Dissecting the relationship between hypertensive disorders of pregnancy and branched-chain amino acids: An integrated investigation combining Mendelian randomization, transcriptomics, and machine learning.

Empirical investigations have identified associations between elevated branched-chain amino acids (BCAAs) levels and an increased incidence of hypertensive disorders of pregnancy (HDP). The aim of this study is to rigorously explore the causal linkage between BCAAs concentrations and the risk of developing HDP. A bidirectional Mendelian randomization (MR) analysis was conducted to ascertain the causal relationship between BCAAs levels and the risk of HDP. Instrumental genetic variables derived from the genome-wide association studies of serum BCAAs levels - encompassing total BCAAs, leucine, isoleucine and valine from the UK Biobank, and HDP data (16,417 cases and 213,893 controls) from the FinnGen consortium - were utilized. We conducted inverse-variance weighted, MR-Egger, simple mode, and weighted MR estimates. To assess the heterogeneity and potential presence of horizontal pleiotropy among the instrumental variables, Cochran Q statistic and the MR-Egger intercept were employed. Simultaneously, transcriptomic data were utilized in conjunction with machine learning to identify key genes through which BCAAs influence HDP. Single-cell techniques were employed to analyze the major cell populations. The forward MR analysis indicated a significant positive correlation between the levels of total BCAAs (OR: 1.300, 95% CI: 1.117-1.462; P < .0001), leucine (OR: 1.096, 95% CI: 1.123-1.505; P < .0001), and valine (OR: 1.299, 95% CI: 1.141-1.478; P < .0001) with the risk of HDP. Isoleucine levels (OR: 1.266, 95% CI: 1.054-1.521; P = .012) demonstrated a positive association with HDP risk that did not reach statistical significance after Bonferroni correction. The reverse analysis revealed no causal effect of HDP on the levels of total BCAAs (OR: 0.992, 95% CI: 0.967-1.018; P = .543), leucine (OR: 1.005, 95% CI: 0.973-1.039; P = .750), isoleucine (OR: 1.000, 95% CI: 0.974-1.026; P = .973), and valine (OR: 0.988, 95% CI: 0.962-1.014; P = .354). Transcriptomic analysis identified MCCC2 and BCAT2 as key genes through which BCAAs affect the occurrence of HDP, and these genes are predominantly expressed in endothelial cells. We provide robust evidence Our findings suggest that HDP was associated with an increased level of BCAAs, and the effects may be related to the expression levels of MCCC2 and BCAT2 in endothelial cells.