TNFSF4 – Systemic Lupus Erythematosus

TNFSF4 encodes the OX40 ligand (OX40L), a T-cell costimulatory molecule implicated in the regulation of T-cell proliferation and survival. Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by autoantibody production, immune complex deposition and multiorgan inflammation (MONDO:0007915).

Large-scale genome-wide association studies (GWAS) have repeatedly identified TNFSF4 single-nucleotide polymorphisms (SNPs) as genome-wide significant risk loci for SLE. In a Chinese Han discovery cohort of 1,047 cases and 1,205 controls (1,047 cases [PMID:19838193]; replication in 3,152 cases and 7,050 controls [PMID:19838193]), the rs2205960 variant reached P = 5.17 × 10⁻⁴². Subsequent studies in Hispanic Mestizo (804 patients, 667 controls [PMID:20848568]), North Indian (394 cases, 583 controls [PMID:30041578]), Malay (476 cases, 509 controls [PMID:27519474]) and Mexican cohorts (395 cases, 500 controls [PMID:32809147]) confirmed association of rs2205960 and additional SNPs (rs1234314, rs844648, rs704840) with SLE risk. Meta-analyses across >10,000 SLE cases and matched controls show consistent odds ratios 1.2–1.4 across ancestries.

The variant spectrum at the TNFSF4 locus includes multiple noncoding and intronic SNPs with regulatory potential. The T-allele of rs2205960 (G > T) and C-allele of rs1234314 (G > C) have been most consistently associated with increased SLE susceptibility, without evidence for rare loss-of-function alleles or coding changes.

Inheritance of SLE is complex and multifactorial. There is no evidence of Mendelian segregation for TNFSF4 variants; familial aggregation arises from polygenic risk. No segregation studies of TNFSF4 variants in multiplex pedigrees have been reported.

Functional assays support a regulatory mechanism: luciferase reporter studies demonstrate that the rs1234314 C-allele reduces promoter activity to 0.32 ± 0.09 RLU relative to the G-allele (P = 0.003) and the rs45454293 T-allele increases activity 4.63 ± 0.92-fold over the C-allele (P < 0.001), confirming allele-specific effects on TNFSF4 transcription ([PMID:36983159]; [PMID:21445270]).

Collectively, TNFSF4 is a robust susceptibility locus for SLE with strong, replicated genetic associations and functional evidence for altered gene regulation. These findings support the use of TNFSF4 genotyping in polygenic risk models and provide a basis for future mechanistic and therapeutic studies.

References

• Nature genetics • 2009 • Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. PMID:19838193
• Arthritis and rheumatism • 2010 • Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus. PMID:20848568
• Lupus • 2018 • Association of ITGAM, TNFSF4, TNFAIP3 and STAT4 gene polymorphisms with risk of systemic lupus erythematosus in a North Indian population. PMID:30041578
• International journal of immunogenetics • 2016 • TNFSF4 polymorphisms are associated with systemic lupus erythematosus in the Malaysian population. PMID:27519474
• Clinical rheumatology • 2021 • TNFSF4 is a risk factor to systemic lupus erythematosus in a Latin American population. PMID:32809147
• Journal of clinical medicine • 2023 • Exploring the Bio-Functional Effect of Single Nucleotide Polymorphisms in the Promoter Region of the TNFSF4, CD28, and PDCD1 Genes. PMID:36983159
• PLoS one • 2011 • A common polymorphism in the promoter region of the TNFSF4 gene is associated with lower allele‐specific expression and risk of myocardial infarction. PMID:21445270

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