Genetic predispositions to rheumatoid arthritis in Malaysian population

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

Genetic Biomarkers as Predictors of Response to Tocilizumab in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Rheumatoid arthritis (RA) is a lifelong, debilitating disease which incredibly impacts a patient’s quality of life if not treated to the optimal target. The clinical response of tocilizumab, an interleukin-6 (IL-6) inhibitor, is associated with several gene polymorphisms, particularly targeting the IL-6 pathway. This systematic review and meta-analysis seeks to investigate genetic biomarkers that predict the treatment outcome of tocilizumab therapy in RA patients. After evaluating the quality of retrieved records, five studies were chosen to carry out a quantitative synthesis involving 591 participants. We analysed genetic markers of IL-6R single nucleotide polymorphism (SNP)s rs12083537, rs2228145 and rs4329505, FCGR3A, CD69, GALNT18 and FCGR2A. A plausible finding based on meta-analysis revealed that RA patients with homozygous AA genotype for rs12083537 polymorphism of the IL-6R gene demonstrate a better response to TCZ treatment as opposed to homozygous and heterozygous patients with the G allele. Nonetheless, limitations in evaluating the available studies by meta-analysis include a lack of studies with dissimilarities in study design and outcome definitions, small sample sizes with low statistical power and heterogeneity of cohorts, a restricted the number of tested SNPs and small effects for the selected variants. Inconsistent finding remains as a great challenge to forge ahead towards personalised medicine for RA management

Human leucocyte antigens profiling in Malay female patients with systemic lupus erythematosus: are we the same or different

Objective SLE is a heterogeneous autoimmune disease, in terms of clinical presentation, incidence and severity across diverse ethnic populations. We investigated the human leucocyte antigens (HLA) profile (ie, HLA-A, HLA-B and HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1) in Malaysian Malay female patients with SLE and determined the generalisability of the published HLA risk factors across different ethnic populations globally including Malaysia. Methods One hundred Malay female patients with SLE were recruited between January 2016 and October 2017 from a nephrology clinic. All patients were genotyped for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1 alleles using PCR sequence-specific oligonucleotides method on Luminex platform. A total of 951 HLA genotyped population-based Malay control subjects was used for association testing by means of OR with 95% CIs. Results Our findings convincingly validated common associations between HLA-A∗11 (OR=1.65, p=3.36×10 -3, corrected P (Pc)=4.03×10 -2) and DQB1∗05:01 (OR=1.56, p=2.02×10 -2, Pc=non-significant) and SLE susceptibility in the Malay population. In contrast, DQB1∗03:01 (OR=0.51, p=4.06×10 -4, Pc=6.50×10 -3) were associated with decreased risk of SLE in Malay population. Additionally, we also detected novel associations of susceptibility HLA genes (ie, HLA-B∗38:02, DPA1∗02:02, DPB1∗14:01) and protective HLA genes (ie, DPA1∗01:03). When comparing the current data with data from previously published studies from Caucasian, African and Asian populations, DRB1∗15 alleles, DQB1∗03:01 and DQA1∗01:02 were corroborated as universal susceptibility and protective genes. Conclusions This study reveals multiple HLA alleles associated with susceptibility and protection against risk of developing SLE in Malay female population with renal disorders. In addition, the published data from different ethnic populations together with our study further support the notion that the genetic effects from association with DRB1∗15:01/02, DQB1∗03:01 and DQA1∗01:02 alleles are generalised to multiple ethnic populations of Caucasian, African and Asian descents

Correction: A Replication Study Confirms the Association of Dendritic Cell Immunoreceptor (DCIR) Polymorphisms with ACPA - Negative RA in a Large Asian Cohort.

[This corrects the article DOI: 10.1371/journal.pone.0041228.]

A replication study confirms the association of dendritic cell immunoreceptor (DCIR) polymorphisms with ACPA - negative RA in a large Asian cohort.

Dendritic cell immunoreceptor (DCIR) has been implicated in development of autoimmune disorders in rodent and DCIR polymorphisms were associated with anti-citrullinated proteins antibodies (ACPA)-negative rheumatoid arthritis (RA) in Swedish Caucasians. This study was undertaken to further investigate whether DCIR polymorphisms are also risk factors for the development of RA in four Asian populations originated from China and Malaysia.We genotyped two DCIR SNPs rs2377422 and rs10840759 in Han Chinese population (1,193 cases, 1,278 controls), to assess their association with RA. Subsequently, rs2377422 was further genotyped in three independent cohorts of Malaysian-Chinese subjects (MY_Chinese, 254 cases, 206 controls), Malay subjects (MY_ Malay, 515 cases, 986 controls), and Malaysian-Indian subjects (MY_Indian, 378 cases, 285 controls), to seek confirmation of association in various ethnic groups. Meta-analysis was preformed to evaluate the contribution of rs2377422 polymorphisms to the development of ACPA-negative RA in distinct ethnic groups. Finally, we carried out association analysis of rs2377422 polymorphisms with DCIR mRNA expression levels.DCIR rs2377422 was found to be significantly associated with ACPA -negative RA in Han Chinese (OR 1.92, 95% CI 1.27-2.90, P=0.0020). Meta-analysis confirms DCIR rs2377422 as a risk factor for ACPA-negative RA across distinct ethnic groups (OR(overall) =1.17, 95% CI 1.06-1.30, P=0.003). The SNP rs2377422 polymorphism showed significant association with DCIR mRNA expression level, i.e. RA-risk CC genotype exhibit a significant increase in the expression of DCIR (P=0.0023, Kruskal-Wallis).Our data provide evidence for association between DCIR rs2377422 and RA in non-Caucasian populations and confirm the influence of DCIR polymorphisms on RA susceptibility, especially on ACPA-negative RA