database.json

{
  "genes": {
    "CYP2D6": {
      "chromosome": "22",
      "variants": {
        "rs3892097": {
          "star_allele": "*4",
          "effect": "no_function",
          "clinical_significance": "Loss of function variant",
          "ref": "G",
          "alt": "A"
        },
        "rs5030655": {
          "star_allele": "*6",
          "effect": "no_function",
          "clinical_significance": "Frameshift mutation causing non-functional enzyme",
          "ref": "T",
          "alt": "TA"
        },
        "rs16947": {
          "star_allele": "*2",
          "effect": "normal_function",
          "clinical_significance": "Normal function variant",
          "ref": "G",
          "alt": "A"
        },
        "rs1065852": {
          "star_allele": "*10",
          "effect": "decreased_function",
          "clinical_significance": "Decreased enzyme activity",
          "ref": "C",
          "alt": "T"
        },
        "rs28371725": {
          "star_allele": "*41",
          "effect": "decreased_function",
          "clinical_significance": "Reduced enzyme activity",
          "ref": "C",
          "alt": "T"
        }
      }
    },
    "CYP2C19": {
      "chromosome": "10",
      "variants": {
        "rs4244285": {
          "star_allele": "*2",
          "effect": "no_function",
          "clinical_significance": "Splicing defect causing loss of function",
          "ref": "G",
          "alt": "A"
        },
        "rs4986893": {
          "star_allele": "*3",
          "effect": "no_function",
          "clinical_significance": "Premature stop codon",
          "ref": "G",
          "alt": "A"
        },
        "rs12248560": {
          "star_allele": "*17",
          "effect": "increased_function",
          "clinical_significance": "Increased transcription and enzyme activity",
          "ref": "C",
          "alt": "T"
        }
      }
    },
    "CYP2C9": {
      "chromosome": "10",
      "variants": {
        "rs1799853": {
          "star_allele": "*2",
          "effect": "decreased_function",
          "clinical_significance": "Reduced warfarin metabolism",
          "ref": "C",
          "alt": "T"
        },
        "rs1057910": {
          "star_allele": "*3",
          "effect": "no_function",
          "clinical_significance": "Significantly reduced enzyme activity",
          "ref": "A",
          "alt": "C"
        }
      }
    },
    "SLCO1B1": {
      "chromosome": "12",
      "variants": {
        "rs4149056": {
          "star_allele": "*5",
          "effect": "decreased_function",
          "clinical_significance": "Reduced hepatic uptake of statins; increased myopathy risk",
          "ref": "T",
          "alt": "C"
        },
        "rs2306283": {
          "star_allele": "*1b",
          "effect": "increased_function",
          "clinical_significance": "Increased transporter activity",
          "ref": "A",
          "alt": "G"
        }
      }
    },
    "TPMT": {
      "chromosome": "6",
      "variants": {
        "rs1800462": {
          "star_allele": "*2",
          "effect": "no_function",
          "clinical_significance": "Loss of TPMT enzyme activity",
          "ref": "C",
          "alt": "G"
        },
        "rs1800460": {
          "star_allele": "*3B",
          "effect": "no_function",
          "clinical_significance": "Loss of TPMT enzyme activity",
          "ref": "C",
          "alt": "T"
        },
        "rs1142345": {
          "star_allele": "*3C",
          "effect": "no_function",
          "clinical_significance": "Loss of TPMT enzyme activity",
          "ref": "A",
          "alt": "G"
        }
      }
    },
    "DPYD": {
      "chromosome": "1",
      "variants": {
        "rs3918290": {
          "star_allele": "*2A",
          "effect": "no_function",
          "clinical_significance": "Complete DPD deficiency; severe fluoropyrimidine toxicity",
          "ref": "C",
          "alt": "T"
        },
        "rs55886062": {
          "star_allele": "*13",
          "effect": "no_function",
          "clinical_significance": "Non-functional DPD enzyme",
          "ref": "A",
          "alt": "C"
        },
        "rs67376798": {
          "star_allele": "D949V",
          "effect": "decreased_function",
          "clinical_significance": "Reduced DPD activity",
          "ref": "T",
          "alt": "A"
        }
      }
    }
  },
  "drug_gene_mapping": {
    "CODEINE": {
      "primary_gene": "CYP2D6",
      "mechanism": "CYP2D6 converts codeine to morphine (active metabolite). Variations in CYP2D6 activity directly affect analgesic efficacy and toxicity risk.",
      "risk_rules": {
        "PM": {
          "risk_label": "Ineffective",
          "severity": "high",
          "confidence": 0.95,
          "recommendation": "Avoid codeine. Use alternative analgesics not metabolized by CYP2D6 such as morphine, non-opioid analgesics, or acetaminophen.",
          "cpic_guideline": "CPIC recommends avoiding codeine in CYP2D6 poor metabolizers due to lack of analgesic effect."
