Abstract
Homocysteine (Hcy) is well known to be increased in the metabolic syndrome (MetS) incidence. However, it remains unclear whether the relationship is causal or not. Recently, Mendelian Randomization (MR) has been popularly used to assess the causal influence. In this study, we adopted MR to investigate the causal influence of Hcy on MetS in adults using three independent cohorts. We considered one-sample MR and two-sample MR. We analyzed one-sample MR in 5902 individuals (2090 MetS cases and 3812 controls) from the KARE and two-sample MR from the HEXA (676 cases and 3017 controls) and CAVAS (1052 cases and 764 controls) datasets to evaluate whether genetically increased Hcy level influences the risk of MetS. In observation studies, the odds of MetS increased with higher Hcy concentrations (odds ratio (OR) 1.17, 95%CI 1.12–1.22, p < 0.01). One-sample MR was performed using two-stage least-squares regression, with an MTHFR C677T and weighted Hcy generic risk score as an instrument. Two-sample MR was performed with five genetic variants (rs12567136, rs1801133, rs2336377, rs1624230, and rs1836883) by GWAS data as the instrumental variables. For sensitivity analysis, weighted median and MR–Egger regression were used. Using one-sample MR, we found an increased risk of MetS (OR 2.07 per 1-SD Hcy increase). Two-sample MR supported that increased Hcy was significantly associated with increased MetS risk by using the inverse variance weighted (IVW) method (beta 0.723, SE 0.119, and p < 0.001), the weighted median regression method (beta 0.734, SE 0.097, and p < 0.001), and the MR–Egger method (beta 2.073, SE 0.843, and p = 0.014) in meta-analysis. The MR–Egger slope showed no evidence of pleiotropic effects (intercept −0.097, p = 0.107). In conclusion, this study represented the MR approach and elucidates the significant relationship between Hcy and the risk of MetS in the Korean population.
Highlights
During recent decades, metabolic disease has become a major health concern worldwide with the spread of the Western diet and lifestyle, and the increase in the elderly population
We identified that the blood homocysteine levels were associated with a decrease in the RFS score
Using five genetic variants based on linkage disequilibrium (LD)-clumping, we found that increased Hcy was significantly associated with increased Metabolic syndrome (MetS) risk using weighted median regression (estimate,0.73 (0.54–0.92); p < 0.01) and inverse variance weighted (IVW)
Summary
Metabolic disease has become a major health concern worldwide with the spread of the Western diet and lifestyle, and the increase in the elderly population. Metabolic syndrome (MetS) is defined by WHO as a pathologic condition characterized by hypertension, glucose abnormalities, central obesity, and hyperlipidemia [1]. The global prevalence of overweight and obesity has continuously been growing and has reached epidemic proportions [2]. With this phenomenon, cardio-metabolic abnormalities and MetS are expected to become more prevalent in youth, as well. Homocysteine (Hcy) is an amino acid intermediate formed during the metabolism of the essential amino acid methionine. Hcy can be recycled into methionine with the aid of vitamin B12 and folic acid, or converted into cysteine with vitamin B6 as a cofactor
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