rs2233287

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.

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.

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 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 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.

Case-control study of 716 Meniere's disease patients and 1,628 controls using ImmunoChip genotyping identified intronic variants rs3774937 (C allele) and rs4648011 (G allele) in the NFKB1 gene associated with faster hearing loss progression in patients with unilateral sensorineural hearing loss (corrected p=0.009 and p=0.003, respectively). These variants reduced median time to reach hearing stage 3 (≥40 dB) by approximately 2 years. No single variants reached genome-wide significance for MD susceptibility, and these NFKB1 variants did not influence hearing in bilateral MD.