        },
        "IM": {
          "risk_label": "Adjust Dosage",
          "severity": "moderate",
          "confidence": 0.85,
          "recommendation": "Reduced codeine efficacy expected. Consider alternative analgesics or monitor closely for inadequate pain relief. If codeine is used, be aware that higher doses may not compensate due to metabolic ceiling.",
          "cpic_guideline": "CPIC suggests using alternative analgesics for CYP2D6 intermediate metabolizers if inadequate response."
        },
        "NM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.92,
          "recommendation": "Standard codeine dosing is appropriate. Monitor for expected analgesic response and standard opioid side effects.",
          "cpic_guideline": "CPIC: Use label-recommended age- or weight-specific dosing."
        },
        "RM": {
          "risk_label": "Adjust Dosage",
          "severity": "moderate",
          "confidence": 0.88,
          "recommendation": "Increased conversion to morphine possible. Use lower doses and monitor for opioid toxicity symptoms including respiratory depression, sedation, and confusion.",
          "cpic_guideline": "CPIC recommends caution with rapid metabolizers; consider lower doses or alternative analgesics."
        },
        "URM": {
          "risk_label": "Toxic",
          "severity": "critical",
          "confidence": 0.96,
          "recommendation": "AVOID codeine. Ultra-rapid metabolism causes dangerously high morphine levels. Life-threatening respiratory depression reported. Use alternative non-CYP2D6 analgesics.",
          "cpic_guideline": "CPIC strongly recommends avoiding codeine in ultra-rapid metabolizers due to risk of fatal respiratory depression."
        },
        "Unknown": {
          "risk_label": "Unknown",
          "severity": "moderate",
          "confidence": 0.30,
          "recommendation": "Insufficient genetic data to determine CYP2D6 metabolizer status. Consider pharmacogenomic testing before prescribing codeine. Use standard dosing with enhanced monitoring.",
          "cpic_guideline": "Consider comprehensive CYP2D6 genotyping."
        }
      }
    },
    "CLOPIDOGREL": {
      "primary_gene": "CYP2C19",
      "mechanism": "CYP2C19 bioactivates clopidogrel from prodrug to active antiplatelet metabolite. Reduced CYP2C19 function leads to diminished platelet inhibition and increased cardiovascular event risk.",
      "risk_rules": {
        "PM": {
          "risk_label": "Ineffective",
          "severity": "critical",
          "confidence": 0.95,
          "recommendation": "Avoid clopidogrel. Use alternative antiplatelet agents such as prasugrel or ticagrelor which do not depend on CYP2C19 activation.",
          "cpic_guideline": "CPIC recommends alternative antiplatelet therapy for CYP2C19 poor metabolizers."
        },
        "IM": {
          "risk_label": "Adjust Dosage",
          "severity": "high",
          "confidence": 0.88,
          "recommendation": "Reduced clopidogrel activation expected. Consider alternative antiplatelet therapy (prasugrel/ticagrelor) or use with enhanced platelet function monitoring.",
          "cpic_guideline": "CPIC recommends alternative antiplatelet for intermediate metabolizers undergoing PCI."
        },
        "NM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.92,
          "recommendation": "Standard clopidogrel dosing is appropriate. Expected normal antiplatelet response.",
          "cpic_guideline": "CPIC: Use label-recommended dosing."
        },
        "RM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.90,
          "recommendation": "Enhanced clopidogrel activation. Standard dosing appropriate with normal monitoring. May have enhanced antiplatelet effect.",
          "cpic_guideline": "CPIC: Use label-recommended dosing."
        },
        "URM": {
          "risk_label": "Safe",
          "severity": "low",
          "confidence": 0.88,
          "recommendation": "Enhanced clopidogrel activation. Standard dosing appropriate. Monitor for increased bleeding risk.",
          "cpic_guideline": "CPIC: Use label-recommended dosing; monitor for bleeding."
