The Homocysteine and Metabolic Syndrome: A Mendelian Randomization Study

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.

Increased serum homocysteine in first episode and drug-naïve individuals with schizophrenia: sex differences and correlations with clinical symptoms

“…Moreover, stress, poor lifestyle, age, catabolic dysregulation, and genetics can lead to abnormalities in Hcy, while abnormal Hcy levels may be considered as an etiological or risk factor in neurodegenerative diseases such as dementias, Alzheimer’s disease, Parkinson’s disease, cardiovascular diseases, and metabolic disease [ 21 – 23 ], but individuals in northern Italy with severe mental illness may not be at higher risk of cardiovascular disease than the general population, especially in the relatively wealthy areas and with traditional healthy dietary habits such as the Mediterranean diet [ 24 ]. A recent Mendelian Randomization study reported that in the general population, higher Hcy concentration was a risk factor for metabolic syndrome, but not for body mass index (BMI) [ 25 ], while another study reported that higher Hcy levels correlated with lower BMIs in schizophrenia patients [ 26 ]. In addition, several studies have reported that sex may also be a factor affecting Hcy in the general population [ 27 ], in bipolar disorders [ 28 ], and even in rat animal models [ 29 ].…”

Association of baseline and changes in adiponectin, homocysteine, high-sensitivity C-reactive protein, interleukin-6, and interleukin-10 levels and metabolic syndrome incidence: Tehran lipid and glucose study

“…However, the mechanisms involved in Hcy-associated diseases have not been entirely clarified, and whether the relationship between MetS and Hcy level is causal remains obscure. However, recently, using the Mendelian randomization approach, a significant relationship was elucidated between Hcy and the risk of MetS in the Korean population [ 110 ]. On the other hand, Hcy increases inflammatory responses and correlates with IL-6, TNFα, and hs-CRP levels [ 111 ].…”

Habitual Tea Consumption Increases the Incidence of Metabolic Syndrome in Middle-Aged and Older Individuals

“…In addition to increasing the risk of hypertension, HHcy increases the risk of dyslipidemia. This can be partially explained by HHcy-associated hypomethylation, which results in lipid accumulation and the downregulation of the synthesis of phosphatidylcholine that is required for very low-density lipoprotein assembly and homeostasis [ 56 ]. Low HDL-C levels are attributed to the homocysteine-induced inhibition of enzymes or molecules involved in HDL particle assembly [ 57 ].…”