RA Susceptibility Research Articles

Mannose-binding Lectin Gene Polymorphisms in Brazilian Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a disease with unknown etiology but it is probably multifactorial. RA susceptibility is related to genetic, hormonal, immunologic, and environmental factors. Mannose-binding lectin (MBL) is an important protein of the human innate immune system, encoded by the MBL2 gene. Polymorphisms in MBL2 were associated with several diseases, and may be an important factor in RA susceptibility. We analyzed 3 MBL2 gene polymorphisms in 322 Brazilian patients with RA and 345 ethnically matched healthy controls. MBL2 gene variants were analyzed through polymerase chain reaction sequencing. Considering MBL2 B, C, and D alleles separately, a significant difference in both genotypic and allelic frequencies, particularly concerning frequency of the C allele, was observed comparing European-derived and African-derived individuals (European-derived patients 0.022 vs African-derived patients 0.205; European-derived controls 0.029 vs African-derived controls 0.144; both p < 0.001). We also analyzed MBL2 genotype in relation to extraarticular manifestations. Considering MBL2 variants together, we found an increased frequency of the OO genotype among patients with rheumatoid nodules (p = 0.031), although this association lost significance after Bonferroni correction. Our findings suggest an association of MBL2 genotypes with some clinical manifestations of RA, but more studies are needed to clarify the actual role of MBL in RA.

Association of the MDR1 3435 polymorphism in patients with refractory rheumatoid arthritis in a Chinese population

To evaluate whether the multidrug resistance gene 1 (MDR1) exon 26 polymorphisms are associated with the refractory rheumatoid arthritis (RRA). The study was carried out on two hundred and twenty-three patients with RA treated and one hundred and three normal controls. The RA treated were divided into two groups according the response to disease-modifying antirheumatic drugs (DMARDs). There were 108 patients in the effective group and 115 patients in the ineffective group. Genotypes of the C3435T polymorphism were determined by polymerase chain reaction followed by restriction digestion (PCR-RFLP). There were significant differences in the genotype frequency and allele frequency among three groups. Compared to responders and controls, the nonresponders carried more CC genotype (χ(2) = 5.306, P = 0.021; χ(2) = 7.810, P = 0.005) and more C allele (χ(2) = 6.601, P = 0.010; χ(2) = 12.172, P = 0.000). But, there were no statistically significant differences in genotype nor allele frequency between RA and healthy controls. The results from our study suggest that the C3435T MDR1 gene polymorphism may not be related with the RA susceptibility, but may influence the efficacy of RA therapy with DMARDs, and the 3435CC genotype may be related with RRA.

Pulmonary dysfunction, smoking, socioeconomic status and the risk of developing rheumatoid arthritis

Environmental risk factors are of potential interest for both prevention and treatment of RA. The purpose of this study was to examine the effect of pulmonary function, smoking and socio-economic status on the future risk of RA. Between 1974 and 1992, 22 444 men and 10 902 women were included in the Malmö Preventive Medicine Program (MPMP). Pulmonary function was assessed by a standard screening spirometry. Chronic obstructive pulmonary disease (COPD) and restrictive pulmonary dysfunction were defined based on pulmonary function tests. Individuals who developed RA were identified by linking the MPMP database to national and local RA registers. The patients were classified according to the 1987 ACR criteria for RA. Four matched controls for every case were selected. We identified 290 cases of incident RA (151 men/139 women; mean age at diagnosis 60 years). The median time from inclusion to diagnosis was 12 years. Forced vital capacity and forced expiratory volume within 1 s values were similar in cases and controls, overall and also in separate analysis of those screened ≤8 years before diagnosis. There was no association between COPD or restrictive pulmonary dysfunction and subsequent development of RA. Current smoking was a strong predictor for RA [odds ratio (OR) 1.79; 95% CI 1.32, 2.42]. Blue-collar workers had an increased risk of RA (OR 1.54; 95% CI 1.12, 2.10), independent of smoking. Pulmonary dysfunction did not predict RA, but smoking and low socio-economic status were independent risk factors for RA. Other effects of smoking may be important for RA susceptibility.

Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA), a systemic inflammatory disease with complex genetic aetiology, associates with excess cardiovascular morbidity and mortality. Dyslipidaemia, a major cardiovascular risk factor has been reported to predate the...

Genetik der rheumatoiden Arthritis

Genetic influences on susceptibility to and clinical course of rheumatoid arthritis have been known for a long time, but have so far eluded systematic, genome-wide analysis. In recent years, the availability of new typing techniques and international consortia with large patient cohorts has generated a wealth of new information on the genetic basis of this autoimmune disease. Newly described associations between immunologically relevant gene polymorphisms and RA susceptibility have already been replicated with great statistical power, and are currently incorporated into new, pathogenetically relevant functional pathways. The resulting new concepts identify cell populations of great potential relevance for the pathogenesis of the disease, and ultimately might lead to new diagnostic and therapeutic approaches in RA.

A polymorphism in the 3’-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility

ObjectivesRheumatoid arthritis (RA) is a chronic inflammatory disorder with many genetic factors predisposing to disease susceptibility. MicroRNAs are a new discovered class of molecules that participate in post-transcriptional regulation of genes’ expression. MicroRNA-146a was found to be increased in synovial fibroblasts, synovial tissue and PBMC from patients with RA. The aim of the present study was to reveal if there is any association of miRNA-146a variant rs2910164 and the two interleukin (IL) 1 receptor associated kinase (IRAK1, a target gene of mir-146a) polymorphisms rs3027898 and rs1059703 with RA predisposition. MethodsOne hundred and thirty-six RA patients and 147 controls were enrolled in the study. ResultsStrong statistically significant difference was observed in IRAK1 rs3027898 A>C polymorphism distribution between RA patients and controls (p=0.044), which was higher comparing the distribution of allele A vs. allele C between the studied groups (p=0.017). ConclusionThis is the first study that addresses association of a variant in a target of miR-146a, IRAK1 gene, with RA susceptibility. Further studies in other ethnic groups of patients could help to understand the extent of the proposed association.

How microchimerism can impart HLA susceptibility in patients with rheumatoid arthritis

Rheumatoid arthritis, a chronic inflammatory joint disease, is strongly associated with HLA-DRB1*01 and *04 alleles that have in common similar 5-amino acid motifs in the third hypervariable region of DRB1 (QKRAA, QRRAA, RRRAA), the so called shared epitope (SE). Most patients with RA carry 1 or 2 doses of the SE, with particular genetic combinations at higher risk. In recent work we provided evidence that patients who lack HLA-DRB1*01 and/or *04 alleles can acquire RA susceptibility through fetal, maternal or iatrogenic microchimerism. We also discuss how Mc carrying HLA-DRB1*04 alleles is more likely to be present in the peripheral blood of RA patients compared to Mc carrying HLA-DRB1*01 alleles. We further analyze our results in light of the hierarchy for RA risk with different combinations of the SE. How Mc could contribute to RA susceptibility and whether it also contributes to the hierarchy of risk observed with particular combinations of SE-containing alleles is certainly the beginning of an intriguing story and may offer hope for future therapeutic and/or preventative interventions.

The impact of HLA-DRB alleles on the subclass titres of antibodies against citrullinated peptides

