Abstract P207: Heterogeneity in Obesity in Relation to Related to Hypertension: Investigating the Role of Metabolic Pathways
Authors: Howard Annie Green , Mhatre Sachin , Sha Wei , Lloyd-Jones Donald , Rushing Blake , McRitchie Susan , Du Xiuxia , Li Yuanyan , Sumner Susan , Avery Christy L , North Kari E , Gordon-Larsen Penny 
Published: March 2023

Background:
While obesity is associated with hypertension, there is heterogeneity in risk by weight status and we know little about whether and which metabolic pathways play a role in exacerbating differential risk across weight status categories.

Methods:
Fasting blood was collected at the Yr. 20 follow-up exam in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We conducted Ultra-High-Performance Liquid Chromatography high resolution mass spectrometry untargeted metabolomics in 1,769 individuals (ages 37-54, 58% female, 66% Black) classified as normotensive (no hypertension diagnosis or medication and SBP/DBP ≤ 130/80). We identified 7,522 metabolomic peaks and 8 principal components, which we included in a multivariable-adjusted proportional hazards model with an interaction term to assess whether the association between these metabolite measures and incident hypertension (HTN) varied by BMI. We then employed multivariate analysis using Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) models using 70% of the sample within each obesity category to predict incident HTN at ten years in normal weight, overweight and obese groups based on the high dimensional metabolomics data. The remaining 30% of individuals in each obesity category were then used to evaluate the predictive value of the OPLS-DA models. Finally, we used mummichog software and Fisher’s exact tests, to conduct pathway enrichment analysis using data from both the individual peak and the OPLS-DA models.

Results:
We identified 723 metabolites where the association with long term risk of HTN differed by BMI, although none were statistically significant after adjustment for multiple comparisons. However, we found strong evidence of effect modification for metabolites via principal components and OPLS-DA. For the 3
rd
principal component, which explained 5% of the variation across all peaks, we found a significant interaction with BMI (p-value = 0.0043). In external test data sets, OPLS-DA models predicted incident HTN relatively well in normal weight individuals (AUC of 77%) but not well in overweight and obese individuals (AUC of 49% and 56% respectively). We identified several pathways with a differential HTN risk by BMI shown in the OPLS-DA and proportional hazards models. In the phenylamine pathway there was substantial differentiation between those with and without incident HTN risk for normal weight only and across the lysine degradation pathway only for individuals who were obese.

Conclusions:
Our findings identify variation in hypertension risk by BMI, with suggestive evidence for a role of metabolomic pathways and combinations of metabolites. Overall, metabolites predicted 10-year incident hypertension very well in individuals of normal weight (but not obese status), indicating heterogeneity in hypertension risk by weight status.