Germline genetic variants with implications for disease risk and therapeutic outcomes

Abstract

Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care.

Keywords: ADBR1; BRCA; CFTR; CMT genes; COMT; G6PD; INFL3; RYR1; UGT1A1; disease genetics; genetics; pharmacogenetics; pharmacogenomics.

Fig. 1.

Role of UGT1A1 in bilirubin and irinotecan glucuronidation and impact of genetic variation. A: in individuals not carrying genetic variants that decrease UGT1A1 activity, the enzyme maintains homeostatic regulation of bilirubin and inactivates SN-38, the active metabolite irinotecan via glucuronidation. This patient experiences neither hyperbilirubinemia or high risk of irinotecan toxicity. B: reduced activity of UGT1A1 secondary to genetic variation results in a reduction in the glucuronidation of bilirubin, increasing the concentration of unconjugated bilirubin, and leading to an increased likelihood for jaundice or other clinical manifestations of hyperbilirubinemia. Atazanavir, a UGT1A1 inhibitor, also reduces UGT1A1 activity, increasing the likelihood for hyperbilirubinemia, especially in individuals who also carry genetic variants of UGT1A1. Reduced activity of UGT1A1 decreases the glucuronidation of SN-38, increasing the systemic concentrations of this active metabolite, which increases the risk of irinotecan toxicity primarily manifesting as neutropenia.