| Domain | Finding | Specific details | Quantitative data | Population / geography | Source |
|---|---|---|---|---|---|
| HLA association | Strongest genetic signal maps to HLA class II | Recent genetics review states AOSD shows a unique association with HLA genes, especially class II, unlike many other systemic autoinflammatory diseases | No pooled OR provided in the retrieved review abstract | Multicenter literature review; strongest evidence emphasized across cohorts | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271) |
| HLA association | Amino-acid polymorphisms in HLA class II explain major risk in Han Chinese AOSD | The retrieved Journal of Autoimmunity study identified amino-acid variants in **HLA-DQα1** and **HLA-DRβ1** as explaining the major association signal | **Ser at position 34 in HLA-DQα1**: *p* = **1.44 × 10^-14**; **Asn in HLA-DRβ1** also significantly associated | Han Chinese population | Teng et al., 2021, *J Autoimmun* (doi:10.1016/j.jaut.2020.102562) |
| HLA association | Specific HLA class II alleles implicated | The same study reported associations for three main HLA class II alleles including **HLA-DQB1***- and **HLA-DRB1***-linked signals | Exact allele-level ORs not available from retrieved snippet | Han Chinese population | Teng et al., 2021, *J Autoimmun* (doi:10.1016/j.jaut.2020.102562) |
| Non-HLA genetics | Variants of uncertain significance found by next-generation sequencing, but no pathogenic monogenic variants | In 24 clinically diagnosed AOSD patients undergoing NGS, variants were seen in **NOD2**, **TNFRSF1A**, **TNFAIP3**, and **SCN9A**; none were classified pathogenic | Genetic variants in **5/24 (20.8%)**; all were **VUS** | Northern Spain multicenter cohort | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271) |
| Non-HLA genetics | Specific VUS observed | **NOD2 c.2104C>T**, **NOD2 c.2251G>A**, **TNFRSF1A c.224C>T**, **TNFAIP3 c.1939A>C**, **SCN9A c.2617G>A** | Four of five variant carriers had severe/refractory disease requiring biologics | Northern Spain multicenter cohort | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271) |
| Non-HLA genetics | Candidate susceptibility genes beyond HLA remain suggestive rather than definitive | Retrieved literature notes polymorphisms in genes encoding inflammatory mediators have been reported; unobtainable but identified papers include **CSF1/M-CSF** association work | No validated causal gene established | Multiple populations; evidence heterogeneous | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271); retrieved unobtainable citation: Chen et al., 2020, *J Immunol Res* doi:10.1155/2020/8640719 |
| Non-HLA genetics | MIF polymorphisms | Recent retrieved snippets mention macrophage migration inhibitory factor (**MIF**) polymorphisms as discussed in broader Still’s disease genetics literature, but no primary quantitative estimate was available in the retrieved accessible abstracts | Not available from accessible retrieved content | Population-specific effects suggested in review snippets | Pietsch & Savic, 2026, *Curr Rheumatol Rep* (doi:10.1007/s11926-026-01210-6) |
| Genetic architecture | Overall inheritance model | Reviews describe AOSD as **non-familial**, **multigenic/polygenic**, and **multifactorial**, not a Mendelian disorder | No penetrance or carrier frequency established | General | Ma et al., 2021, *Rheumatology* (doi:10.1093/rheumatology/keab485); Galozzi et al., 2022, *Biologics* (doi:10.2147/BTT.S290329) |
| Epidemiology | Disease rarity | AOSD is consistently described as a **rare** systemic autoinflammatory disease; reliable epidemiologic data remain limited | No single global prevalence estimate available from retrieved accessible abstracts | Global | Tomaras et al., 2021, *J Clin Med* (doi:10.3390/jcm10040733); Qin et al., 2022, *Front Immunol* (doi:10.3389/fimmu.2022.950641) |
| Incidence | Poland urban incidence estimate | Bibliometric review summarized prior epidemiology showing incidence in urban Poland | **0.33 per 100,000 person-years** | Urban Poland | Qin et al., 2022, *Front Immunol* (doi:10.3389/fimmu.2022.950641) |
| Age distribution | Typical onset in adulthood | Adult cohorts cluster around early-to-mid adulthood; a recent genetics cohort had mean age around the early 40s | Mean age **42.2 ± 17.9 years** in Spanish NGS cohort; U.S. claims cohort mean age **43.08 ± 13.9 years** | Spain; United States | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271); Lenert et al., 2020, *Rheumatology* (doi:10.1093/rheumatology/kez622) |
| Sex ratio | Female predominance in contemporary cohorts | AOSD shows female predominance in at least some modern cohorts, though historic studies have varied | U.S. claims cohort: **68.9% female** | United States | Lenert et al., 2020, *Rheumatology* (doi:10.1093/rheumatology/kez622) |
| Geographic distribution | Research concentration by country | Bibliometric analysis found highest research output from **Japan**, followed by the **United States** and **France**, reflecting established expertise and possibly case concentration/reporting | Japan **355 papers (14.96%)**; U.S. **329 (13.86%)**; France **215 (9.06%)** | Global publication landscape | Qin et al., 2022, *Front Immunol* (doi:10.3389/fimmu.2022.950641) |
| Population-specific findings | Han Chinese cohort reveals fine-mapped HLA amino-acid risk architecture | The Han Chinese study suggests ethnicity-specific fine-mapping can localize risk to amino-acid residues rather than only broad HLA alleles | Strongest reported association: **HLA-DQα1 position 34 Ser**, *p* = **1.44 × 10^-14** | Han Chinese | Teng et al., 2021, *J Autoimmun* (doi:10.1016/j.jaut.2020.102562) |
| Population-specific findings | Afro-Caribbean epidemiology under active study | A population-based Afro-Caribbean study in Martinique was retrieved but unobtainable, indicating attention to ancestry-specific epidemiology and outcomes | Data not available in accessible content | Martinique, French West Indies | Retrieved unobtainable citation: de Fritsch et al., 2023, *J Autoimmun* doi:10.1016/j.jaut.2023.103086 |
| Elderly-onset subgroup | Older-age onset recognized as a clinically relevant subset | Retrieved papers indicate a distinct elderly-onset phenotype is being studied, but detailed epidemiologic rates were unavailable in accessible abstracts | Not available from accessible content | Japan; other cohorts | Retrieved unobtainable citations: Li et al., 2023, *J Transl Autoimmun* doi:10.1016/j.jtauto.2023.100196; Tada et al., 2024, *Drugs Aging* doi:10.1007/s40266-024-01137-6 |
| Data provenance | Nature of evidence base | Most epidemiology/genetics information comes from **aggregated disease-level resources**, retrospective cohorts, claims databases, case series, and association studies rather than EHR-only molecularly confirmed registries | Example cohorts: **24-patient** NGS series; **106-case** U.S. claims cohort | Spain; United States; literature synthesis/global | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271); Lenert et al., 2020, *Rheumatology* (doi:10.1093/rheumatology/kez622) |
| Evidence gap | What is not established | No monogenic causal gene, no validated pathogenic recurrent variant, no robust penetrance estimates, and no consistent worldwide prevalence estimate were available from the retrieved accessible sources | Not available | General | Prieto-Peña et al., 2024, *Front Immunol* (doi:10.3389/fimmu.2024.1474271); Qin et al., 2022, *Front Immunol* (doi:10.3389/fimmu.2022.950641) |


*Table: This table summarizes the currently accessible evidence on Adult-Onset Still Disease genetics and population epidemiology from the retrieved literature. It highlights the strongest HLA class II associations, currently reported non-HLA variants, and key demographic and incidence findings, while also making clear where evidence remains limited.*