rs2476601

A meta-analysis of 53 case-control studies (23,972 cases and 24,896 controls) examining PTPN22 gene rs2476601 (C1858T) polymorphism and rheumatoid arthritis (RA) susceptibility. The pooled analysis detected significant positive association across all genetic models: dominant model (OR=1.63, 95% CI=1.47-1.79), recessive model (OR=2.50, 95% CI=2.06-3.05), allelic model (OR=1.72, 95% CI=1.53-1.94), and homozygote models (TT vs CC: OR=2.79, 95% CI=2.28-3.41). Stratified analysis showed strong associations in Caucasian and African populations.

This pilot screening study evaluated 32 SNPs in viral immune response genes for association with hospitalized seasonal influenza in adults of European ancestry using a discovery group (26 cases, 993 controls) and two validation groups (84 cases, 4,076 controls; 128 cases, 9,187 controls). The study failed to replicate the previously reported association between IFITM3 rs12252 and hospitalized influenza (P > 0.05), and a preliminary finding of association with SLFN13 rs8072510 (P = 0.0099 in discovery group) was not confirmed in validation groups.

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 candidate gene study of 130 Danish children with type 1 diabetes examined associations between 20 diabetes-related SNPs and diabetic retinopathy progression over 16 years. The CTSH/rs3825932 variant was associated with reduced risk of progression to proliferative diabetic retinopathy (OR=0.20, p=2.4×10⁻³, p_adjust=0.048), while ERBB3/rs2292239 was associated with increased risk of two-step DR progression (OR=2.76, p=7.5×10⁻³, p_adjust=0.15). The CTSH association remained significant after multiple testing correction.

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.

A case-control study of 165 Chinese UC patients and 300 healthy controls examining PTPN22 gene polymorphisms. The -1123G/C variant (rs2488457) showed significant association with UC, with C carriers having higher frequency in patients than controls (66.7% vs 53.3%, OR=1.75, P=0.005) and association with extensive colitis (P=0.029). PTPN22 mRNA levels were elevated in inflamed colonic tissue and correlated with disease activity.

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.

This genome-wide association study identified genetic determinants of granulomatosis with polyangiitis (GPA/Wegener's) in 987 cases and 2,731 controls. HLA-DPB1*04 and HLA-DPA1 variants accounted for 32 significant SNP associations in the HLA region, with peak signals at rs9277554 (HLA-DPB1) and rs9277341 (HLA-DPA1). An independent association was found at rs26595 near SEMA6A on chromosome 5, confirming the critical role of immunogenetic factors in GPA susceptibility.

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

A candidate gene association study in 100 Russian vitiligo patients and 100 controls identified a strong novel association between GSTP1 rs1138272 (Ala114Val, OR=13.03, Bonferroni-adjusted P=0.0015) and vitiligo susceptibility. Cumulative analysis of multiple xenobiotic metabolizing genes showed that carrying higher numbers of risk alleles was associated with increased vitiligo risk (9-16 vs 3-8 alleles: OR=2.79, P=0.00063), supporting a polygenic model for vitiligo involving detoxification pathway genes.

In Chinese Han populations, the PTPN22 promoter polymorphism -1123G>C (rs2488457) is associated with rheumatoid arthritis susceptibility with OR=1.517 (95% CI 1.154-1.995, P=0.003). The well-documented exon 14 variant 1858C>T (rs2476601) and the 788G>A variant (rs33996649) were not polymorphic in this Chinese cohort, suggesting population-specific genetic risk variants for RA.

A two-stage genome-wide association study of 649 early-onset myasthenia gravis patients identified HLA-B*08 as the major genetic risk factor (OR=6.41, p=2.87×10⁻¹¹³) and TNIP1 Pro151Ala (rs2233290, OR=1.92, p=3.4×10⁻⁹) as a novel non-HLA locus. Together with PTPN22 (rs2476601, OR=1.71, p=8.2×10⁻¹⁰), these loci account for 62.9% of population attributable risk, implicating dysregulation of NF-κB signaling pathways in myasthenia gravis pathogenesis.

