Demler, Olga

Abstract Background Glycosylation, a key post-translational modification, plays a crucial role in biological pathways related to atherosclerosis. Purpose To investigate whether specific immunoglobulin G (IgG) N-glycosylation patterns are associated with premature myocardial infarction (MI) and to evaluate whether a glycan-based score improves case identification beyond traditional cardiovascular risk factors. Methods We measured 27 IgG N-glycans using capillary gel electrophoresis in 377 cases of premature first MI (men ≤55 years; women ≤65 years) and 377 controls matched for age (±5 years), sex, and nationality from the Gulf PREVENT study, a case-control study investigating risk factors for premature MI in the United Arab Emirates. We performed conditional logistic regression to evaluate associations between IgG N-glycans and premature MI, adjusting for age, body mass index, LDL-C, HDL-C, hs-CRP, hypertension, diabetes, and smoking. Using LASSO regression, we derived a novel IgG glycan score as a linear combination of selected glycans associated with premature MI. We evaluated model performance using likelihood ratio tests and the area under the curve (AUC) adapted for the case-control design, using 10-fold cross-validation. Results After adjusting for cardiovascular risk factors, glycan peaks (P) 4, 13, 23, and 27 were positively associated with premature MI (false discovery rate [FDR]<0.05). Bisecting N-acetylglucosamine (GlcNAc) was the consistent glycosylation pattern among these four glycans. In contrast, P 22, a core-fucosylated and monogalactosylated glycan, had inverse association (FDR=0.02) with premature MI. An IgG glycan score, composed of Ps 2, 4, 8, 17, 20, and 24, was associated with twofold increase in premature MI risk per standard deviation increment (aOR,1.98 [95%CI,1.56–2.52]; P<0.001) after adjusting for cardiovascular risk factors. Further, the IgG glycan score significantly improved model fit and performance, as indicated by a significant improvement in the likelihood ratio test and AUC (P<0.001). Conclusion We identified novel IgG N-glycosylation patterns that were associated with premature MI independent of cardiovascular risk factors. Glycans enriched with bisecting GlcNAc had increased risk, while core fucosylation and monogalactosylation had decreased risk. A novel IgG glycan score had 2-fold increased risk of premature MI independent of other risk factors and improved model performance. These findings highlight the potential of IgG N-glycans as biomarkers and therapeutic targets for premature MI.

Abstract Background Premature coronary heart disease (CHD) is a major cause of death in women. We aimed to characterize biomarker profiles of women who developed CHD before and after age 65 years. Methods In the Women’s Health Study (median follow-up 21.5 years), women were grouped by age and timing of incident CHD: baseline age <65 years with premature CHD by age 65 years (25 042 women; 447 events) and baseline age ≥65 years with nonpremature CHD (2982 women; 351 events). Associations of 44 baseline plasma biomarkers measured using standard assays and a nuclear magnetic resonance (NMR)-metabolomics assay were analyzed using Cox models adjusted for clinical risk factors. Results Twelve biomarkers showed associations only with premature CHD and included lipoprotein(a), which was associated with premature CHD [adjusted hazard ratio (HR) per SD: 1.29 (95% CI 1.17–1.42)] but not with nonpremature CHD [1.09(0.98–1.22)](Pinteraction = 0.02). NMR-measured lipoprotein insulin resistance was associated with the highest risk of premature CHD [1.92 (1.52–2.42)] but was not associated with nonpremature CHD (Pinteraction <0.001). Eleven biomarkers showed stronger associations with premature vs nonpremature CHD, including apolipoprotein B. Nine NMR biomarkers showed no association with premature or nonpremature CHD, whereas 12 biomarkers showed similar significant associations with premature and nonpremature CHD, respectively, including low-density lipoprotein (LDL) cholesterol [1.30(1.20–1.45) and 1.22(1.10–1.35)] and C-reactive protein [1.34(1.19–1.50) and 1.25(1.08–1.44)]. Conclusions In women, a profile of 12 biomarkers was selectively associated with premature CHD, driven by lipoprotein(a) and insulin-resistant atherogenic dyslipoproteinemia. This has implications for the development of biomarker panels to screen for premature CHD.