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- Chun-Lai, Too, et al.
(författare)
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Recognizing rheumatoid arthritis: oncoprotein survivin opens new possibilities: a population-based case-control study.
- 2015
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Ingår i: Medicine. - 1536-5964. ; 94:4
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Tidskriftsartikel (refereegranskat)abstract
- Survivin is a biomarker of cancer known for its anti-apoptotic and cell-cycle regulating properties. In the context of non-cancer pathology, high levels of survivin may be measured in blood and synovial fluid of patients with rheumatoid arthritis (RA) and associate with early joint damage and poor therapy response. The aim of the study was to investigate the value of survivin measurements in blood for diagnosis of RA in the frame of the Malaysian epidemiological investigation of rheumatoid arthritis (MyEIRA) study. The study enrolled RA patients from eight rheumatology centres in Peninsular Malaysia. The healthy controls matched by age, gender and ethnicity were recruited on the community basis from the residential area of the patients. Levels of survivin were measured in blood of RA patients (n=1233) and controls (n=1566) by an enzyme-linked immuno-sorbent assay (ELISA). The risk for RA was calculated as odds ratio (OR) and 95% confidence intervals in the individuals with high levels of survivin. The risk was calculated in relation to antibodies against cyclic citrullinated peptides (ACPA), detected by ELISA and HLA-DRB1 shared epitope (SE) alleles, identified by the polymerase chain reaction using sequence specific oligonucleotide method. High levels of survivin were detected in 625 of 1233 (50.7%) RA cases and in 85 of 1566 (5.4%) controls, indicating its high specificity for RA. Survivin was association with an increase in RA risk in the patients having neither SE-alleles nor ACPA (OR=5.40, 95% CI 3.81-7.66). For the patients combining survivin, SE, and ACPA, the estimated risk for RA was 16-folds higher compared to the survivin negative patients with SE and ACPA(OR=16.21, 95% CI 5.70-46.18). To conclude, detection of survivin in blood provides a simple test to improve diagnostic and to increase predictability for RA.
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| 2. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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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.
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| 5. |
- Too, Chun Lai, et al.
(författare)
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Differences in the Spectrum of Anti-Citrullinated Protein Antibody Fine Specificities Between Malaysian and Swedish Patients With Rheumatoid Arthritis : Implications for Disease Pathogenesis
- 2017
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 69:1, s. 58-69
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Antibodies to the citrullinated protein antigens (ACPAs) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different fine specificities in different populations is unclear. This study sought to examine the fine specificity of the antibody responses toward citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in more frequently studied cohorts of Caucasian subjects. Methods. A multiplex analytic microarray system was used to analyze the occurrence of antibodies to 10 different citrullinated peptides (filaggrin [fil307-324], vimentin [Vim2-17, Vim60-75], fibrinogen [Fiba563-583, Fib alpha 580-600, Fib beta 36-52, Fib beta 62-81a, Fib beta 62-81b], enolase [Eno5-21], and type II collagen [CitCII355-378]) in serum samples from 4,089 RA patients (1,231 Malaysian and 2,858 Swedish) and 827 healthy control subjects (249 Malaysian and 578 Swedish). The positive reaction threshold for each peptide was set separately for each population based on a specificity of 98%. Results. Distinct differences in the frequencies of 5 ACPA fine specificities (Vim60-75, Vim2-17, Fibb62-81b, Eno5-21, and CitCII355-378) were found between the Malaysian and Swedish RA populations, despite a nearly identical percentage of patients in each population who were positive for anti-cyclic citrullinated peptide 2 ish RA patients, the frequencies of antibodies to Vim60-75 (54% versus 44%, corrected P [P-corr] =1.06 x 10(-8)) and CitCII355-378 (17% versus 13%, P-corr = 0.02) were significantly higher, while the frequencies of antibodies to Vim2-17 (25% versus 32%, P-corr = 1.91 x 10(-4)), Fib beta 62-81b (15% versus 30%, P-corr = 2.47 x 10(-22)), and Eno5-21 (23% versus 50%, P-corr = 3.64 x 10(-57)) were significantly lower. Conclusion. Serum ACPA fine specificities differ between RA patients in different populations, although the total proportions of individuals positive for ACPAs are similar. Differing patterns of ACPA fine specificity could be attributed to variations in genetic and/or environmental factors.
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| 6. |
- Too, Chun Lai
(författare)
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Genetic predispositions to rheumatoid arthritis in Malaysian population
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Genetic predisposition is a significant and fundamental determinant of susceptibility to rheumatoid arthritis (RA), a complex autoimmune disease with a painful and disabling condition. The vast majority of genetic studies in RA have been centered on populations of European descent with very few studies on East Asian populations. In this thesis, we aimed to determine the genetic predisposition to RA in the Malaysian population residing in the South East Asian region. More specifically, we addressed the question of how far the identified RA risk loci in Europeans and East Asians can be translated across different populations. We undertook this investigation using the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) case control study involving mainly the early RA cases, which comprised of Malay, Chinese and Indian ethnic groups. We showed that different HLA-DRB1 shared epitope (SE) alleles, which are common in Asian (i.e. DRB1*0405), but not in European populations conferred significantly increased risk of developing anti-citrullinated protein antibody (ACPA)-positive, but not ACPA-negative RA. With the preponderance of the DRB1*12 alleles in our study population, we demonstrated a novel protective effect of DRB1*1202 associated with ACPA-positive RA in Malay and Chinese populations. The combination between genetic and environment factors is widely believed to be the major trigger of RA development. Our analysis of gene-environment interaction between smoking and HLA-DRB1 shared epitope (SE) alleles revealed a strong association with ACPA-positive RA and this interaction seem to apply between smoking and DRB1*0405 allele, which is common in Asian populations. Polymorphisms in the peptidylarginine deiminase type IV (PADI4) gene have been repeatedly shown to associate with RA susceptibility in individuals of Asian descent, but weak or no association was observed in the European populations, despite of comparable risk allele frequency between these populations. We scrutinized the entire PADI locus including PADI1, PADI2, PADI3, PADI4 and PADI6 genes with a set of 320 single nucleotide polymorphisms (SNPs) for association with RA. Our findings revealed an association between PADI4 in the diverse populations from Malaysia. In addition, we also suggest a novel association in a PADI2 gene. Approximately 40% of RA patients are diagnosed as having ACPA-negative disease. As yet, few validated risk alleles were associated exclusively with ACPA-negative RA. We investigated the association between the previously reported ACPA-negative-associated dendritic cell immunoreceptor (DCIR) polymorphisms and RA in four independent Asian populations from China and Malaysia. Our results provide evidence for an association between the DCIR variant and RA in non-European populations. We also confirmed the genetic effect of DCIR polymorphisms on RA risk particularly in ACPA-negative RA. Taken together, this thesis provides evidence that no single population is sufficient for fully uncovering the risk variants underlying RA in all populations. Therefore, studies in diverse population could provide a better understanding of genetic architecture of RA especially in the RA susceptibility risk loci.
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