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

Abstract

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.

Keywords

Rac1 / GnomAD / Treatment-resistant hypertension / Plasmodium falciparum / Genetic constraint / UTR variants

References

[1] Bailly C, Beignet J, Loirand G, Sauzeau V. Rac1 as a therapeutic anticancer target: Promises and limitations. Biochemical Pharmacology, 2022, 203: 115180.

[2] Bailly C, Degand C, Laine W, Sauzeau V, Kluza J. Implication of Rac1 GTPase in molecular and cellular mitochondrial functions. Life Sciences, 2024, 342: 122510.

[3] Benet-Pagès A, Rosenbloom KR, Nassar LR, Lee CM, Raney BJ, Clawson H, Kuhn RM. Variant interpretation: UCSC genome browser recommended track sets. Human Mutation, 2022, 43(8): 998-1011. SUBPAGE:STRING:ABSTRACT;WEBSITE:WEBSITE:PERICLES;JOURNAL:JOURNAL:10981004;WGROUP:STRING:PUBLICATION

[4] Buso G, Agabiti-Rosei C, Lemoli M, Corvini F, Muiesan ML. The global burden of resistant hypertension and potential treatment options. European Cardiology Review, 2024, 19: e07.

[5] Champaneria, M. K., Patel, R. S., & Oroszi, T. L. (2023). When blood pressure refuses to budge: Exploring the complexity of resistant hypertension. Frontiers in Cardiovascular Medicine, 10. https://doi.org/10.3389/FCVM.2023.1211199

[6] Crosas-Molist E, Samain R, Kohlhammer L, Orgaz JL, George SL, Maiques O, Sanz-Moreno V. RHO GTPase SIGNALING IN CANCER PROGRESSION AND DISSEMINATION. Physiological Reviews, 2022, 102(1): 455-510.

[7] Dwivedi, S. R., Mishra, L. C., & Mishra, G. (2023). An analytical approach to progression in malaria therapeutics. Natural Product Based Drug Discovery against Human Parasites: Opportunities and Challenges, 471–490. https://doi.org/10.1007/978-981-19-9605-4_21

[8] Harrison, J. (2024). Impact of the Genomics Revolution on Drug Development and Personalized Medicine in Pharmaceutics. IJIPE-International Journal of Innovation in Pharmacy Education, 1(1). Retrieved from https://jagunifiedinternational.in/journals/ijipe/

[9] Hoang Nguyen, K. H., Le, N. V., Nguyen, P. H., Nguyen, H. H. T., Hoang, D. M., & Huynh, C. D. (2025). Human immune system: Exploring diversity across individuals and populations. Heliyon, 11(2).

[10] Hong J, Lee D, Hwang A, Kim T, Ryu HY, Choi J. Rare disease genomics and precision medicine. Genomics & Informatics 2024, 2024, 22:1(1): 1-11.

[11] Jiang R, Lou L, Shi W, Chen Y, Fu Z, Liu S, Yang J. Statins in mitigating anticancer Treatment-Related cardiovascular disease. International Journal of Molecular Sciences 2024, 2024, 25(18): 10177.

[12] Kaur S, Roberts DD. Differential intolerance to loss of function and missense mutations in genes that encode human matricellular proteins. Journal of Cell Communication and Signaling 2021, 2021, 15:1(1): 93-105.

[13] Kobayashi M, Pitt B, Ferreira JP, Rossignol P, Girerd N, Zannad F. Aldosterone-targeted therapies: Early implementation in resistant hypertension and chronic kidney disease. European Heart Journal, 2025.

[14] Lamb FS, Choi H, Miller MR, Stark RJ. Vascular inflammation and smooth muscle contractility: The role of Nox1-Derived superoxide and LRRC8 anion channels. Hypertension, 2024, 81(4): 752-763.

[15] Lu, C., Wang, L., & Wang, W. (2023). Traditional Chinese Medicines for Malaria Therapy, 279–290. https://doi.org/10.1007/978-3-031-32902-9_12

[16] Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, Januszewicz A, Kjeldsen SE. 2023 ESH guidelines for the management of arterial hypertension the task force for the management of arterial hypertension of the European society of hypertension: Endorsed by the international society of hypertension (ISH) and the European renal association (ERA). Journal of Hypertension, 2023, 41(12): 1874-2071.

[17] Motelow JE, Povysil G, Dhindsa RS, Stanley KE, Allen AS, Feng YCA, Goldstein DB. Sub-genic intolerance, clinvar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals. American Journal of Human Genetics, 2021, 108(6): 965-982.

[18] Mukherjee T, Mohanty S, Kaur J, Das M, Adhikary K, Chatterjee P, Maiti R. Exploring Small-Molecule inhibitors targeting MAPK pathway components: Focus on ERK, MEK1, and MEK2 kinases in Cancer treatment. Chemical Biology Letters, 2024, 11(2): 659-659.

[19] Paone S, Olivieri A. Role of host small GTPases in apicomplexan parasite infection. Microorganisms 2022, 2022, 10(7): 1370.

[20] Powell, G. (2022). Patterns of selective constraint across the mouse and human genomes.

[21] Rizig M, Bandres-Ciga S, Makarious MB, Ojo OO, Crea PW, Abiodun OV, Tavadyan Z. Identification of genetic risk loci and causal insights associated with parkinson’s disease in African and African admixed populations: A genome-wide association study. The Lancet Neurology, 2023, 22(11): 1015-1025.

[22] Shaikh MS, Baig MS, Ali SS, Ahmad A, Shaikh MM, Mahaparale PR, Faiyazuddin M. Review on cerebral malaria—Pathogenesis and role of EphA2 receptor in maintaining blood brain barrier integrity. Health Sciences Review, 2024, 11: 100175.

[23] Sibomana O. Genetic diversity landscape in African population: A review of implications for personalized and precision medicine. Pharmacogenomics and Personalized Medicine, 2024, 17: 487-496. WGROUP:STRING:PUBLICATION

[24] Singh, A., Rathi, B., Verma, A. K., & Singh, I. K. (2024). Natural product based drug discovery against human parasites. Opportunities and Challenges.

[25] Takaishi, K., Kinoshita, H., Kawashima, S., & Kawahito, S. (2021). Human Vascular Smooth Muscle Function and Oxidative Stress Induced by NADPH Oxidase with the Clinical Implications. Cells 2021, Vol. 10, Page 1947, 10(8), 1947. https://doi.org/10.3390/CELLS10081947

[26] Tátrai E, Ranđelović I, Surguta SE, Tóvári J. Role of hypoxia and Rac1 Inhibition in the metastatic cascade. Cancers 2024, 2024, 16(10): 1872.

[27] Zhang Z, Liu M, Zheng Y. Role of Rho GTPases in stem cell regulation. Biochemical Society Transactions, 2021, 49(6): 2941-2955.

[28] Zimmer S, Goody PR, Oelze M, Ghanem A, Mueller CF, Laufs U, Wassmann S. Inhibition of Rac1 GTPase decreases vascular oxidative stress, improves endothelial function, and attenuates atherosclerosis development in mice. Frontiers in Cardiovascular Medicine, 2021, 8: 680775.

Funding

BANGA Africa(BANGA Africa)

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare