| 1. |
|
|
| 2. |
- Ishigaki, Kazuyoshi, et al.
(författare)
-
Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
-
Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
-
Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
|
|
| 3. |
|
|
| 4. |
- Jiang, Xia, et al.
(författare)
-
An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis
- 2016
-
Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 55:1, s. 149-155
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the gene–environment interaction between smoking and single nucleotide polymorphisms (SNPs), using Immunochip material, on the risk of developing either of two serologically defined subsets of RA.Methods: Interaction between smoking and 133 648 genetic markers from the Immunochip was examined for two RA subsets, defined by the presence or absence of ACPA. A total of 1590 ACPA-positive and 891 ACPA-negative cases were compared with 1856 controls in the Swedish Epidemiological Investigation of RA (EIRA) case–control study. Logistic regression models were used to determine the presence of interaction. The proportion attributable to interaction was calculated for each smoking–SNP pair. Replication was carried out in an independent dataset from northern Sweden. To further validate and extend the results, interaction analysis was also performed using genome-wide association studies data on EIRA individuals.Results: In ACPA-positive RA, 102 SNPs interacted significantly with smoking, after Bonferroni correction. All 102 SNPs were located in the HLA region, mainly within the HLA class II region, 51 of which were replicated. No additional loci outside chromosome 6 were identified in the genome-wide association studies validation. After adjusting for HLA-DRB1 shared epitope, 15 smoking–SNP pairs remained significant for ACPA-positive RA, with 8 of these replicated (loci: BTNL2, HLA-DRA, HLA-DRB5, HLA-DQA1, HLA-DOB and TAP2). For ACPA-negative RA, no smoking–SNP pairs passed the threshold for significance.Conclusion: Our study presents extended gene variation patterns involved in gene–smoking interaction in ACPA-positive, but not ACPA-negative, RA. Notably, variants in HLA-DRB1 and those in additional genes within the MHC class II region, but not in any other gene regions, showed interaction with smoking.
|
|
| 5. |
|
|
| 6. |
- Klareskog, Lars, et al.
(författare)
-
Genes, environment and immunity in the development of rheumatoid arthritis
- 2006
-
Ingår i: Current Opinion in Immunology. - : Elsevier BV. - 0952-7915 .- 1879-0372. ; 18:6, s. 650-655
-
Tidskriftsartikel (refereegranskat)abstract
- The combined role of genes, environment and immunity in the development of rheumatoid arthritis (RA) has been the subject of recent investigations. New data support a gene-environment interaction between smoking and the MHC class II HLA-DRB1 shared epitope (SE) genes in anti-citrulline antibody (anti-CP(+)) RA but not in anti-CP(-) disease. These data from genetic epidemiology, together with information on citrullination in the lungs of smokers, have prompted the formulation of a new etiological hypothesis for anti-CP(+) RA, suggesting that smoking in the context of HLA-DR SE might trigger immunity to citrulline-modified proteins and that this immunity, after several years, might cause arthritis.
|
|
| 7. |
- Klareskog, Lars, et al.
(författare)
-
Immunity to Citrullinated Proteins in Rheumatoid Arthritis
- 2008
-
Ingår i: Annual Review of Immunology. - : Annual Reviews. - 0732-0582 .- 1545-3278. ; 26, s. 651-675
-
Forskningsöversikt (refereegranskat)abstract
- Antibodies to citrullinated proteins (ACPA), i.e., to peptides posttranslationally modified by the conversion of arginine to citrulline, are specific serological markers for rheumatoid arthritis (RA). Studies on anticitrulline immunity, summarized in this review, demonstrate that the criterion-based syndrome RA should be subdivided into at least two distinct subsets (ACPA-positive and ACPA-negative disease). A new etiological model is proposed for ACPA-positive RA, built on MHC class II-dependent activation of adaptive immunity. Fundamentals of this model include the following: (a) ACPA antedate onset of arthritis; (b) ACPA may aggravate arthritis in rodents; (c) ACPA are triggered in the context of genes that confer susceptibility to RA (HLA-DRB1 SE) and by environmental agents triggering RA (smoking or bacterial stimuli); (d) ACPA may complex with citrullinated proteins present in target tissue as part of a multistep process for arthritis development. The model provides a new basis for molecular studies on the pathogenesis of ACPA-positive arthritis.
|
|
| 8. |
- Källberg, Henrik, et al.
(författare)
-
Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis
- 2007
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 80:5, s. 867-875
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 9. |
- Källberg, Henrik, et al.
(författare)
-
Smoking is a major preventable risk factor for rheumatoid arthritis : estimations of risks after various exposures to cigarette smoke
- 2011
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 70:3, s. 508-511
-
Tidskriftsartikel (refereegranskat)abstract
- Background Earlier studies have demonstrated that smoking and genetic risk factors interact in providing an increased risk of rheumatoid arthritis (RA). Less is known on how smoking contributes to RA in the context of genetic variability, and what proportion of RA may be caused by smoking. Objectives To determine the association between the amount of smoking and risk of RA in the context of different HLA-DRB1 shared epitope (SE) alleles, and to estimate proportions of RA cases attributed to smoking. Design, Setting and Participants Data from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) case-control study encompassing 1204 cases and 871 controls were analysed. Main Outcome Measure Estimated OR to develop RA and excess fraction of cases attributable to smoking according to the amount of smoking and genotype. Results Smoking was estimated to be responsible for 35% of anticitrullinated protein/peptide antibody (ACPA)positive cases. For each HLA-DRB1 SE genotype, smoking was dose-dependently associated with an increased risk of ACPA-positive RA (p trend <0.001). In individuals carrying two copies of the HLA-DRB1 SE, 55% of ACPA-positive RA was attributable to smoking. Conclusions Smoking is a preventable risk factor for RA. The increased risk due to smoking is dependent on the amount of smoking and genotype.
|
|
| 10. |
- Laki, Judit, et al.
(författare)
-
Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis
- 2012
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:7, s. 2078-2084
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Production of anticitrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLADRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA. Methods HLADRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients. Results No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLADRB1*15 allele was associated with high ACPA levels (P = 0.0002). A similar trend was detected in HLADRB1*15positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLADRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P < 0.0001 by Mantel-Haenszel test with a fixed-effects model). Conclusion Our data indicate that HLADRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLADRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.
|
|
