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Background <p>Genetics influence medication response yet integrating family health history (FHH) of medication response with pharmacogenomics remains underexplored. The objective of this study was to examine cross-generational medication exposure patterns and assess the utility of FHH for medication response using electronic health records.</p> Methods <p>Genes &amp; Health (G&amp;H) data from Bangladeshi and Pakistani participants were analysed for parent-offspring trios with medication exposure. Premature discontinuation of amitriptyline was defined as discontinuation within three months. Logistic regression and Fisher’s exact test explored the relationship between parental discontinuation, offspring discontinuation, and <i>CYP2C19</i> loss-of-function variants.</p> Results <p>13% of offspring prescriptions overlap with parental prescriptions, primarily short-term treatments (antibiotics, vaccines, steroids). In 96 trios, cross-generational amitriptyline exposure is observed. Parental discontinuation does not predict offspring discontinuation (<i>p</i> = 0.275, OR 1.70). However, offspring with two-generation histories of early discontinuation are significantly enriched for <i>CYP2C19</i> predicted poor metabolizers (38% vs. 10.5%, <i>p</i> = 0.049, OR 4.86).</p> Conclusions <p>FHH of medication response can highlight individuals enriched for pharmacogenomic variants. This is a clinically useful finding, which may flag psychiatric patients with a two-generation history of early amitriptyline discontinuation or intolerance as a priority for pharmacogenomic testing. This study demonstrates the potential of integrating FHH into clinical pharmacogenomics for actionable insights.</p>

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Family health history and pharmacogenomics show cross generation premature amitriptyline discontinuation is associated with CYP2C19 loss of-function enrichment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月13日

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  • Emma F. Magavern,
  • Gabriel Marengo,
  • Maia Megase,
  • Damian Smedley,
  • Mark J. Caulfield

摘要

Background

Genetics influence medication response yet integrating family health history (FHH) of medication response with pharmacogenomics remains underexplored. The objective of this study was to examine cross-generational medication exposure patterns and assess the utility of FHH for medication response using electronic health records.

Methods

Genes & Health (G&H) data from Bangladeshi and Pakistani participants were analysed for parent-offspring trios with medication exposure. Premature discontinuation of amitriptyline was defined as discontinuation within three months. Logistic regression and Fisher’s exact test explored the relationship between parental discontinuation, offspring discontinuation, and CYP2C19 loss-of-function variants.

Results

13% of offspring prescriptions overlap with parental prescriptions, primarily short-term treatments (antibiotics, vaccines, steroids). In 96 trios, cross-generational amitriptyline exposure is observed. Parental discontinuation does not predict offspring discontinuation (p = 0.275, OR 1.70). However, offspring with two-generation histories of early discontinuation are significantly enriched for CYP2C19 predicted poor metabolizers (38% vs. 10.5%, p = 0.049, OR 4.86).

Conclusions

FHH of medication response can highlight individuals enriched for pharmacogenomic variants. This is a clinically useful finding, which may flag psychiatric patients with a two-generation history of early amitriptyline discontinuation or intolerance as a priority for pharmacogenomic testing. This study demonstrates the potential of integrating FHH into clinical pharmacogenomics for actionable insights.