rs6920220

In an Algerian case-control study of 358 subjects (147 healthy, 89 IBD, 122 CRC), the rs28362491 -94 ATTG insertion/deletion polymorphism in the NF κ B1 promoter showed significant association with increased inflammatory bowel disease (IBD) risk, with the deletion allele conferring elevated risk (OR = 2.034; 95% CI, 1.16-3.55; p = 0.012). Functional assays in LoVo colon cancer cells demonstrated that SOX9 transcription factor modulates NF κ B1 promoter activity in an allele-specific manner at the SNP site. Two other tested variants (rs6920220 in TNFAIP3 and rs419598 in IL1RN) showed no significant associations with IBD or colorectal cancer.

This functional study integrates epigenomic datasets (ATAC-seq, Hi-C, ChIP-seq, RNA-seq) from fibroblast-like synoviocytes (FLS) to map the functional relevance of 101 fine-mapped rheumatoid arthritis GWAS associations. FLS regulatory elements account for 24% of RA heritability, and the study assigns putative target genes to RA risk loci, identifying TNFAIP3, IFNAR1, CDK6, RBPJ and others as disease-relevant genes. TNF stimulation reveals dynamic chromatin interactions and differential gene expression at RA-associated regulatory regions.

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 candidate gene association study examined five TNFAIP3 SNPs (rs10499194, rs610604, rs7753873, rs5029928, rs9494885) in 722 Chinese Han Behcet's disease patients and 1,415 controls. The strongest association was rs9494885 with BD (TC genotype OR=2.03, p=1.83×10⁻¹⁰), while rs10499194 and rs7753873 showed weaker associations. The rs9494885 TT genotype was protective (OR=0.50, p=1.23×10⁻¹⁰).

This case-control study of 155 children with childhood-onset rheumatoid arthritis (CORA) and 684 healthy controls examined whether five RA-associated genetic variants also confer susceptibility to CORA. Variants in PTPN22 (rs2476601, OR 1.61), STAT4 (rs7574865, OR 1.41), and TNFAIP3 (rs10499194, OR 0.60) showed significant associations with CORA in a similar magnitude and direction as in adult RA. A weighted genetic risk score (wGRS) incorporating these variants plus HLA alleles was strongly associated with CORA risk (p<2×10⁻¹⁶), with individuals in the top quintile having 11.66-fold increased odds compared to the bottom quintile.

Meta-analysis of 10 studies examining associations between TNFAIP3 polymorphisms (rs6920220, rs10499194, rs2230926) and rheumatoid arthritis across multiple ethnic populations. rs6920220 showed strong association with RA in Europeans (OR 1.227, p < 1.0×10⁻⁹), rs10499194 in Asians (OR 1.254, p = 6.7×10⁻⁴), and rs2230926 across all subjects (OR 1.390, p = 1.9×10⁻⁶).

A Tunisian case-control study tested the rs6920220 SNP in the TNFAIP3 gene region (6q23) for association with rheumatoid arthritis. The rare A allele showed a trend toward increased risk (25.5% in cases vs 22.5% in controls, P=0.35, OR=1.18) and genotypes containing the A allele were more prevalent in RA patients (45.4% vs 39.3%, P=0.26, OR=1.29), but results did not reach statistical significance. The findings suggest TNFAIP3 may play a role in RA pathogenesis through modulation of the NF-κB pathway.

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 study examined 27 previously identified rheumatoid arthritis (RA) risk alleles in 556 autoantibody-positive African-American RA cases and 791 controls. Twenty-four of 27 SNPs showed consistent odds ratios between African-Americans and Europeans; three SNPs (CCR6 rs3093023, TAGAP rs394581, TNFAIP3 rs6920220) showed opposite directions of effect. A genetic risk score analysis indicated that African-American cases were significantly enriched for European RA risk alleles (p=0.00005), suggesting that RA genetic risk factors are largely shared across ancestry groups.

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).

This association study of 664 German Wegener's granulomatosis (WG) patients and 952 controls evaluated 22 SNPs across 13 candidate genes identified from RA and SLE studies. The strongest finding was a protective four-SNP IRF5 haplotype (rs2004640_G/rs60344245_del/rs2070197_T/rs10954213_G) with reduced WG risk (p=0.0000897, OR 0.73, 95% CI 0.62-0.85). SNPs in TNFAIP3 and CDK6 also showed nominally significant associations, suggesting WG shares some genetic risk factors with other autoimmune diseases.

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 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.

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.

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 study of 1,123 Korean rheumatoid arthritis patients and 1,008 controls found that genetic variants at PTPN22, TRAF1/C5, 6q23, 4q27, CD40, and CCL21 previously associated with Caucasian RA were not associated with Korean RA. The PADI4 variant rs2240340 showed strong association (p=1.15×10⁻⁸, OR=1.43), demonstrating substantial genetic heterogeneity between ethnic populations.

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.

This journal issue contains multiple genetic association studies on rheumatoid arthritis (RA). A key REMARCA study (146 aCCP+ RA patients vs 314 controls) identified polymorphisms in CTLA4 (rs231775 +49A/G), IL10 (rs1800872 -592A/C), and IL6R (rs8192284 +358A/C) associated with high inflammatory disease activity, with CTLA4 and IL10 minor alleles showing increased risk (OR=1.4, p=0.02 and OR=1.9, p<0.0001 respectively) and IL6R minor allele being protective (OR=0.7, p=0.03). A separate study analyzed NOS3, PPARG, PPARGC1A, PPARGC1B and PAI1 polymorphisms in 73 RA patients for cardiovascular risk.

Candidate gene association study of 122 early rheumatoid arthritis (RA) patients and 314 healthy controls found that PTPN22 rs2476601 (OR=1.5, 95% CI 1.0-2.3, p=0.05) and TNFAIP3 rs675520 (OR=1.7) polymorphisms were significantly associated with RA risk. Anti-cyclic citrullinated peptide (ACPA) antibody production was associated with PTPN22, TNFAIP3, CTLA4, and TNF-α polymorphisms in a dose-dependent manner.