The association between HLA-DR haplotypes and RA have been well established. However, the molecular mechanisms of how HLA mediates susceptibility and/or progression of the disease remain elusive. We therefore turned to the RA-specific antibodies directed against citrullinated peptide antigens (ACPAs) and investigated the association between HLA-DRB1 shared epitope (SE) alleles and the IgG subclass titres of cyclic citrullinated peptide (CCP)- and mutated citrullinated vimentin (MCV)-specific antibodies. One hundred and twenty-seven RA patients were typed for their HLA-DRB1 haplotypes applying low resolution and alleles potentially carrying the SE were sequenced. All patients' sera were analysed by ELISA for the presence of ACPA and 77 patients positive for CCP-specific antibodies were further analysed for the respective IgG subclasses. Subclass titres were then correlated to the presence of a SE. Finally, all patients were screened for the HLA-DRB4-associated splice variant. We found a gene dosage effect of the HLA-DRB1*04-associated SE on both the MCV- and CCP-specific IgG3 levels. The HLA-DRB4-associated splice variant accumulates in ACPA-negative RA patients. Both the dose-dependent increase in IgG3 among ACPA and the accumulation of the splice variant in ACPA-negative patients imply differential expression of the HLA alleles as the mechanism contributing to the susceptibility and/or disease progression of RA. The preponderance of IgG3 hints at a skewing towards a Th1 response and is reminiscent of increased signal strengths at the immunological synapse. Likewise, the abrogation of HLA-DRB4 expression due to the splice variant reduces the signal strength and seems to protect from ACPA development.

The role of rheumatoid arthritis genetic susceptibility markers in the prediction of erosive disease in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register

Objectives. Recent whole-genome and candidate gene association studies in RA have identified a number of single nucleotide polymorphisms (SNPs) that predispose to disease with moderate risk. It remains poorly understood how recently identified genetic factors may contribute to RA severity. We therefore sought to investigate the role of recently identified RA susceptibility SNP markers in predicting erosive outcome in patients with recent-onset inflammatory polyarthritis (IP).Methods. DNA and X-ray data were available for 1049 patients who were registered between 1990 and 2003 with the Norfolk Arthritis Register (NOAR); a primary care-based inception cohort of patients with recent-onset IP. Demographic and clinical data were recorded at inclusion, and at yearly assessments thereafter. Patients were genotyped for 18 SNP markers. The presence of serum anti citrullinated peptide antibodies (ACPAs) was assessed in samples collected at inclusion to the NOAR. The association of serological and genetic markers with poor radiological (Larsen) score at Years 1 and 5, and erosions at Years 1 and 5 was investigated.Results. Baseline ACPA positivity was associated with erosive disease and higher radiological damage. SNP markers within the TRAF1/C5 locus were associated with erosive disease at Year 1 [rs2900180: odds ratio (OR) 1.53 (95% CI 1.14, 2.05)] and Year 5 [rs2900180: OR 1.47 (95% CI 1.07, 2.02)]. None of the SNP markers tested was associated with Larsen score.Conclusion. Our results are in keeping with a previous report and suggest that the TRAF1/C5 region is associated with risk of development of radiological erosions in IP/RA patients. The finding requires replication in other large data sets.

Association between transforming growth factor-β1 T869C polymorphism and rheumatoid arthritis: a meta-analysis

The results of studies on association between TGF-beta1 T869C polymorphism and susceptibility to RA are controversial. The absence of a replication of linkage might be due to different ethnicities. The aim of this study was to perform a preliminary investigation on the effect size of TGF-beta1 T869C polymorphism on RA susceptibility through a meta-analysis. Case-control studies on the association of TGF-beta1 T869C with RA were searched up to March 2009, and the genotype frequencies in the control group were found to be consistent with the Hardy-Weinberg equilibrium. The effect summary odds ratio (OR) and 95% CIs were obtained. Publication bias was tested by funnel plot with Egger's regression test, and heterogeneity was assessed. Seven studies comprising 1122 cases and 1132 controls were included. Heterogeneity was observed (chi(2 )= 17.16; P = 0.009). Under the random effects model, the common OR was 1.38 (95% CI 0.95, 2.01; P = 0.09). In the subgroup meta-analysis, there was an association between TGF-beta1 T869C polymorphism and RA in the people of Asian descent (OR = 1.93; 95% CI 1.42, 2.62; P < 0.0001), but not in the people of non-Asian descent (OR = 0.88; 95% CI 0.65, 1.19; P = 0.41). There was no evidence of publication bias according to Funnel plot and Egger's regression test (a = 4.778; P = 0.14). There was heterogeneity between studies, and no clear evidence of an association on a worldwide population was observed. Subgroup analysis results suggest that TGF-beta1 T869C might play a role in RA susceptibility for Asians but not for non-Asians. Further studies are required for definite conclusions.