Study of 507 Spanish rheumatoid arthritis patients examining genetic and environmental factors influencing age of disease onset. Shared epitope, anti-CCP antibodies, and higher education were individually associated with younger onset (P=0.033, 0.004, <0.0001). Patients carrying all three genetic markers (HLA-SE, PTPN22 rs2476601, STAT4 rs7574865) showed disease onset 9.56 years earlier than those with none (P=0.004). Combined genetic and environmental factors demonstrated additive effects on age at RA onset.

This meta-analysis of 10 comparative studies (4,238 JIA patients, 6,012 controls) confirms that the PTPN22 1858 C/T polymorphism (rs2476601), specifically the T allele, is associated with juvenile idiopathic arthritis (JIA) susceptibility in Europeans (OR 1.311, 95% CI 1.205-1.427, P < 1×10⁻⁸). Additionally, the MIF -173 C/G polymorphism's C allele shows association with JIA in all subjects (OR 1.482, 95% CI 1.202-1.828, P = 2.3×10⁻⁴).

This review article by Ota and Kuwana synthesizes genetic studies on systemic sclerosis (SSc), a complex autoimmune disease. Multiple genetic association studies, including GWAS and candidate gene approaches, have identified SSc susceptibility genes primarily involved in innate immunity (IRF4, IRF5, IRF7, IRF8, TNFAIP3), adaptive immune response (TNFSF4, CD247, PTPN22, CSK, STAT4, BLK), IL-12 signaling (IL-12A, IL-12RB1, IL-12RB2, TYK2), apoptosis/autophagy (ATG5, GSDMA, GSDMB, NOTCH4), and vascular homeostasis/fibrosis (PPARG). The review emphasizes that identified risk variants are predominantly located in non-coding regulatory regions and influence gene expression rather than protein structure.

A doctoral thesis investigating endothelin receptor antagonists (mainly bosentan) for primary prevention of pulmonary hypertension in systemic sclerosis patients. The study reviews genetic variants associated with systemic sclerosis and analyzes clinical outcomes of endothelin receptor antagonist treatment in a cohort of Spanish systemic sclerosis patients, with logistic regression analysis showing a protective effect of bosentan treatment (OR 2.2-4.1) against pulmonary hypertension development.

This study evaluated two PTPN22 coding variants (R263Q and R620W) in inflammatory bowel disease using case-control analysis and meta-analysis. The R263Q variant (rs33996649) showed association with reduced UC risk (pooled OR=0.69, 95% CI 0.51-0.93, P=0.013) but not CD. The R620W variant (rs2476601) was associated with reduced CD risk (pooled OR=0.81, 95% CI 0.75-0.89, P=7.4E-06) but not UC, demonstrating differential effects of these two autoimmunity-associated variants on CD versus UC.

This study examined 40 SNPs (34 CD-associated and 6 UC-associated) in 2374 Canadian IBD patients (1144 CD, 1230 UC/IBDU) and 1057 healthy controls. While most immune-related variants showed similar frequencies between CD and UC, the two diseases diverged significantly in genes related to innate immunity and autophagy (NOD2, ATG16L1, IRGM), which were more prevalent in CD. In patients with colon-only CD, genetic overlap with UC was nearly complete, suggesting a shared genetic basis for colonic disease.

This review article updates the genetics of systemic sclerosis (SSc), a multifactorial autoimmune disease. Key findings include identification of multiple susceptibility genes through candidate studies (STAT4 rs7574865, PTPN22 rs2476601, CD226 rs763361, TNFAIP3 rs5029939, and others) and genome-wide association studies revealing loci at HLA, STAT4, CD247, TNPO3/IRF5, and novel regions (TNIP1, RHOB). A large GWAS (N=2,296 cases/5,171 controls) identified HLA-DQB1 (rs6457617) as the strongest association and replicated CD247 rs2056626. Gene-gene interaction studies demonstrated additive effects of STAT4, IRF5, and NLRP1 variants on disease susceptibility.

