3.2+/-3.1 years. Information on patient demographics and cumulative clinical and laboratory manifestations over the course of the disease was registered, including family history of RA in first-degree relatives, extra-articular manifestations, rheumatoid factor, anti-CCP3 antibodies, TNF single nucleotide polymorphism at -308 position, and HLA-DRB1 status. Radiographs were scored according to the Sharp-van der Heijde method. Survival analyses of the time at appearance of substantial joint damage were performed by using Weibull models. A review of literature about the influence of familial RA on the progression of disease was done. Our results show that family history of RA is consistently associated with joint damage (i.e. erosive and joint narrowing disease). This effect was not found in all the populations reviewed. In addition, we confirm the effect of HLA-DRB1 shared epitope and anti-CCP seropositivity on erosive disease. Family history of RA is a key risk factor for joint damage and depends on the investigated population because variations in both additive and non-additive genetic factors and the environmental variance are specific to the population. Our results emphasize the usefulness of assessing familial disease, testing anti-CCP antibodies and genotyping HLA-DRB1 gene in patients with RA because these factors may be used to predict clinical outcomes and guide therapeutic interventions.
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PMID:Familial disease, the HLA-DRB1 shared epitope and anti-CCP antibodies influence time at appearance of substantial joint damage in rheumatoid arthritis. 1911 26

We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P < or = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.
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PMID:Genome-wide association study of determinants of anti-cyclic citrullinated peptide antibody titer in adults with rheumatoid arthritis. 1928 9

STAT4 is a transcription factor that has been implicated in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Recently, several reports has documented that a STAT4 haplotype is associated with RA, SLE and Sjogren's syndrome. To summarize and review these findings, we conducted a meta-analysis of all relevant reports published before September 2008. Studies on STAT4 rs7574865 single nucleotide polymorphism (SNP) of RA and SLE were identified using PubMed. Meta-analyses were performed for 15,609 patients with RA and 15,793 controls from 14 published studies and for 2,478 patients with SLE and 5,058 controls from 8 published studies. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on random effects models were calculated for all available studies. The overall ORs for the minor T allele of STAT4 rs7574865 SNP were 1.27 (95% CI 1.20-1.34) in RA and 1.57 (95% CI 1.44-1.71) in SLE. Asian controls have significantly higher allele frequency (32%) for the minor T allele of STAT4 rs7574865 SNP than population of European origin (22%), however, there was no significant difference of ORs for RA and SLE by ethnicity. No apparent effect of anti-CCP positivity was found in stratified analysis. The risk of STAT4 genotype for SLE was significantly higher than for RA in populations of European origin and Asian. The results of our meta-analysis demonstrated that STAT4 rs7574865 SNP is significantly associated with RA and SLE. In addition to specific alleles of HLA-DRB1, the minor T allele of STAT4 rs7574865 SNP is a common RA risk factor in populations of European origin and Asian.
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PMID:Association of STAT4 polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. 1947 40

Our objective was to determine whether the presence of the human leukocyte antigen HLA-DRB1 locus is associated with production of anti-cyclic citrullinated peptide antibodies (anti-CCP Abs) and to what extent they are associated with increased susceptibility to and severity of rheumatoid arthritis (RA) in Egyptian patients. Twenty-nine RA patients gave informed consent to participate in a case-control study that was approved by the Ain Shams University Medical Ethics Committee. RA disease activity and severity were determined using the simplified disease activity index and Larsen scores, respectively. We used a wide scale national study on the pattern of HLA typing in normal Egyptians as a control study. Anti-CCP Abs and HLA-DRB1 typing were determined for all subjects. The alleles most strongly associated with RA were HLA-DRB1 [*01 , *04 and *06] (41.4%). RA patients with serum anti-CCP Ab titers above 60 U/mL had a significantly higher frequency of HLA-DRB1*01 (58.3%) and HLA-DRB1*04 alleles (83.3%). Significant positive correlations were found between serum and synovial anti-CCP Ab titer, RA disease activity, and severity (r = 0.87, 0.66 and 0.63, respectively; P < 0.05). HLA-DRB1 SE+ alleles [*01 and *04] were highly expressed among Egyptian RA patients. The presence of these alleles was associated with higher anti-CCP Ab titer, active and severe RA disease. Early determination of HLA-DRB1 SE+ alleles and serum anti-CCP Ab could facilitate the prediction of the clinical course and prognosis of RA when first evaluated leading to better disease control.
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PMID:Effect of the human leukocyte antigen HLA-DRB1 and anti-cyclic citrullinated peptide on the outcome of rheumatoid arthritis patients. 1973 89


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