Gamma-glutamyl-leucine levels are causally associated with elevated cardio-metabolic risks

Qiong Wu; Jiankang Li; Jinghan Zhu; Xiaohui Sun; Di He; Jun Li; Zongxue Cheng; Xuhui Zhang; Yuying Xu; Qing Chen; Yimin Zhu; Maode Lai

doi:10.3389/fnut.2022.936220

Gamma-glutamyl-leucine levels are causally associated with elevated cardio-metabolic risks

Front Nutr. 2022 Nov 24:9:936220. doi: 10.3389/fnut.2022.936220. eCollection 2022.

Authors

Qiong Wu^{1

2

3}, Jiankang Li⁴, Jinghan Zhu⁵, Xiaohui Sun⁶, Di He^{1

2}, Jun Li^{1

2}, Zongxue Cheng^{1

2}, Xuhui Zhang^{7

8}, Yuying Xu^{1

2}, Qing Chen⁹, Yimin Zhu^{1

2

10}, Maode Lai^{11

12}

Affiliations

¹ Department of Epidemiology and Biostatistics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
² Department of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ Department of Epidemiology and Biostatistics, School of Public Health, Hangzhou Normal University, Hangzhou, China.
⁴ Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
⁵ The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
⁶ Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
⁷ Hangzhou Center for Disease Control and Prevention, Hangzhou, China.
⁸ Affiliated Hangzhou Center of Disease Control and Prevention, School of Public Health, Zhejiang University, Hangzhou, China.
⁹ Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, China.
¹⁰ Cancer Center, Zhejiang University, Hangzhou, China.
¹¹ Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China.
¹² State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Abstract

Objective: Gamma-glutamyl dipeptides are bioactive peptides involved in inflammation, oxidative stress, and glucose regulation. Gamma-glutamyl-leucine (Gamma-Glu-Leu) has been extensively reported to be associated with the risk of cardio-metabolic diseases, such as obesity, metabolic syndrome, and type 2 diabetes. However, the causality remains to be uncovered. The aim of this study was to explore the causal-effect relationships between Gamma-Glu-Leu and metabolic risk.

Materials and methods: In this study, 1,289 subjects were included from a cross-sectional survey on metabolic syndrome (MetS) in eastern China. Serum Gamma-Glu-Leu levels were measured by untargeted metabolomics. Using linear regressions, a two-stage genome-wide association study (GWAS) for Gamma-Glu-Leu was conducted to seek its instrumental single nucleotide polymorphisms (SNPs). One-sample Mendelian randomization (MR) analyses were performed to evaluate the causality between Gamma-Glu-Leu and the metabolic risk.

Results: Four SNPs are associated with serum Gamma-Glu-Leu levels, including rs12476238, rs56146133, rs2479714, and rs12229654. Out of them, rs12476238 exhibits the strongest association (Beta = -0.38, S.E. = 0.07 in discovery stage, Beta = -0.29, S.E. = 0.14 in validation stage, combined P-value = 1.04 × 10^-8). Each of the four SNPs has a nominal association with at least one metabolic risk factor. Both rs12229654 and rs56146133 are associated with body mass index, waist circumference (WC), the ratio of WC to hip circumference, blood pressure, and triglyceride (5 × 10^-5 < P < 0.05). rs56146133 also has nominal associations with fasting insulin, glucose, and insulin resistance index (5 × 10^-5 < P < 0.05). Using the four SNPs serving as the instrumental SNPs of Gamma-Glu-Leu, the MR analyses revealed that higher Gamma-Glu-Leu levels are causally associated with elevated risks of multiple cardio-metabolic factors except for high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (P > 0.05).

Conclusion: Four SNPs (rs12476238, rs56146133, rs2479714, and rs12229654) may regulate the levels of serum Gamma-Glu-Leu. Higher Gamma-Glu-Leu levels are causally linked to cardio-metabolic risks. Future prospective studies on Gamma-Glu-Leu are required to explain its role in metabolic disorders.

Keywords: GWAS; Gamma-glutamyl-leucine; Mendelian randomization; metabolic risk factors; metabolic syndrome.

Associated data

figshare/10.6084/m9.figshare.20103644.v1