This is a research highlight discussing PTPN22 splice forms and their role in rheumatoid arthritis. The paper reviews findings that RA patients show altered expression ratios of PTPN22 isoforms (LYP_v1 and LYP_v2) in peripheral blood mononuclear cells compared to healthy controls, with the LYP_v1/LYP_v2 ratio significantly elevated in RA. The R620W variant (rs2476601) and R263Q variant (rs33996649) in PTPN22 are associated with autoimmune disease susceptibility, with the W620 allele increasing RA risk.

This genome-wide pathway analysis study identified MSRA (rs10903323) as a novel rheumatoid arthritis susceptibility locus through pathway prioritization of previous GWAS data. In a combined analysis of 1,818 RA patients and 2,498 controls, rs10903323 was associated with RA (P = 3.19 × 10⁻⁴, OR 1.28), while rs12029840 near HIPK1 showed stronger replication (P = 1.64 × 10⁻⁸, OR 1.55). The findings implicate oxidative stress and the MSRA-mediated apoptosis pathway in RA pathogenesis.

This case-control study of 1,744 RA patients and 1,650 Spanish controls attempted to replicate previously reported gene-gene interactions with PTPN22 rs2476601 and GSTM1 in rheumatoid arthritis susceptibility. The study failed to replicate any of the reported interactions despite adequate statistical power and multiple testing approaches. Only PTPN22 rs2476601 showed significant association with RA (OR 1.53, 95% CI 1.29-1.80, P=4.61×10⁻⁷), but epistatic interactions with six SNPs and the GSTM1-shared epitope interaction were not confirmed.

This is a comprehensive review of genetic factors in systemic sclerosis (SSc), a complex autoimmune disease. The review synthesizes findings from candidate gene analysis and genome-wide association studies identifying numerous SNPs and genetic variants associated with SSc susceptibility, primarily in genes involved in innate immunity (IRF4, IRF5, IRF7, IRF8, TNFAIP3), adaptive immunity (TNFSF4, PTPN22, STAT4, BLK, PRDM1), and cell death pathways (ATG5, DNASE1L3, GSDMA/B, NOTCH4). HLA class II genes are associated with SSc-related autoantibodies rather than SSc itself, with DRB1 alleles carrying the FLEDR amino acid sequence critical for anti-topo I antibody responses.

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 review updates knowledge on genetic factors in systemic sclerosis (SSc) susceptibility and disease expression. GWAS and candidate gene studies have identified multiple SSc-associated genetic variants primarily located in non-coding regions that influence gene expression through eQTL effects. Major risk genes include those involved in innate immunity (IRF4, IRF5, IRF7, IRF8, TNFAIP3), adaptive immune response (PTPN22, STAT4, TNFSF4, CD247), and cell death pathways (ATG5), while few genes directly involve fibrosis or vascular homeostasis. HLA class II genes associate with SSc-related autoantibodies rather than SSc itself. Multi-omics approaches are needed to characterize the complex molecular architecture and identify biomarkers.

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 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 study of 591 late-onset Finnish type 1 diabetes patients (ages 15-40) and 1,538 controls identified SNPs at the INS (rs689, OR=0.57, p=2.77×10⁻⁹), PTPN22 (rs2476601, OR=1.50, p=3.98×10⁻⁶), and IFIH1 (rs1990760, OR=0.81, p=0.0028) loci significantly associated with disease. Notably, IL2RA SNPs (rs11594656 and rs41295061) showed no disease association but had independent effects on age at diagnosis (HR=0.83 and 0.74, p=0.015 and 0.006 respectively), making IL2RA a major determinant of disease onset timing.

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.

