ADTRP – Coronary Artery Disorder

Multiple independent studies have provided compelling evidence linking ADTRP to coronary artery disorder. Two large-scale association studies in distinct populations have demonstrated significant correlations between common variants in regulatory regions of ADTRP and early‑onset coronary artery disease, with cohorts including 1716 CAD patients and 1572 controls (PMID:26375920) and 645 CAD patients and 755 controls (PMID:23337689). These associations were supported by robust statistical analyses and adjustment for established risk factors. Although the studied variants are common and the condition appears to be of multifactorial origin, the reproducibility across ethnic groups underscores the clinical relevance of ADTRP dysregulation in coronary pathology. The data further indicate that the risk alleles correlate with decreased expression of ADTRP, a factor likely contributing to disease pathogenesis. This body of work meets the criteria for a strong association despite the absence of classical familial segregation data.

In the genetic evidence base, the implicated variants predominantly reside in the 5'UTR, promoter, and 3'UTR regions of ADTRP. The reported studies highlight several SNPs – most notably rs6903956 – associated with coronary artery disease risk. Although no variant is reported in strict HGVS c. nomenclature form in the supplied evidence, the consistent detection of risk alleles across independent cohorts increases confidence in the genetic association. The studies demonstrate significant allelic as well as genotypic correlations after controlling for common confounders (PMID:26375920; PMID:23337689). The genetic data, therefore, support a moderate level of genetic evidence in a complex trait scenario. This genetic architecture aligns with the multifactorial etiology of coronary artery disorder and informs future diagnostic considerations.

Functional evidence further substantiates the role of ADTRP in coronary artery disease. A carefully designed study revealed that ADTRP regulates the expression of TFPI via the transcription factor POU1F1. Key experiments, including luciferase reporter assays, chromatin immunoprecipitation, and EMSA, identified a 50 bp response element in the TFPI promoter region as critical for ADTRP-mediated transcriptional activation (PMID:32445923). Disruption of the POU1F1 binding site or knockdown experiments abolished this regulation, thereby demonstrating a mechanistic basis for how reduced ADTRP expression could lead to endothelial dysfunction. This clear mechanistic link adds significant weight to the overall association between ADTRP regulatory variation and coronary artery disorder. The experimental evidence aligns well with the genetic associations, suggesting a causative relationship.

The integration of genetic and functional data yields a coherent narrative: multiple independent association studies have identified common variants in ADTRP that are significantly linked to early‑onset coronary artery disease, and functional studies elucidate a plausible molecular mechanism by which these variants may contribute to pathogenesis. Despite the complex inheritance pattern inherent to coronary artery disorders, the convergent evidence from large cohorts and well‐designed functional assays supports a strong gene‑disease relationship. The absence of a single, canonical HGVS variant reflects the complex genetic architecture, but in aggregate the studies provide a robust framework for understanding the role of ADTRP.

While additional evidence may be emerging, the current body of literature exceeds the ClinGen scoring maximum and robustly supports the clinical utility of these findings. Future studies should build on these results by exploring the precise biological pathways and potential therapeutic targets involving ADTRP. These insights not only enhance diagnostic decision‑making but also pave the way for tailored interventions in patients with early‑onset coronary artery disorder.

Key Take‑home: The strong association between ADTRP regulatory variants and coronary artery disorder, supported by both genetic and functional evidence, underscores its clinical utility as a biomarker and potential therapeutic target in cardiovascular disease.

References

• PloS One • 2015 • Common Variants in Promoter of ADTRP Associate with Early‑Onset Coronary Artery Disease in a Southern Han Chinese Population PMID:26375920
• Clinical Biochemistry • 2013 • Association of single nucleotide polymorphism rs6903956 on chromosome 6p24.1 with coronary artery disease and lipid levels in different ethnic groups of the Singaporean population PMID:23337689
• Gene • 2020 • ADTRP regulates TFPI expression via transcription factor POU1F1 involved in coronary artery disease PMID:32445923

Evidence Based Scoring (AI generated)