rs2104286

This functional genetic study examined 183 fibroblast strains from systemic sclerosis (SSc) patients and controls to identify SNP-trait associations with extracellular matrix gene expression in response to silica stimulation. SNP rs58905141 in TNFAIP3 (6q23.3) was consistently associated with MMP3 and MMP1 dose-response expression with 3.6 to 12.7-fold changes, remaining genome-wide significant in meta-analysis across Caucasian, African American, and Hispanic cohorts. Two other SSc-associated loci, IL2RA and ITGAM, also showed significant associations with MMP expression in silica-stimulated fibroblasts.

A two-stage case-control study in a Chinese Han population examined 820 Behçet's disease (BD) and 900 VKH syndrome patients versus 1,800 controls. The miR-182/rs76481776 SNP showed significantly decreased CC genotype and C allele frequencies in BD (OR=0.55-0.58, P=3.36×10⁻⁴ to 3.25×10⁻⁷) and VKH patients (OR=0.53-0.57, P=1.11×10⁻⁴ to 7.89×10⁻⁸). Other SNPs in miR-27a, FoxO1, and IL2RA showed no significant associations. Functional analysis revealed increased miR-182 expression in TT/CT genotypes compared to CC in anti-CD3/CD28 antibody-stimulated CD4+ T cells (P=2.1×10⁻²).

This extended UK genome-wide association study identified a novel rheumatoid arthritis susceptibility locus at 22q12 (rs1043099, P = 6.9 × 10⁻⁹, OR = 0.84) in 3,034 cases and 5,271 controls, and confirmed 16 previously known RA loci, strengthening evidence for genetic contributors to RA in the UK population.

This systematic literature review examines interleukin and interleukin receptor gene polymorphisms associated with rheumatoid arthritis (RA) pathogenesis, diagnostics, and treatment. The paper summarizes polymorphisms in multiple IL genes (IL-1B rs16944, rs1143634; IL-6 rs1800795, rs1800796; IL-10 rs1800896; IL-23R rs11209026; IL-17A rs2275913 and others) across diverse populations, their associations with RA susceptibility and disease severity, and discusses current and future immunologic therapeutic targets including TNF inhibitors and IL-6 receptor antagonists.

This meta-analysis of 7 genome-wide association studies identified three novel multiple sclerosis susceptibility loci: rs170934 near EOMES (3p24.1, OR=1.17, P=1.6×10⁻⁸), rs2150702 in MLANA (9p24.1, OR=1.16, P=3.3×10⁻⁸), and rs6718520 near THADA (2p21, OR=1.17, P=3.4×10⁻⁸). The analysis encompassed 5,545 cases and 12,153 controls and identified 10 additional loci with suggestive evidence of association (P<1×10⁻⁶), including IL12B, TAGAP, PLEK, and ZMIZ1, which are shared with other inflammatory diseases.

This study applied Bayesian epistasis association mapping (BEAM/BEAM2) methods to genome-wide association studies data from the Welcome Trust Case Control Consortium (WTCCC) to identify high-order SNP interactions in rheumatoid arthritis. The analysis identified 319 high-order epistatic interactions across the genome, with many validated using data from the North American Rheumatoid Arthritis Consortium (NARAC). Key findings include inter-chromosomal interactions primarily on chromosomes 1, 3, 6, and 9, with enriched GO terms implicating synapse, calcium ion binding, and membrane pathways.

This cohort study of 2,324 subjects with inflammatory polyarthritis tested 17 rheumatoid arthritis (RA) susceptibility SNPs for association with all-cause and cardiovascular disease (CVD) mortality. Carriage of the CCL21 risk allele rs2812378 was associated with increased CVD mortality (HR 1.33, 95% CI 1.01-1.75) and all-cause mortality (HR 1.40, 95% CI 1.04-1.87), with the strongest effects observed in anti-CCP antibody-positive patients with both the CCL21 risk alleles and shared epitope (SE) alleles (all-cause HR 3.20, 95% CI 1.52-6.72; CVD HR 3.73, 95% CI 1.30-10.72). SNPs at the TRAF1/C5 locus were not significantly associated with mortality in this study.

