Citation: Butnariu, L.I.; Gorduza, E.V.; Florea, L.; T , arc˘ a, E.; Mois ˘ a, S , .M.; Tradafir, L.M.; Cojocaru, E.; Luca, A.-C.; St ˘ atescu, L.; B ˘ adescu, M.C. The Genetic Architecture of the Etiology of Lower Extremity Peripheral Artery Disease: Current Knowledge and Future Challenges in the Era of Genomic Medicine. Int. J. Mol. Sci. 2022, 23, 10481. https://doi.org/ 10.3390/ijms231810481 Academic Editors: Antonino Tuttolomondo and Giuseppe Miceli Received: 24 August 2022 Accepted: 6 September 2022 Published: 9 September 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). International Journal of Molecular Sciences Review The Genetic Architecture of the Etiology of Lower Extremity Peripheral Artery Disease: Current Knowledge and Future Challenges in the Era of Genomic Medicine Lăcrămioara Ionela Butnariu 1 , Eusebiu Vlad Gorduza 1 , Laura Florea 2 , Elena T , arcă 3, * , S , tefana Maria Moisă 4, * , Laura Mihaela Tradafir 4 , Elena Cojocaru 5 , Alina-Costina Luca 6 , Laura Stătescu 7,8 and Minerva Codrut , aBădescu 9,10 1 Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ias , i, Romania 2 Department of Nefrology–Internal Medicine, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ias , i, Romania 3 Department of Surgery II—Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ia¸ si, Romania 4 Department of Pediatrics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ias , i, Romania 5 Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ia¸ si, Romania 6 Department of Mother and Child, Medicine-Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ia¸ si, Romania 7 Medical III Department-Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ia¸ si, Romania 8 Screening Center for Oncological Diseases, Regional Institute of Oncology, 700115 Ias , i, Romania 9 Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Ias , i, Romania 10 III Internal Medicine Clinic, “St. Spiridon” County Emergency Clinical Hospital, 1 Independence Boulevard, 700111 Ias , i, Romania * Correspondence: elena.tuluc@umfiasi.ro (E.T , .); stefana-maria.moisa@umfiasi.ro (S , .M.M.) Abstract: Lower extremity artery disease (LEAD), caused by atherosclerotic obstruction of the arteries of the lower limb extremities, has exhibited an increase in mortality and morbidity worldwide. The phenotypic variability of LEAD is correlated with its complex, multifactorial etiology. In addition to traditional risk factors, it has been shown that the interaction between genetic factors (epistasis) or between genes and the environment potentially have an independent role in the development and progression of LEAD. In recent years, progress has been made in identifying genetic variants associated with LEAD, by Genome-Wide Association Studies (GWAS), Whole Exome Sequencing (WES) studies, and epigenetic profiling. The aim of this review is to present the current knowledge about the genetic factors involved in the etiopathogenic mechanisms of LEAD, as well as possible directions for future research. We analyzed data from the literature, starting with candidate gene- based association studies, and then continuing with extensive association studies, such as GWAS and WES. The results of these studies showed that the genetic architecture of LEAD is extremely heterogeneous. In the future, the identification of new genetic factors will allow for the development of targeted molecular therapies, and the use of polygenic risk scores (PRS) to identify individuals at an increased risk of LEAD will allow for early prophylactic measures and personalized therapy to improve their prognosis. Keywords: lower extremity peripheral artery disease; atherosclerosis; genetic risk factors; heritability; polymorphism; modifier genes; epigenetics; GWAS; PRS Int. J. Mol. Sci. 2022, 23, 10481. https://doi.org/10.3390/ijms231810481 https://www.mdpi.com/journal/ijms