        },
        "Unknown": {
          "risk_label": "Unknown",
          "severity": "moderate",
          "confidence": 0.30,
          "recommendation": "Insufficient data. Consider CYP2C19 genotyping especially if undergoing PCI. Use standard dosing with monitoring.",
          "cpic_guideline": "Consider CYP2C19 genotyping before initiating clopidogrel."
        }
      }
    },
    "WARFARIN": {
      "primary_gene": "CYP2C9",
      "mechanism": "CYP2C9 metabolizes S-warfarin (the more potent enantiomer). Reduced CYP2C9 function leads to decreased warfarin clearance and increased bleeding risk at standard doses.",
      "risk_rules": {
        "PM": {
          "risk_label": "Toxic",
          "severity": "critical",
          "confidence": 0.94,
          "recommendation": "Significantly reduce warfarin dose (30-70% reduction). Initiate at much lower dose with frequent INR monitoring. Consider alternative anticoagulants (DOACs).",
          "cpic_guideline": "CPIC recommends significantly reduced initial warfarin dose for CYP2C9 poor metabolizers based on pharmacogenomic dosing algorithms."
        },
        "IM": {
          "risk_label": "Adjust Dosage",
          "severity": "high",
          "confidence": 0.90,
          "recommendation": "Reduce warfarin starting dose by 20-40%. More frequent INR monitoring required during initiation. Use pharmacogenomic dosing calculator.",
          "cpic_guideline": "CPIC recommends reduced initial dose using pharmacogenomic dosing algorithm."
        },
        "NM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.90,
          "recommendation": "Standard warfarin dosing protocol. Initiate with standard dose and titrate based on INR monitoring.",
          "cpic_guideline": "CPIC: Use standard clinical dosing algorithm."
        },
        "RM": {
          "risk_label": "Adjust Dosage",
          "severity": "low",
          "confidence": 0.80,
          "recommendation": "May require higher warfarin doses due to increased metabolism. Monitor INR closely and titrate accordingly.",
          "cpic_guideline": "Consider higher dose requirements; monitor INR."
        },
        "URM": {
          "risk_label": "Ineffective",
          "severity": "moderate",
          "confidence": 0.82,
          "recommendation": "Rapid warfarin metabolism may lead to subtherapeutic INR at standard doses. Consider higher doses with close INR monitoring or alternative anticoagulants.",
          "cpic_guideline": "Monitor for subtherapeutic response; dose adjustment likely needed."
        },
        "Unknown": {
          "risk_label": "Unknown",
          "severity": "moderate",
          "confidence": 0.30,
          "recommendation": "Insufficient genetic data. Use standard clinical dosing with careful INR monitoring. Consider CYP2C9 and VKORC1 genotyping.",
          "cpic_guideline": "Consider pharmacogenomic testing for warfarin dosing optimization."
        }
      }
    },
    "SIMVASTATIN": {
      "primary_gene": "SLCO1B1",
      "mechanism": "SLCO1B1 encodes the OATP1B1 transporter responsible for hepatic uptake of simvastatin acid. Reduced function variants decrease hepatic uptake, increasing systemic simvastatin exposure and myopathy risk.",
      "risk_rules": {
        "PM": {
          "risk_label": "Toxic",
          "severity": "critical",
          "confidence": 0.93,
          "recommendation": "Avoid simvastatin. High risk of myopathy and rhabdomyolysis. Use alternative statins with lower SLCO1B1 dependence (pravastatin, rosuvastatin, fluvastatin).",
          "cpic_guideline": "CPIC recommends avoiding simvastatin >20mg or using alternative statins for SLCO1B1 poor function."
        },
        "IM": {
          "risk_label": "Adjust Dosage",
          "severity": "high",
          "confidence": 0.88,
          "recommendation": "Limit simvastatin to 20mg daily maximum. Monitor for muscle symptoms (myalgia, weakness). Consider CK levels at baseline. Alternative lower-risk statins may be preferred.",
          "cpic_guideline": "CPIC recommends simvastatin dose not exceed 20mg daily; consider alternatives."
        },
        "NM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.90,
          "recommendation": "Standard simvastatin dosing appropriate. Monitor for standard statin side effects. Routine CK monitoring not required unless symptomatic.",
          "cpic_guideline": "CPIC: Prescribe desired starting dose and adjust based on disease-specific guidelines."
