Coronary artery disease (CAD) is one of the most prevalent cardiovascular disorders and a leading cause of morbidity and mortality worldwide. The present study aimed to investigate the association of Klotho gene polymorphisms (rs564481, rs751229348, and rs2501789490) with CAD susceptibility and to evaluate their relationship with sex and hypertension status. This observational case-control study included 60 CAD patients and 30 control subjects aged 30–70 years. Peripheral blood samples were collected from participants at the Specialized Center for Heart Diseases, Surgery, and Catheterization in Ramadi City, Anbar, Iraq, between September 2025 and November 2025. Genomic DNA was extracted, and Klotho gene polymorphisms were analyzed. The results showed that allele and genotype frequencies of rs564481 and rs2501789490 did not differ significantly between CAD patients and controls (p > 0.05). In contrast, rs751229348 demonstrated a significant association at the allele level, with the C allele showing a possible association with CAD susceptibility (OR = 1.89, p = 0.036). Genotype distributions of all investigated SNPs were consistent with Hardy–Weinberg equilibrium in both patients and controls (p > 0.05). Significant differences in genotype distribution according to sex were observed for rs564481 (p = 0.005), rs751229348 (p = 0.005), and rs2501789490 (p = 0.001). Furthermore, rs751229348 was significantly associated with blood pressure status (p = 0.029), whereas rs564481 and rs2501789490 showed no significant association with hypertension. In conclusion, the findings suggest that Klotho genetic variation, particularly rs751229348, may contribute modestly to CAD susceptibility and related cardiovascular traits in the studied population. However, these findings require confirmation through larger studies and functional investigations to clarify the biological role of Klotho polymorphisms in cardiovascular disease.
Keywords
Coronary Artery DiseaseKlotho GenePolymorphisms
References
G. A. Roth et al., “Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 study,” Journal of the American College of Cardiology, vol. 76, no. 25, pp. 2982-3021, 2020.
S. Karslı, S. Yazar, M. Karaca, and T. Yurdun, “Klotho gene polymorphism as a susceptibility factor for oxidative DNA damage in coronary artery disease,” Journal of Research in Pharmacy, vol. 27, no. 5, pp. 2079-2086, 2023.
R. Elosua, “Road to unravel gene-environment interactions on cardiovascular complex diseases,” Circulation: Genomic and Precision Medicine, vol. 11, no. 8, p. e002040, 2018.
X. Sun, L. Chen, Y. He, and L. Zheng, “Circulating α-Klotho levels in relation to cardiovascular diseases: A Mendelian randomization study,” Frontiers in Endocrinology, vol. 13, p. 842846, 2022.
H. Akbari et al., “Association of Klotho gene polymorphism with hypertension and coronary artery disease in an Iranian population,” BMC Cardiovascular Disorders, vol. 18, no. 1, p. 237, 2018.
J. Donate-Correa et al., “Association of Klotho with coronary artery disease in subjects with type 2 diabetes mellitus and preserved kidney function: A case-control study,” International Journal of Molecular Sciences, vol. 24, no. 17, p. 13456, 2023.
J. Donate-Correa et al., “Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease,” Journal of Cellular and Molecular Medicine, vol. 20, no. 1, pp. 128-133, 2015.
J. Donate-Correa et al., “Klotho, oxidative stress, and mitochondrial damage in kidney disease,” Antioxidants, vol. 12, no. 2, p. 239, 2023.
M. M. K. Eldin Alsayed et al., “The association of Klotho G-395A gene polymorphism with cardiovascular complications in pediatric patients with end-stage renal disease,” GEGET, vol. 20, no. 1, pp. 23-37, 2025.
S. Yokoyama et al., “A Klotho gene single nucleotide polymorphism is associated with the onset of stroke and plasma Klotho concentration,” Aging (Albany NY), vol. 11, no. 1, p. 104, 2018.
P.-H. Wu et al., “The association between single nucleotide polymorphisms of Klotho gene and mortality in elderly men: The MrOS Sweden study,” Scientific Reports, vol. 10, no. 1, p. 10243, 2020.