This multi-cohort genetic association study of 1,283 RA patients found that the PTPRC/CD45 gene variant rs10919563 (G allele) is associated with favorable response to anti-TNF therapy (OR 0.55, P=0.0001). Of 31 established RA risk alleles tested, only PTPRC reached genome-wide significance for therapy response, with stronger associations in autoantibody-positive patients (OR 0.55, 95% CI 0.39-0.76) compared to seronegative patients.

This case-control association study of juvenile idiopathic arthritis (JIA) in 809 JIA cases and 3,521 controls identified susceptibility loci shared with other autoimmune diseases. Three novel loci were identified: PTPN2 (strongest signals rs7234029, p=7.19×10⁻¹¹, OR=1.59; rs1893217, p=3.48×10⁻⁸, OR=1.52; rs2542151, p=3.05×10⁻⁷, OR=1.45), COG6 (rs7993214, p=3.98×10⁻³, OR=0.79), and ANGPT1 (rs1010824, p=4.93×10⁻³, OR=0.77). Four previously reported JIA loci were confirmed: PTPN22, STAT4, C12orf30, and IL2-IL21. Odds ratios ranged from 1.20 to 1.65 in meta-analysis of initial and independent replication cohorts (n=1,015 cases and 1,568 controls).

A case-control association study of 1,316 Korean RA patients and 1,006 controls found that rs7021206 in TRAF1 intron 3 is significantly associated with rheumatoid arthritis susceptibility (OR 1.21, P = 0.0037), while rs3761847, which is associated with RA in Caucasians, showed no association in Koreans due to different linkage disequilibrium patterns. Fine-mapping identified a 66-kb haplotype region spanning TRAF1 containing variants associated with RA across both Asian and Caucasian populations.

A case-control association study found that genetic variants in TNFAIP3 (rs10499194, OR 0.74; rs6920220, OR 1.3), STAT4 (rs7574865, OR 1.24), and C12ORF30 (rs17696736, OR 1.2) loci previously associated with other autoimmune diseases are also significantly associated with juvenile idiopathic arthritis, supporting shared genetic susceptibility among clinically distinct autoimmune phenotypes.

This systematic literature review examines interleukin (IL) and interleukin receptor gene polymorphisms associated with rheumatoid arthritis (RA), covering studies from the past 10 years. The review discusses the pathogenesis of RA as a multifactorial autoimmune disease where genetic factors account for approximately 60% of disease risk. Multiple polymorphisms across IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IL-17, IL-18, and IL-23R genes have been investigated in various populations, with inconsistent results across populations. The paper also reviews current and future therapeutic targets including anti-TNF, anti-IL-1, anti-IL-6, and anti-IL-17 treatments.

This association study identifies IL2RA/CD25 as a susceptibility locus for juvenile idiopathic arthritis (JIA). SNP rs2104286 showed significant association with JIA in UK cases (n=654, OR 0.76 [95% CI 0.66-0.88], P=0.0002), which was replicated in North American cases (n=747, OR 0.84 [95% CI 0.65-0.99], P=0.05). Meta-analysis confirmed highly significant association (OR 0.76 [95% CI 0.62-0.88], P=4.9×10⁻⁵). A second SNP (rs41295061) showed modest evidence for association. The gene encodes the IL-2 receptor α chain and plays a critical role in regulatory T cell development.

A meta-analysis of 4,107 type 2 diabetes cases and 5,187 controls from three GWA studies found no evidence that common variants altering circulating inflammatory protein levels (IL-18, IL-6R, CRP, IL1RN, PAI1, MIF) or variants predisposing to autoimmune diseases (type 1 diabetes, rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, SLE) are associated with type 2 diabetes risk. For example, rs2250417 in IL18 showed OR=1.00 (95% CI 0.99-1.03) versus the expected OR of ~1.15 if inflammation were causal, suggesting inflammatory markers are likely secondary rather than causative in type 2 diabetes.

Applied multilocus localized haplotype clustering to Wellcome Trust Case Control Consortium data (14,000 cases of 7 common diseases + 3,000 controls) to identify disease-associated loci with stronger evidence than single-marker tests. Identified three highly significant associations: 10p15.1 with type 1 diabetes (p=5.1×10⁻⁹), 12q15 with type 2 diabetes (p=1.9×10⁻⁷), and 15q26.2 with hypertension (p=2.8×10⁻⁸), plus 9p21.3 with type 2 diabetes (p=2.8×10⁻⁸). Stringent genotype quality filtering effectively removed false positives from genotyping artifacts.