Scholarlink

Background <p>Genetic constraint and population-specific variant landscapes are pivotal in evaluating drug target feasibility. Rac1, a GTPase implicated in treatment-resistant hypertension and <i>Plasmodium falciparum</i> invasion of red blood cells (RBCs), represents a high-priority therapeutic candidate. This study leverages genome aggregation database (gnomAD) data to analyze Rac1’s genetic profile, focusing on its dual role in host-pathogen interactions and cardiovascular pathology.</p> Methods <p>We interrogated Rac1’s genetic constraint metrics (LOEUF, missense Z-scores), minor allele frequencies (MAF), and functional annotations across five global populations: African/African American (AFR), Admixed American (AMR), East Asian (EAS), Non-Finnish European (NFE), and South Asian (SAS). Variant Effect Predictor (VEP) focused on 3’/5’ untranslated regions (UTRs), complemented by ANOVA to assess population-specific variant distributions.</p> Results <p>Rac1 appears to demonstrate strong intolerance to loss-of-function mutations (LOEUF = 0.25), underscoring potential on-target toxicity risks. Population-specific MAF disparities emerged in UTRs: AFR exhibited the highest 3’ UTR mean MAF (0.0112) and maximum MAF (0.716), while 5’ UTR MAFs were uniformly low across populations (e.g., AFR = 0.0000605, NFE = 0.00000285). ANOVA revealed no significant population-dependent differences in UTR variant distributions (<i>p-values</i>: AFR = <i>0.676</i>; AMR = 0.973; EAS = <i>0.967</i>; NFE = <i>0.985</i>; SAS = <i>0.976</i>), supporting conserved regulatory architecture. Functional domains (e.g., GTPase-binding regions) lacked pathogenic variants, whereas non-conserved regions harbored missense polymorphisms. UTR variants clustered in transcriptionally active regions, potentially modulating Rac1’s roles in hypertension and RBC remodeling.</p> Conclusions <p>While Rac1’s high genetic constraint signals caution for direct inhibition, UTR variants and non-essential domains may present safer therapeutic windows for modulating its activity in treatment-resistant hypertension or disrupting Plasmodium invasion. AFR-specific enrichment of high-frequency 3’ UTR variants, despite globally conserved distributions, highlights the importance of inclusive trial designs to address genetic diversity in these conditions. This study illustrates how gnomAD-driven population genetics can refine target prioritization, balancing efficacy and safety in drug discovery pipelines for infectious and cardiovascular diseases.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Population genetic profiling of Rac1 via GnomAD informs miRNA-Driven precision targeting for treatment-resistant hypertension and malaria

  • 期刊论文

  • 发表日期：

    2025年7月4日

查看全文
  • Selassie Louis Ameke,
  • Kwadwo Fosu,
  • Lucas Amenga-Etego,
  • Kwabena Amofa Nketia Sarpong,
  • Samuel Kojo Kwofie

摘要

Background

Genetic constraint and population-specific variant landscapes are pivotal in evaluating drug target feasibility. Rac1, a GTPase implicated in treatment-resistant hypertension and Plasmodium falciparum invasion of red blood cells (RBCs), represents a high-priority therapeutic candidate. This study leverages genome aggregation database (gnomAD) data to analyze Rac1’s genetic profile, focusing on its dual role in host-pathogen interactions and cardiovascular pathology.

Methods

We interrogated Rac1’s genetic constraint metrics (LOEUF, missense Z-scores), minor allele frequencies (MAF), and functional annotations across five global populations: African/African American (AFR), Admixed American (AMR), East Asian (EAS), Non-Finnish European (NFE), and South Asian (SAS). Variant Effect Predictor (VEP) focused on 3’/5’ untranslated regions (UTRs), complemented by ANOVA to assess population-specific variant distributions.

Results

Rac1 appears to demonstrate strong intolerance to loss-of-function mutations (LOEUF = 0.25), underscoring potential on-target toxicity risks. Population-specific MAF disparities emerged in UTRs: AFR exhibited the highest 3’ UTR mean MAF (0.0112) and maximum MAF (0.716), while 5’ UTR MAFs were uniformly low across populations (e.g., AFR = 0.0000605, NFE = 0.00000285). ANOVA revealed no significant population-dependent differences in UTR variant distributions (p-values: AFR = 0.676; AMR = 0.973; EAS = 0.967; NFE = 0.985; SAS = 0.976), supporting conserved regulatory architecture. Functional domains (e.g., GTPase-binding regions) lacked pathogenic variants, whereas non-conserved regions harbored missense polymorphisms. UTR variants clustered in transcriptionally active regions, potentially modulating Rac1’s roles in hypertension and RBC remodeling.

Conclusions

While Rac1’s high genetic constraint signals caution for direct inhibition, UTR variants and non-essential domains may present safer therapeutic windows for modulating its activity in treatment-resistant hypertension or disrupting Plasmodium invasion. AFR-specific enrichment of high-frequency 3’ UTR variants, despite globally conserved distributions, highlights the importance of inclusive trial designs to address genetic diversity in these conditions. This study illustrates how gnomAD-driven population genetics can refine target prioritization, balancing efficacy and safety in drug discovery pipelines for infectious and cardiovascular diseases.