H. H. Ibrahim, “Evaluation of anti-aging Klotho and apolipoprotein E4 levels in coronary artery disease patients and their relation with some biomarkers of Alzheimer’s disease: Case-control study,” Tikrit Journal of Pharmaceutical Sciences, vol. 19, no. 2, pp. 87-98, 2025.
A. Ansari-Moghaddam et al., “Prevalence of metabolic syndrome and population attributable risk for cardiovascular, stroke, and coronary heart diseases as well as myocardial infarction and all-cause mortality in Middle East: Systematic review and meta-analysis,” Obesity Medicine, vol. 14, p. 100086, 2019.
J. Lee et al., “Association between serum Klotho levels and cardiovascular disease risk factors in older adults,” BMC Cardiovascular Disorders, vol. 22, no. 1, p. 442, 2022.
H. A. A. Razaaq and H. A. Abdul-Razzaq, “Polymorphism of E-selection gene for coronary artery disease in Ramadi/Anbar-Iraq,” in AIP Conference Proceedings, vol. 2437, no. 1, p. 020050, 2022.
A. I. Sayed and A. I. Sayed, “Gender differences in coronary artery disease, clinical characteristics, and angiographic features in the Jazan region, Saudi Arabia,” Cureus, vol. 14, no. 10, 2022.
S. Karsli Ceppioğlu et al., “Assessment of matrix Gla protein, Klotho gene polymorphisms, and oxidative stress in chronic kidney disease,” Renal Failure, vol. 33, no. 9, pp. 866-874, 2021.
V. Majumdar, D. Nagaraja, and R. Christopher, “Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke,” Biochemical and Biophysical Research Communications, vol. 403, no. 3-4, pp. 412-416, 2010.
A. H. Mohammed, R. K. Hassan, and S. M. Ali, “Evaluation of oxidative stress biomarkers and genetic variations associated with cardiovascular diseases,” Iraqi Journal for Applied Science, vol. 2, no. 3, pp. 115-123, 2024.
S. Kanmani et al., “Toxicity of tobacco Nicotiana tabacum Linnaeus (Solanaceae) leaf extracts to the rice weevil Sitophilus oryzae Linnaeus 1763 (Coleoptera: Curculionidae),” Journal of Basic and Applied Zoology, vol. 82, no. 1, p. 10, 2021.
K. C. Lidani et al., “Genome-wide association study of angiotensinogen levels and key single nucleotide polymorphism associations with blood pressure,” Journal of Hypertension, vol. 43, no. 9, pp. 1500-1509, 2025.
S. Rojo-Tolosa et al., “Single nucleotide polymorphisms in the vitamin D metabolic pathway and their relationship with high blood pressure risk,” International Journal of Molecular Sciences, vol. 24, no. 6, p. 5974, 2023.
K. Wang et al., “Klotho improves cardiac fibrosis, inflammatory cytokines, ferroptosis, and oxidative stress in mice with myocardial infarction,” Journal of Physiology and Biochemistry, vol. 79, no. 2, pp. 341-353, 2023.
T. K. Fard et al., “Klotho, FOXO1 and cytokines associations in patients with coronary artery disease,” Cytokine, vol. 141, p. 155443, 2021.
S. Zhang et al., “Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis,” Neuron, vol. 110, no. 6, pp. 992-1008, 2022.
S. Cadena-Ullauri et al., “Population admixture and APOB variant landscape in Ecuadorian mestizo patients with cardiac diseases: Potential implications for familial hypercholesterolemia genetics,” Journal of Cardiovascular Development and Disease, vol. 13, no. 1, p. 36, 2026.
M. F. Gagliardi et al., “Tetralogy of Fallot: Genetic, epigenetic and clinical insights into a multifactorial congenital heart disease,” Genes, vol. 17, no. 2, p. 181, 2026.
A. T. Marees et al., “A tutorial on conducting genome-wide association studies: Quality control and statistical analysis,” International Journal of Methods in Psychiatric Research, vol. 27, no. 2, p. e1608, 2018.