DNA microarray analysis of rheumatoid arthritis susceptibility genes identified by genome-wide association studies

normalized using the global ratio median. Only gene expression data that were collected from at least 80% of samples from each group were selected for further analysis. Th e unpaired Mann–Whitney test was used to determine statistically signifi cant diff erences in the mRNA expression levels between the RA and healthy groups. Statistical signifi cance was set at P <0.05. Th e results of our DNA microarray analysis showed that the expressions of four out of the six RA susceptibility genes were signifi cantly higher in RA patients than in healthy individuals (1.0 x 10 –16 to 2.32 x 10 –5 )

Conditional analysis of the major histocompatibility complex in rheumatoid arthritis

We performed a whole-genome association study of rheumatoid arthritis susceptibility using Illumina 550k single-nucleotide polymorphism (SNP) genotypes of 868 cases and 1194 controls from the North American Rheumatoid Arthritis Consortium (NARAC). Structured association analysis with adjustment for potential population stratification yielded 200 SNPs with p < 1 x 10-8 for association with RA, all of which were on chromosome 6 in a 2.7-Mb region of the major histocompatibility complex (MHC). Given the extensive linkage equilibrium in the region and known risk of HLA-DRB1 alleles, we then applied conditional analyses to ascertain independent signals for RA susceptibility among these 200 candidate SNPs. Conditional analyses incorporating risk categories of the HLA-DRB1 "shared epitope" revealed three SNPs having independent associations with RA (conditional p < 0.001). This supports the presence of significant effects on RA susceptibility in the MHC in addition to the shared epitope.

Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci

Objective. Five loci—the shared epitope (SE) of HLA-DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region—have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone.Methods. We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci.Results. Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93).Conclusions. This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.

DNase1 exon2 analysis in Tunisian patients with rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome and healthy subjects

Autoimmune diseases (AID) are caused by the loss of immunological tolerance against self-antigens. The deoxyribonuclease I (DNASE1) gene seems to participate in the genetic susceptibility of some AID. In fact, two mutations were reported among systemic lupus erythematosus (SLE) patients from Japan and Spain (the 172 A → T mutation (K5X) and the 46_72 deletion, respectively). The aim of our work was to evaluate the DNASE1 contribution in the genetic susceptibility of rheumatoid arthritis (RA, n = 151), Sjögren syndrome (SS, n = 55) and SLE (n = 34) in Tunisia. DNA from patients and healthy subjects (n = 232) were explored. Both reported mutations were absent among patient and control subjects. The DNASE1 exon2 sequence was analysed among 26 control subjects to identify new polymorphic variations that are possible. Five known SNPs were explored. The G/T transversion (rs8176927: R2S) was the most polymorphic functional nonsynonymous SNP. Using PCR-RFLP method, all DNAs were genotyped for rs8176927 for a case-control design. The statistical analysis showed no significant differences between patients and controls genotype data. In conclusion, our study showed, on the one hand, the absence of the K5X mutation and the 46_72 deletion in Tunisian patients affected with RA, SS and SLE and healthy subjects, and, on the other hand, the absence of association between the R2S polymorphism and the genetic susceptibility of RA, SS and SLE.

Interleukin-1 promoter region polymorphism role in rheumatoid arthritis: a meta-analysis of IL-1B-511A/G variant reveals association with rheumatoid arthritis