        },
        "RM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.85,
          "recommendation": "Standard simvastatin dosing appropriate. Normal hepatic uptake expected.",
          "cpic_guideline": "Use standard dosing."
        },
        "URM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.82,
          "recommendation": "Enhanced hepatic uptake. Standard dosing appropriate. May have improved hepatic drug targeting.",
          "cpic_guideline": "Use standard dosing."
        },
        "Unknown": {
          "risk_label": "Unknown",
          "severity": "moderate",
          "confidence": 0.30,
          "recommendation": "Insufficient data. Use conservative simvastatin dosing. Monitor for myopathy symptoms. Consider SLCO1B1 genotyping.",
          "cpic_guideline": "Consider pharmacogenomic testing if using high-dose simvastatin."
        }
      }
    },
    "AZATHIOPRINE": {
      "primary_gene": "TPMT",
      "mechanism": "TPMT methylates thiopurine drugs, diverting metabolism away from cytotoxic thioguanine nucleotides (TGN). Reduced TPMT activity leads to TGN accumulation causing severe myelosuppression.",
      "risk_rules": {
        "PM": {
          "risk_label": "Toxic",
          "severity": "critical",
          "confidence": 0.97,
          "recommendation": "AVOID azathioprine or reduce dose to 10% of standard. If used, requires drastically reduced dose with weekly CBC monitoring. Life-threatening myelosuppression expected at standard doses. Consider alternative immunosuppressants.",
          "cpic_guideline": "CPIC recommends drastically reduced dose (10% of normal) or alternative agent for TPMT poor metabolizers."
        },
        "IM": {
          "risk_label": "Adjust Dosage",
          "severity": "high",
          "confidence": 0.92,
          "recommendation": "Reduce azathioprine dose to 30-70% of standard. Initiate at reduced dose with CBC monitoring every 1-2 weeks during first months. Titrate based on tolerance and blood counts.",
          "cpic_guideline": "CPIC recommends starting at reduced dose (30-70% of full dose) for TPMT intermediate metabolizers."
        },
        "NM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.92,
          "recommendation": "Standard azathioprine dosing appropriate. Standard monitoring with periodic CBC.",
          "cpic_guideline": "CPIC: Start with normal starting dose. Adjust based on disease-specific guidelines."
        },
        "RM": {
          "risk_label": "Adjust Dosage",
          "severity": "low",
          "confidence": 0.78,
          "recommendation": "Increased TPMT activity may reduce efficacy due to rapid drug inactivation. May require higher doses or alternative immunosuppressant if inadequate response.",
          "cpic_guideline": "Monitor for therapeutic response; dose increase may be needed."
        },
        "URM": {
          "risk_label": "Ineffective",
          "severity": "moderate",
          "confidence": 0.80,
          "recommendation": "Ultra-rapid TPMT metabolism likely causes subtherapeutic TGN levels. Consider higher doses with monitoring or alternative immunosuppressant.",
          "cpic_guideline": "Consider alternative therapy or dose adjustment based on TGN levels."
        },
        "Unknown": {
          "risk_label": "Unknown",
          "severity": "high",
          "confidence": 0.30,
          "recommendation": "TPMT status unknown. STRONGLY recommend TPMT genotyping or phenotyping before initiating azathioprine. If urgent, start at reduced dose with intensive CBC monitoring.",
          "cpic_guideline": "CPIC recommends TPMT testing prior to azathioprine initiation."
        }
      }
    },
    "FLUOROURACIL": {
      "primary_gene": "DPYD",
      "mechanism": "DPD (encoded by DPYD) catabolizes >80% of fluorouracil. DPD deficiency causes fluorouracil accumulation leading to severe and potentially fatal toxicity including myelosuppression, mucositis, neurotoxicity, and hand-foot syndrome.",
      "risk_rules": {
        "PM": {
          "risk_label": "Toxic",
          "severity": "critical",
          "confidence": 0.97,
          "recommendation": "AVOID fluorouracil and capecitabine. Complete DPD deficiency causes life-threatening toxicity. Use alternative chemotherapy regimens. If no alternatives, use at most 25-50% dose with intensive monitoring.",
          "cpic_guideline": "CPIC recommends avoiding fluoropyrimidines in DPD-deficient patients or using drastically reduced dose with therapeutic drug monitoring."
