rs5029939

Genome-wide association study in 1,174 Korean SLE cases and 4,248 controls identified 12 genome-wide significant loci, including a novel locus spanning ATG16L2, FCHSD2, and P2RY2 peaking at rs11235667 (P=1.0×10⁻⁸, OR=0.59). The study replicated 10 previously established SLE risk loci (STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, IRAK1-MECP2) and identified novel independent effects in TNFAIP3 and TNFSF4. HLA-DRB1*1501 and HLA-DQB1*0602 were the strongest HLA associations (P=5.55×10⁻¹⁶, OR=1.85 and OR=1.90 respectively).

Whole-exome sequencing identified ATP8B4 as a novel susceptibility gene for systemic sclerosis (SSc), with the missense variant rs55687265 (c.1308C>G, F436L) showing the strongest association (discovery: P=9.35×10⁻¹⁰, OR=6.11; replication: P=0.012, OR=1.86; meta-analysis: P=1.92×10⁻⁷, OR=2.5). ATP8B4 overexpression was confirmed in SSc patients' peripheral blood mononuclear cells (P=0.0005). Additional genes ASB10, CNGB3, HLA-DRB5, and HSPB2 also showed significant associations (P<10⁻⁵).

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.

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 identified PLD4 as a novel susceptibility gene for systemic sclerosis (SSc) in a Japanese population, with rs2841277 showing significant association (P=0.00017, OR=1.25). The study also confirmed associations between SSc and rs6932056 in TNFAIP3 (P=0.0000095, OR=1.50) and rs2280381 in IRF8 (P=0.0030, OR=1.26). rs2841280 in PLD4 exon 2 was found in strong linkage disequilibrium with rs2841277 and introduces an amino acid change (E27Q).

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 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.

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 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.

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.