ADRA1D – Gastroparesis

The association between ADRA1D and gastroparesis has been evaluated in multiple pharmacogenetic studies. In one study, 48 patients treated with domperidone showed significant correlations between drug side effects and polymorphisms in ADRA1D (PMID:21063774). A second independent study enrolling 100 gastroparesis patients treated with metoclopramide further identified an association between clinical response and an ADRA1D single nucleotide polymorphism (rs2236554) (PMID:22688145). These studies contribute collectively to a robust clinical dataset supporting the gene–disease association.

The clinical validity is reinforced by a cumulative evaluation of 48 patients (PMID:21063774) and 100 patients (PMID:22688145), which together represent a sizable cohort with significant pharmacogenetic findings. Although the studies did not report familial segregation, the reproducible outcomes across distinct patient groups indicate a reproducible link between ADRA1D variation and variable treatment outcomes in gastroparesis.

Genetic evidence for the association remains moderate given that the reported evidence stems from pharmacogenetic correlation studies. The metoclopramide study reported a significant association with the ADRA1D SNP (rs2236554) in 100 patients (PMID:22688145), albeit without an accompanying specific HGVS coding variant. This pharmacogenetic signal, despite the absence of a definitive coding change in the published literature, supports ADRA1D as a genetic contributor to drug-related response in gastroparesis.

Functional data further bolster the clinical findings. A key functional study demonstrated that ADRA1D receptor stability and signaling were modulated by its interaction with alpha-syntrophin via a PDZ domain-mediated mechanism. This interaction was shown to affect inositol phosphate formation and receptor expression in cellular assays, offering insights into the molecular basis for the altered drug responses observed in clinical studies (PMID:16533813). Such experimental evidence underscores the biological plausibility of ADRA1D involvement in gastroparesis.

While these studies provide compelling evidence, it is important to note that typical segregation data from family studies is lacking. Nevertheless, the multi-patient cohort data and consistent pharmacogenetic correlations provide a strong narrative supporting the clinical utility of testing ADRA1D variants in patients with gastroparesis. The convergence of clinical, genetic, and functional evidence enhances confidence in the association.

In conclusion, the integration of genetic and experimental findings points to a strong association between ADRA1D and gastroparesis. This evidence not only aids diagnostic decision‑making in a personalized medicine framework but also underscores the potential for tailoring therapeutic strategies based on ADRA1D genotype.

Key Take‑home message: ADRA1D represents a clinically actionable pharmacogenetic marker that can inform treatment decisions in gastroparesis.

References

• Digestive diseases and sciences • 2011 • Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side‑effects PMID:21063774
• Journal of clinical gastroenterology • 2012 • Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters PMID:22688145
• The Journal of biological chemistry • 2006 • Syntrophins regulate alpha1D-adrenergic receptors through a PDZ domain‑mediated interaction PMID:16533813

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