        },
        "IM": {
          "risk_label": "Adjust Dosage",
          "severity": "high",
          "confidence": 0.92,
          "recommendation": "Reduce fluorouracil starting dose by 25-50%. Monitor closely for toxicity including CBC, mucositis assessment, and neurotoxicity screening. Dose titration based on tolerance.",
          "cpic_guideline": "CPIC recommends 25-50% dose reduction for DPYD intermediate metabolizers with dose titration based on toxicity and pharmacokinetics."
        },
        "NM": {
          "risk_label": "Safe",
          "severity": "none",
          "confidence": 0.90,
          "recommendation": "Standard fluorouracil dosing per oncology protocol. Standard toxicity monitoring applies.",
          "cpic_guideline": "CPIC: Use label-recommended dosage and administration."
        },
        "RM": {
          "risk_label": "Adjust Dosage",
          "severity": "low",
          "confidence": 0.75,
          "recommendation": "Rapid DPD metabolism may reduce fluorouracil efficacy. Standard dosing with monitoring for therapeutic response. Dose increase may be considered based on pharmacokinetic monitoring.",
          "cpic_guideline": "Monitor for therapeutic response."
        },
        "URM": {
          "risk_label": "Ineffective",
          "severity": "moderate",
          "confidence": 0.78,
          "recommendation": "Ultra-rapid DPD activity may lead to subtherapeutic fluorouracil levels. Consider pharmacokinetic-guided dosing or alternative chemotherapy.",
          "cpic_guideline": "Consider dose adjustment based on pharmacokinetic monitoring."
        },
        "Unknown": {
          "risk_label": "Unknown",
          "severity": "high",
          "confidence": 0.30,
          "recommendation": "DPD status unknown. STRONGLY recommend DPYD genotyping before fluorouracil administration. DPD deficiency can be fatal. If urgent, start at reduced dose with intensive monitoring.",
          "cpic_guideline": "CPIC recommends DPYD testing prior to fluoropyrimidine therapy."
        }
      }
    }
  },
  "phenotype_rules": {
    "CYP2D6": {
      "activity_scores": {
        "no_function": 0,
        "decreased_function": 0.5,
        "normal_function": 1,
        "increased_function": 1.5
      },
      "phenotype_thresholds": {
        "PM": [0, 0],
        "IM": [0.5, 1],
        "NM": [1.5, 2],
        "RM": [2.5, 2.5],
        "URM": [3, 999]
      }
    },
    "CYP2C19": {
      "activity_scores": {
        "no_function": 0,
        "decreased_function": 0.5,
        "normal_function": 1,
        "increased_function": 1.5
      },
      "phenotype_thresholds": {
        "PM": [0, 0],
        "IM": [0.5, 1],
        "NM": [1.5, 2],
        "RM": [2.5, 2.5],
        "URM": [3, 999]
      }
    },
    "CYP2C9": {
      "activity_scores": {
        "no_function": 0,
        "decreased_function": 0.5,
        "normal_function": 1,
        "increased_function": 1.5
      },
      "phenotype_thresholds": {
        "PM": [0, 0],
        "IM": [0.5, 1],
        "NM": [1.5, 2],
        "RM": [2.5, 2.5],
        "URM": [3, 999]
      }
    },
    "SLCO1B1": {
      "activity_scores": {
        "no_function": 0,
        "decreased_function": 0.5,
        "normal_function": 1,
        "increased_function": 1.5
      },
      "phenotype_thresholds": {
        "PM": [0, 0],
        "IM": [0.5, 1],
        "NM": [1.5, 2],
        "RM": [2.5, 2.5],
        "URM": [3, 999]
      }
    },
    "TPMT": {
      "activity_scores": {
        "no_function": 0,
        "decreased_function": 0.5,
        "normal_function": 1,
        "increased_function": 1.5
      },
      "phenotype_thresholds": {
        "PM": [0, 0],
        "IM": [0.5, 1],
        "NM": [1.5, 2],
        "RM": [2.5, 2.5],
        "URM": [3, 999]
      }
    },
    "DPYD": {
      "activity_scores": {
        "no_function": 0,
        "decreased_function": 0.5,
        "normal_function": 1,
        "increased_function": 1.5
      },
      "phenotype_thresholds": {
        "PM": [0, 0],
        "IM": [0.5, 1],
        "NM": [1.5, 2],
        "RM": [2.5, 2.5],
        "URM": [3, 999]
      }
    }
  }
}