Nuclear magnetic resonance spectroscopy-measured biomarkers and cardiometabolic disease in the Mexico City prospective study

Background: Blood lipids, particularly the cholesterol in low-density lipoproteins (LDL-C), are causally related to atherosclerotic cardiovascular disease. Moreover, adiposity, diabetes, and kidney disease—key cardiovascular risk factors—are all linked to perturbations in blood lipids. However, evidence around blood lipids has mostly relied on simple assays of these biomarkers and primarily comes from studies in high-income countries.
Methods: In 1998-2004, the Mexico City Prospective Study (MCPS) recruited 159,755 adults aged >35 years, who have been followed for cause-specific mortality until January 1st 2018. All participants had body measures taken and glycosylated haemoglobin (HbA1c) measured. Among 40,349 of these participants, NMR quantified plasma concentrations of about 100 biomarkers involving lipoprotein particles, their lipidic compositions (cholesterol, triglycerides, and phospholipids), apolipoproteins, and other metabolic measures including creatinine. Linear regression analyses examined the cross-sectional associations of adiposity, of diabetes, and of kidney function with NMR biomarkers in individuals aged 35-84 years at recruitment. Cox regression analyses yielded hazard ratios (HRs) for the associations of NMR biomarkers with premature mortality (before age 75) due to vascular occlusive causes (ischaemic heart disease, ischaemic stroke, or peripheral arterial disease). All analyses excluded the few participants (<1%) who were using lipid-lowering medications at recruitment. To minimise reverse causation, prospective analyses further excluded those with chronic diseases and deaths in the first 10 years of follow-up.
Results: At recruitment, of the 36,527 participants aged 35-84 years included in the main cross-sectional analyses, about three-quarters had a body-mass index of 25 kg/m2 or above, 17% had diabetes, and 1.5% had an estimated glomerular filtration rate (eGFR) below 60 mL/kg/1.73 m2 (consistent with chronic kidney disease). The NMR metabolic biomarkers showed a complex pattern of correlation that reflected their biochemical characteristics and their pathophysiological relationships. These biomarkers were also correlated with a number of socio-demographic and lifestyle characteristics. General, abdominal, and gluteo-femoral adiposity were cross-sectionally associated with an NMR metabolic profile characterised by higher levels of ApoB, of very-low density lipoprotein (VLDL) particles (and their lipids), of fatty acids, of cholines, of branched-chain amino acids, and of the inflammation biomarker Glyc-A. Mutual adjustment of general and abdominal adiposity showed that their associations with NMR biomarkers were largely independent. However, the associations of gluteo-femoral adiposity were reversed after adjustment for general and abdominal adiposity. Similarly, diabetes and HbA1c were associated with a metabolic profile that consisted in higher levels of VLDL, of ApoB, of triglycerides in all lipoproteins, of fatty acids, of branched-chain amino acids, and of Glyc-A. Finally, low kidney function (i.e. an eGFR <60 mL/min1.73m2) was associated with a metabolic profile involving higher levels of ApoB, of the ApoB-containing lipoproteins VLDL and LDL, of the cholesterol, triglycerides, and phospholipids in these lipoproteins, of several fatty acids, and of Glyc-A irrespective of diabetes status. The NMR metabolic profiles of adiposity, diabetes, and kidney function tended to be qualitatively similar in men and women and at younger and older age. In the 27,518 participants without diabetes or other prior chronic disease at recruitment, there were 117 vascular occlusive deaths more than 10 years later and before age 75 years. Biomarkers related to ApoB-carrying lipoproteins (VLDL and LDL), and their lipids, ApoB, fatty acids, total cholines, phosphatidylcholine, sphingomyelin, and glucose were associated with risk of vascular occlusive death. Each 1-SD higher baseline level of ApoB and of glucose were associated with 26% (HR of 1.26 [95% CI 1.04, 1.52]) and 42% (HRs of 1.42 [95% CI 1.17, 1.73]) higher risk of vascular occlusive mortality, respectively. Similarly, the most informative linear combination of the NMR biomarkers (the first ‘principal component’), which largely reflected ApoB containing particles and their composition, was significantly associated with risk of vascular occlusive death (HR 1.27, 95% CI 1.04, 1.56).
Conclusion: Lipid-lowering therapy is substantially underused in Mexico. Metabolic profiling in this Hispanic population with high levels of obesity demonstrates how adiposity, diabetes, and kidney disease associate with lipid and lipoprotein profiles which are linked to vascular occlusive disease. Future research will extend and combine these metabolomics data with genetic data to explore the causal nature of NMR biomarkers to cause-specific mortality risk in this population.

Advisor: Emberson, J
Herrington, W
Staplin, N
Baigent, C