This workshop review summarizes analytical approaches presented at Genetic Analysis Workshop 16 Group 6 for analyzing multiple correlated phenotypes in genetic studies. Eight research teams employed multivariate methods, longitudinal repeated-measures analysis, and gene-gene interaction detection in rheumatoid arthritis and cardiovascular disease datasets. Key findings included detection of pleiotropy in genes like CETP, TCP11L1, and PMP22 (rs9901139), with joint phenotype analysis demonstrating increased power for variant detection and biological insights.

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 genome-wide association study (GWAS) identified novel genetic susceptibility loci for juvenile idiopathic arthritis (JIA) in a discovery cohort of 279 cases and 184 controls, followed by validation in 321 cases and 2,024 controls. The most strongly associated SNP (rs2187684) mapped to the HLA region (OR 0.61, p=0.00006), and fine-mapping identified 10 SNPs in the VTCN1 gene associated with JIA, with rs2358820 showing the second strongest association (OR 0.45, p=0.003).

A case-control study of 167 RA patients and 177 controls from Turkey investigated the PTPN22 R620W polymorphism (rs2476601). The heterozygous AG genotype was present in 6.6% of RA patients versus 5.1% of controls (p=0.55, OR 1.3, 95% CI 0.53–3.26), showing no significant association with rheumatoid arthritis. The authors attribute this negative finding to the lower frequency of this polymorphism in Turkish populations compared to Northern European populations.

This methodological study develops ProxyGeneLD software for converting genome-wide SNP association data to pathway-enriched gene sets and validates it on multiple large GWAS datasets. The authors demonstrate successful replication of pathway enrichment for plasma HDL levels (with CETP and ABCA1 in lipid metabolism pathways) across independent samples and identify positional gene clustering as a major source of spurious enrichment in pathway analyses of GWAS data.

This review examines genome-wide association studies (GWAS) methodology and challenges in genetic dissection of complex traits. The authors review study design, genotyping platforms, quality control, and statistical analysis approaches for GWAS, citing key examples including associations of rs1051730 (CHRNA3) with lung cancer and nicotine dependence, rs10484554 (HLA-C) with AIDS nonprogression and psoriasis, rs2476601 (PTPN22) with Crohn's disease and type 1 diabetes, and BCL11A variants with fetal hemoglobin levels.

This study examines the association between the PTPN22 C1858T polymorphism (rs2476601) and cytokine profiles in 143 systemic lupus erythematosus (SLE) patients. SLE patients carrying the risk T allele showed significantly higher serum interferon-alpha (IFNα) activity (p=0.027) and lower TNFα levels (p=0.030), with risk allele carriers disproportionately represented in IFNα-predominant or IFNα/TNFα-correlated cytokine profiles compared to TNFα-predominant profiles (p=0.002).

This Norwegian case-control and family study (1,331 cases, 1,625 controls, 421 trios) examined joint effects of HLA, INS, PTPN22, and CTLA4 on type 1 diabetes risk. The high-risk HLA genotype conferred OR=20.6 compared to neutral-risk HLA. The joint effect of HLA and PTPN22 showed significant negative deviation from multiplicativity (p=0.024), while other gene pairs followed multiplicative models. Combined high/intermediate-risk HLA with risk genotypes at all three non-HLA loci showed joint OR=61, though this genotype combination was rare in the population.

This study examined whether genetic markers (HLA-DQB1, PTPN22, INS VNTR, TCF7L2) could distinguish autoimmune from non-autoimmune diabetes in 1,642 young (15-34 years) and 1,619 middle-aged (40-59 years) Swedish diabetic patients. TCF7L2 rs7903146 CT/TT genotypes were significantly more common in young GADA-negative than GADA-positive patients (53% vs 43%; p=0.0004), suggesting TCF7L2 variants help differentiate type 2 diabetes from autoimmune diabetes in young but not middle-aged patients.

Retrospective case-control study of 222 systemic sclerosis patients with digital ulcers examining whether endothelin receptor antagonist bosentan reduces pulmonary hypertension risk. Bosentan treatment was associated with lower pulmonary hypertension incidence (14% vs 28% in controls, p<0.05) and better echocardiographic parameters in multivariate analysis.