IL-1 has a central role mediating inflammation and joint destruction in RA. Single nucleotide polymorphisms (SNPs) and haplotype structure in the promoter region can modulate IL-1 function. This study examined the effects of four common promoter SNPs in the IL-1 region on susceptibility and clinical characteristics of RA in British Caucasian patients and assessed the risk of RA by meta-analysis of published studies. Using PCR-based methods, 756 RA patients and 625 healthy controls (HCs) were genotyped for IL-1A (-889 C/A, rs17561), IL-1B (-511 A/G, rs16944), IL-1B (-1464 C/G, rs1143623) and IL-1B (-3737 G/A, rs4848306) SNPs. Further meta-analysis was performed for IL-1B (-511 A/G) incorporating 3712 RA patients and 2331 HC from six association studies. The IL-1B (-1464 C/G) G allele was found to be less common in the RA group [P = 0.01; odds ratio (OR) 1.24; 95% CI 1.04, 1.48]. There was no association between IL-1 SNPs and the presence of HLA-DRB1 shared epitope, RF or clinical characteristics. Meta-analysis revealed statistically significant association between IL-1B (-511 A/G) and RA (P = 0.02; pooled OR 1.13; 95% CI 1.02, 1.26). There may be a protective effect in RA from the IL-1B (-1464 C/G) G variant. No direct association between the polymorphisms studied and clinical severity characteristics were observed. Further meta-analysis revealed IL-1B (-511 A/G) to be associated with increased susceptibility to RA.

Identification of Human LRG1 Polymorphisms and Their Genetic Association with Rheumatoid Arthritis

Abstract Human leucine-rich alpha-2-glycoprotein 1 (LRG1) was first identified as a trace protein in human serum. The primary sequence of LRG1 includes repeated leucine residues and putative membrane-binding domains. But, there is no published information on the genetic varia-tion of this gene. In this study, LRG1 was identified as one of several upregulated genes in RA patients. We examined the expression levels of LRG1 between an RA patient and a healthy control by RT-PCR and validated that LRG1 was highly expressed in RA patients com-pared with controls. We identified the possible variation sites and single nucleotide polymorphisms (SNPs) in the human LRG1 gene by direct sequencing and analyzed the association of genotype and allele frequencies be-tween RA patients and a control group without RA. We further investigated the relationship between these poly-morphisms and the level of RF or anti-CCP in RA patients. We identified a total of three SNPs (g.-678A＞G, g.-404C＞T and g.1427T＞C) and two variation sites (g.-1198delA and g.-893delA) in the LRG1 gene. Our re-sults suggest that polymorphisms of the LRG1 gene are not associated with the susceptibility of RA in the Korean population.Keywords: HRM, LRG1, polymorphism, rheumatoid arthritis

Mannose-binding lectin polymorphisms are not associated with rheumatoid arthritis--confirmation in two large cohorts

In RA, conflicting results have been described on the association between genotypes of the complement factor mannose-binding lectin (MBL) and disease susceptibility and severity. This might be due to underpowerment of previous research work and the fact that no confirmation cohorts were used. Therefore a different approach is warranted. MBL2 gene polymorphisms were determined in two RA cohorts (378 and 261 cases) and 648 controls. Considering MBL polymorphisms, cases and controls were categorized in groups of high, intermediate and low MBL production. The total sample size allows detection of a potential association between RA susceptibility and MBL groups with an odds ratio of 1.37 (alpha < 0.05; 1-beta > 0.8). Disease severity as defined by the need for anti-TNF therapy was also analysed for possible associations with MBL groups. There was no difference in the frequencies between MBL genotypes of RA cases and controls that are associated with high (cases 54.4%, controls 57.0%), intermediate (cases 28.9%, controls 27.5%) or low (cases 16.7%, controls 15.5%) MBL production. Furthermore, there was no association between MBL groups and disease severity. MBL genotype groups are not associated with RA disease susceptibility or severity in this large study including a confirmation cohort. Compared with previous smaller studies these results add to more definite conclusions.

