N-glycosylation of immunoglobulin G predicts incident hypertension

Abstract

Objectives: Glycosylation of immunoglobulin G (IgG) is an important regulator of the immune system and has been implicated in prevalent hypertension.The aim of this study is to investigate whether the IgG glycome begins to change prior to hypertension diagnosis by analysing the IgG glycome composition in a large population-based female cohort with two independent replication samples.Methods: We included 989 unrelated cases with incident hypertension and 1628 controls from the TwinsUK cohort (mean follow-up time of 6.3 years) with IgG measured at baseline by ultra-performance liquid chromatography and longitudinal BP measurement available. We replicated our findings in 106 individuals from the 10 001 Dalmatians and 729 from KORA S4. Cox regression mixed models were applied to identify changes in glycan traits preincident hypertension, after adjusting for age, mean arterial pressure, BMI, family relatedness and multiple testing (FDR < 0.1). Significant IgG-incident hypertension associations were replicated in the two independent cohorts by leveraging Cox regression mixed models in the 10 001 Dalmatians and logistic regression models in the KORA cohort.Results: We identified and replicated four glycan traits, incidence of bisecting GlcNAc, GP4, GP9 and GP21, that are predictive of incident hypertension after adjusting for confoundes and multiple testing [hazard ratio (95% CI) ranging from 0.45 (0.24-0.84) for GP21 to 2.9 (1.5-5.68) for GP4]. We then linearly combined the four replicated glycans and found that the glycan score correlated with incident hypertension, SBP and DBP. Conclusion:Our results suggest that the IgG glycome changes prior to the development of hypertension.

Immunoglobulin G glycome composition in transition from premenopause to postmenopause

“…Changes in IgG glycosylation from “young” to “old” glycome associate with many health risks that accompany menopause ( Martinić Kavur et al., 2021 ). In some diseases such as rheumatoid arthritis ( Ercan et al., 2010 ; Gudelj et al., 2018b ) and cardiovascular diseases ( Kifer et al., 2021 ; Menni et al., 2018 ; Wittenbecher et al., 2020 ), this change was shown to occur years before disease onset, suggesting the causal role of IgG glycans in disease development. Proinflammatory IgG glycome and the resulting decrease in the ability of IgG to suppress low-grade chronic inflammation may be an important molecular mechanism that mediates the increased health risk in perimenopause, thus this topic should be studied in more detail.…”

Machine learning integration of multimodal data identifies key features of blood pressure regulation

“…BP was measured by a trained nurse and performed with the patient in the sitting position for 3 minutes as previously described. 27 The cuff was placed on the subject's arm so that it was approximately 2-3 cm above the elbow joint of the inner arm, with the air tube lying over the brachial artery. The subject's arm was placed on the table or supported with the palm facing upwards, so that the tab of the cuff was placed at the same level of the heart.…”

High-Throughput Glycomic Methods

“…Cardiovascular diseases (CVD) are the main cause of mortality, and Kifer et al, recently identified four IgG N-glycan traits that associate with an increased risk of incident hypertension. 295 Three glycan traits, representing simple glycan structures containing a core fucose with only one or no galactose residues attached to the bisecting N-acetylglucosamine, significantly increase in individuals who developed hypertension during follow-up when compared with those defined as controls, whereas only one glycan structure decreases, a more complex digalactosylated structure with two sialic acid residues attached to the galactose molecules and without a bisecting N-acetylglucosamine. These results indicate that the IgG glycoprofile of individuals who would develop incidental hypertension during follow-up manifests a proinflammatory pattern and is associated with obesity years before diagnosis, which indeed supports a role of IgG glycosylation in the incident hypertension.…”

“…Interestingly, several IgG glycans strongly correlated with the expected lifespan, suggesting that IgG glycome composition may correlate with all-cause mortality risk. Cardiovascular diseases (CVD) are the main cause of mortality, and Kifer et al, recently identified four IgG N -glycan traits that associate with an increased risk of incident hypertension . Three glycan traits, representing simple glycan structures containing a core fucose with only one or no galactose residues attached to the bisecting N -acetylglucosamine, significantly increase in individuals who developed hypertension during follow-up when compared with those defined as controls, whereas only one glycan structure decreases, a more complex digalactosylated structure with two sialic acid residues attached to the galactose molecules and without a bisecting N -acetylglucosamine.…”