Sharon L T Pek1, S Tavintharan, Xiaomeng Wang, Su Chi Lim, Kaing Woon, Lee Ying Yeoh, Xiaowei Ng, Jianjun Liu, Chee Fang Sum. 1. Clinical Research Unit (S.L.T.P., S.T., S.C.L., K.W., X.N., J.L.), Diabetes Centre (S.T., S.C.L., C.F.S.), and Division of Endocrinology (S.T., S.C.L., C.F.S.), Khoo Teck Puat Hospital, Singapore 768828; Metabolic Disease Research Programme (X.W.), Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798; Division of Nephrology (L.Y.Y.), Department of Medicine, Khoo Teck Puat Hospital, Singapore 768828; Institute of Molecular and Cell Biology (X.W.), A*STAR, Singapore 138673; and Institute of Ophthalmology (X.W.), University College London, London EC1V 9EL, United Kingdom.
Abstract
CONTEXT: Increased arterial stiffness and endothelial dysfunction are associated with peripheral arterial disease (PAD). Leucine-rich-α2-glycoprotein (LRG1) is a proangiogenic factor involved in regulation of the TGFβ signaling pathway. OBJECTIVE: This study in patients with type 2 diabetes mellitus explored the associations of plasma LRG1 with arterial stiffness, endothelial function, and PAD. DESIGN: Based on the ankle brachial index (ABI), patients were classified as having PAD (ABI ≤ 0.9) or as being borderline abnormal (ABI, 0.91-0.99) or normal (ABI, 1.00-1.40). LRG1 was measured by immunoassay; arterial stiffness, by carotid-femoral pulse-wave velocity and augmentation index; and endothelial function, by laser Doppler flowmetry. RESULTS: A total of 2058 patients with type 2 diabetes mellitus were recruited. Mean age (1 SD) was 57.4 (0.2) years. Patients with PAD (n = 258) had significantly higher LRG1 compared to patients with borderline ABI and patients without PAD (19.00 [13.50] vs 17.35 [13.30] and 15.28 [10.40] μg/mL, respectively; P < .0001). Multiple regression analysis revealed that female gender (P < .0001), non-Chinese ethnicity (P < .0001), higher waist circumference (P = .017), lower estimated glomerular filtration rate (P < .0001), higher urine albumin-creatinine ratio (P = .009), lower ABI (P < .0001), higher pulse wave velocity (P = .040), and poorer endothelium-dependent vasodilation (P = .007) were independent significant predictors of higher plasma LRG1 levels. A generalized linear model showed that a 1-SD increase in log LRG1 was associated with an odds ratio of 4.072 (95% confidence interval, 1.889-8.777; P < .0001) for prevalence of PAD, after adjustment for traditional risk factors. CONCLUSIONS: Higher LRG1 is a significant predictor for arterial stiffness, endothelial function, and PAD. The pathobiological basis and the temporal relationships of these associations need to be explored by further mechanistic and prospective studies to understand the clinical significance of these findings.
CONTEXT: Increased arterial stiffness and endothelial dysfunction are associated with peripheral arterial disease (PAD). Leucine-rich-α2-glycoprotein (LRG1) is a proangiogenic factor involved in regulation of the TGFβ signaling pathway. OBJECTIVE: This study in patients with type 2 diabetes mellitus explored the associations of plasma LRG1 with arterial stiffness, endothelial function, and PAD. DESIGN: Based on the ankle brachial index (ABI), patients were classified as having PAD (ABI ≤ 0.9) or as being borderline abnormal (ABI, 0.91-0.99) or normal (ABI, 1.00-1.40). LRG1 was measured by immunoassay; arterial stiffness, by carotid-femoral pulse-wave velocity and augmentation index; and endothelial function, by laser Doppler flowmetry. RESULTS: A total of 2058 patients with type 2 diabetes mellitus were recruited. Mean age (1 SD) was 57.4 (0.2) years. Patients with PAD (n = 258) had significantly higher LRG1 compared to patients with borderline ABI and patients without PAD (19.00 [13.50] vs 17.35 [13.30] and 15.28 [10.40] μg/mL, respectively; P < .0001). Multiple regression analysis revealed that female gender (P < .0001), non-Chinese ethnicity (P < .0001), higher waist circumference (P = .017), lower estimated glomerular filtration rate (P < .0001), higher urine albumin-creatinine ratio (P = .009), lower ABI (P < .0001), higher pulse wave velocity (P = .040), and poorer endothelium-dependent vasodilation (P = .007) were independent significant predictors of higher plasma LRG1 levels. A generalized linear model showed that a 1-SD increase in log LRG1 was associated with an odds ratio of 4.072 (95% confidence interval, 1.889-8.777; P < .0001) for prevalence of PAD, after adjustment for traditional risk factors. CONCLUSIONS: Higher LRG1 is a significant predictor for arterial stiffness, endothelial function, and PAD. The pathobiological basis and the temporal relationships of these associations need to be explored by further mechanistic and prospective studies to understand the clinical significance of these findings.
Authors: Jiexun Wang; Jian-Jun Liu; Resham L Gurung; Sylvia Liu; Janus Lee; Yiamunaa M; Keven Ang; Yi Ming Shao; Justin I-Shing Tang; Peter I Benke; Federico Torta; Markus R Wenk; Subramaniam Tavintharan; Wern Ee Tang; Chee Fang Sum; Su Chi Lim Journal: Diabetologia Date: 2022-06-28 Impact factor: 10.460
Authors: Kuin Tian Pang; Mean Ghim; Chenghao Liu; Hui Min Tay; Chee Wai Fhu; Rui Ning Chia; Beiying Qiu; Padmini Sarathchandra; Adrian H Chester; Magdi H Yacoub; Fiona L Wilkinson; Ria Weston; Christina M Warboys; Han Wei Hou; Peter D Weinberg; Xiaomeng Wang Journal: Front Cell Dev Biol Date: 2021-07-05