| Title: | Leveraging the UK Biobank Cohort to Redefine Penetrance and Phenotypic Spectra of Hemophagocytic Lymphohistiocytosis-Associated Genes |
| Lead Institution: | Huazhong University of Science and Technology |
| Principal investigator: |
Application 982980
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About
I. Research Rationale Recent studies indicate that haemophagocytic lymphohistiocytosis (HLH) functions as an early warning signal of an inborn error of immunity rather than representing a single, discrete disease entity. Current understanding of penetrance and phenotypic spectra for HLH-associated genes relies on clinically ascertained cohorts, inflating risk estimates due to ascertainment bias. We aim at deriving unbiased penetrance estimates and gene-environment maps for HLH variants while testing whether immune co-mutations heighten expressivity. II. Questions 1. What is the true population penetrance of pathogenic/likely pathogenic variants in familial HLH genes? 2. Do HLH gene variants predispose to non-classical phenotypes (e.g., lymphoma, autoimmune disorders)? 3. How do digenic architectures and environmental triggers (e.g., EBV) modulate expressivity? 4. Do patients harboring HLH-associated genetic mutations concurrently carry other immune-related genetic mutations? Does such co-occurrence lead to a higher penetrance? III. Methodology 1. Penetrance quantification: Identify carriers of pathogenic variants in familial HLH-related genes ; Calculate age-dependent penetrance using survival analysis (time-to-HLH or related phenotype emergence) 2. Phenotype expansion analysis: Associate variants with 72 predefined ICD-10 codes (HLH, neuroinflammation, lymphoma, etc.) via logistic regression 3. Risk stratification modeling: Develop gene/variant-specific hazard ratio; Test digenic and polygenic risk score ; Integrate serological data (EBV IgG) as covariate. 4. Compare the frequency of immunoregulatory gene variants between carriers of HLH-related mutations and non-carriers using Fisher's exact test or logistic regression to identify significantly co-occurrent variants.1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 20724 | Association between CALLY index and all-cause mortality in patients with rheumatoid arthritis | Tong Zhang (+1) | 2026 | Frontiers in Nutrition |
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