This multi-population case-control replication study examined the STAT4 polymorphism rs7574865 in 2,072 rheumatoid arthritis (RA) patients and 2,474 controls across Spain, Sweden, and The Netherlands. The T allele of rs7574865 showed significant association with RA risk with combined effect size OR 1.25 (95% CI 1.13-1.37, P = 9.79 × 10^-6). Meta-analysis across all published populations confirmed the association with OR 1.25 (95% CI 1.19-1.33, P = 1 × 10^-5).

Case-control study of 381 UK Caucasian idiopathic inflammatory myopathy (IIM) patients and 748 controls examining PTPN22 SNPs. The R620W variant (rs2476601) showed significant association with overall IIM (OR=1.8, p=0.00007) and particularly with polymyositis (OR=2.2, p=0.0001) and juvenile dermatomyositis (OR=2.1, p=0.0006). The association was independent of the HLA 8.1 haplotype.

A two-stage genome-wide association study (GWAS) in Spanish population identified KLF12 as a new susceptibility locus for rheumatoid arthritis, with rs1324913 showing stronger association (P=0.01) in replication than PTPN22 rs2476601. Joint analysis with three previous GWAS studies confirmed KLF12 and PTPRT as commonly associated loci, with KLF12 SNP rs1887346 and rs9318228 showing P values of 6.03×10⁻⁵ and 3.66×10⁻⁵ in the discovery phase and evidence of replication across multiple populations.

In 4,364 type 1 diabetes cases from Great Britain (10.8% positive for thyroid peroxidase autoantibodies [TPOAbs]), the CTLA4 rs3087243 G allele showed a stronger association with disease in TPOAb-positive cases (OR=1.49, 95% CI=1.29-1.72) compared to TPOAb-negative cases (OR=1.16, 95% CI=1.10-1.24, P=0.0004). The TPOAb-positive subgroup showed a marked female bias (1.97:1 female:male ratio) and represents a form of autoimmune polyendocrine syndrome where tolerance to both insulin-producing cells and thyroid tissue is impaired.

A meta-analysis and case-control study of 649 IBD patients (343 Crohn's disease, 306 ulcerative colitis) and 256 controls examined polymorphisms in PTPN22, NFKB1, and FcGRIIIA genes. The PTPN22 C1858T variant (rs2476601) showed no association with IBD. The NFKB1 -94ATTG deletion was not associated with IBD in this population or in meta-analysis. The FcGRIIIA G559T polymorphism showed a significant association with Crohn's disease (allele T: OR=1.58, 95% CI 1.06-2.35, p=0.023; GT genotype: OR=1.64, 95% CI 1.08-2.5, p=0.019).

This cross-sectional study of 964 RA patients examined associations between genetic variants in IL-1, IL-6, IL-10, PTPN22, and SEPS with radiographic damage severity. IL-6 -174G allele showed allele-dose association with increased radiographic damage (P=0.005) specifically in RF-positive and anti-CCP-positive patients. Conversely, IL-10 -592CC genotype was associated with greater damage (P=0.006) but only in RF-negative and anti-CCP-negative patients. These associations were independent of autoantibody production.

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.

This review examines slowly progressive type 1 diabetes mellitus (SPIDDM), also known as latent autoimmune diabetes in adults (LADA), discussing its pathogenesis, diagnostic markers, and genetic associations. Key findings include T-cell-mediated insulitis and pseudoatrophic islets characteristic of type 1 diabetes, absence of amyloid deposition seen in type 2 diabetes, and identification of multiple genetic susceptibility loci including HLA haplotypes, PTPN22 rs2476601, INS rs689, CTLA4, TCF7L2 rs7903146, ZMIZ1 rs12571751, SH2B3 rs7310615, and PFKFB3 rs1983890. GAD autoantibodies and HLA genotypes are important risk factors for beta-cell failure progression.

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.