New classification of HLA-DRB1alleles in rheumatoid arthritis susceptibility: a combined analysis of worldwide samples

IntroductionRheumatoid arthritis (RA) is a complex polygenic disease of unknown etiology. HLA-DRB1 alleles encoding the shared epitope (SE) (RAA amino acid pattern in positions 72 to 74 of the third hypervariable region of the DRβ1 chain) are associated with RA susceptibility. A new classification of HLA-DRB1 SE alleles has been developed by Tezenas du Montcel and colleagues to refine the association between HLA-DRB1 and RA. In the present study, we used RA samples collected worldwide to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility across various Caucasoid and non-Caucasoid patients.MethodsEighteen subsamples were defined from a total number of 759 cases and 789 controls and grouped in 10 samples on the basis of their ethnic origin. HLA-DRB1 alleles were divided into five groups (S1, S2, S3D, S3P, and X) according to the new HLA-DRB1 allele classification. The whole analysis was performed by comparing carrier frequencies for the five HLA-DRB1 allele groups between RA patients and controls across the 10 Caucasoid and non-Caucasoid samples. The Mantel-Haenszel method of meta-analysis provided a global odds ratio (OR) estimate with 95% confidence interval (CI).ResultsA positive association with RA susceptibility was found for S2 allele carriers (OR 2.15, 95% CI 1.54 to 3.00; p < 10-5) and S3P allele carriers (OR 2.74, 95% CI 2.01 to 3.74; p < 10-5). A negative association was found for S1 alleles (OR 0.60, 95% CI 0.48 to 0.76; p < 10-4) and X alleles (OR 0.58, 95% CI 0.39 to 0.84; p = 4 × 10-3). No significant association was highlighted for the S3D group of alleles (OR 0.89, 95% CI 0.69 to 1.14; p = 0.89). The complementary genotype analysis fit with the genotype risk hierarchy previously reported in Caucasoid RA patients.ConclusionSo far, the present study is the first attempt to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility on both Caucasoid and non-Caucasoid samples. Our results support the hypothesis of a differential role played by different HLA-DRB1 allele groups in RA susceptibility across different ethnic backgrounds and confirm the interest of such an HLA-DRB1 classification in differentiating predisposing and protective alleles.

Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (The Swedish TIRA project)

The genetic background to RA is incompletely understood. As new cytokine-targeted therapies emerge, early predictors of disease severity are becoming increasingly important. The inflammasomes are essential regulators of cytokine production. We investigated whether two polymorphisms in the genes encoding cryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibility and disease course in RA. Genotype frequencies were assessed in 174 Swedish patients with early RA and 360 population-based controls without rheumatic disease. Genotypes were categorized according to the presence (+) or absence (-) of two wild-type alleles and compared between patients and controls. In the RA patients, antibodies towards cyclic citrullinated peptides (anti-CCP) and the 'shared epitope' (SE) were assessed, and medication and measures of disease activity were monitored regularly during 3 yrs. The combination of CIAS1/TUCAN -/-, as compared with CIAS1/TUCAN +/+, was significantly more common among patients than in controls [odds ratio (OR) 2.2, 95% CI 1.03-4.6]. This association was strengthened when patients were divided into anti-CCP+ [OR 2.8 (1.1-6.7)] or presence of > or = 1 SE copy [OR 2.8 (1.3-6.2)]. At most time-points during the 3-yr follow-up, patients with CIAS1/TUCAN -/- showed significantly higher disease activity. Furthermore, CIAS1/TUCAN -/- patients proved to be much more likely to receive TNF-blocking therapy [relative risk 20 (2.6-149)]. Compound polymorphisms in CIAS1 and TUCAN associate with RA susceptibility and severity. The cryopyrin inflammasome needs further attention regarding a possible aetiopathogenetic connection with RA.

Recent advances in the genetics of RA susceptibility

RA is a common autoimmune disease with a complex aetiology in which genetic and environmental factors contribute to disease. The genetic component of RA is largely undefined and, up until very recently, there were only two reproducible associations. The strongest of these associations is of genes within the HLA region, particularly the HLA-DRB1 gene. A second, more modest, association identified has been of the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene. Advances in genotyping technology have facilitated the application of whole genome association approaches to identify disease causal variants. This, coupled with the availability of large case and control collections has enabled the identification of low-to-moderate risk loci. These newer study designs combined with traditional linkage and association studies have accelerated the identification of novel risk loci. The past few months alone have witnessed the identification of three new RA risk loci. In this review, we aim to give an update on recent progress in RA genetics, focusing mainly on the identification of novel loci.