rs763361

This case-control study of 646 Chinese Han subjects (326 SLE patients, 320 controls) investigated the association between CD40 and CD226 gene polymorphisms and systemic lupus erythematosus (SLE) risk. Carriers of the T allele of rs4810485 in CD40 had significantly elevated SLE risk (OR=1.84, 95% CI 1.40-2.29), as did carriers of the T allele of rs763361 in CD226 (OR=1.89, 95% CI 1.38-2.13). Gene-gene interaction analysis revealed a significant two-locus model (p=0.01) with subjects carrying both risk variants at highest risk (OR=2.14, 95% CI 1.67-3.08).

This case-control study demonstrates that the CD226 Gly307Ser variant (rs763361) is significantly associated with rheumatoid arthritis (RA) susceptibility in a Chinese Han population (P=0.005, OR=1.52; adjusted P=0.029, OR=1.45). Meta-analysis across populations confirms the association (overall P<0.001, overall OR=1.12) and suggests a more pronounced genetic effect in non-European populations compared to Europeans.

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 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 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 study of 1,163 SLE patients and 1,482 European controls identified a 3-SNP haplotype (rs763361; rs34794968; rs727088) in the 3'-UTR of CD226 associated with systemic lupus erythematosus (SLE), with the risk haplotype ATC conferring OR 1.24 (95% CI 1.11-1.38). The C allele of rs727088 was responsible for reduced CD226 expression in T and NKT cells, suggesting a functional regulatory role in SLE susceptibility.

This study confirmed association between rs6822844 in the IL2-IL21 region and multiple autoimmune diseases in non-European populations, with significant associations in Colombian samples for systemic lupus erythematosus (OR 0.50, P=0.008), type 1 diabetes (OR 0.43, P=0.014), rheumatoid arthritis (OR 0.61, P=0.019), and primary Sjögren's syndrome (OR 0.46, P=0.033). Meta-analysis of 23 populations showed highly significant overall association (P=2.61×10⁻²⁵, OR 0.73) and disease-specific associations with inflammatory bowel disease (P=3.48×10⁻¹², OR 0.74), rheumatoid arthritis (P=3.61×10⁻⁶, OR 0.77), type 1 diabetes (P=5.33×10⁻⁵, OR 0.61), and celiac disease (P=5.30×10⁻³, OR 0.72).

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.