Global variability of the human IgG glycome

Abstract

Immunoglobulin G (IgG) is the most abundant serum antibody which structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. Composition of the IgG N-glycome changes with age of an individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is known to be affected by both genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of IgG, analyzed in 5 different populations totaling 10,482 IgG glycomes, and of IgG's fragment crystallizable region (Fc), analyzed in 2,579 samples from 27 populations sampled across the world. Country of residence associated with many N-glycan features and the strongest association was with monogalactosylation where it explained 38% of variability. IgG monogalactosylation strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators, and with the expected lifespan. Subjects from developing countries had low levels of IgG galactosylation, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.

Keywords: Fc glycosylation; aging; glycans; immunoglobulin G; mass spectrometry.

Figure 1

Total IgG glycan levels in five different populations. Relationship between age and derived glycan trait (A). Plots describe associations between each of the five glycan traits and chronological age of participant. Blue and red curves represent fitted linear regression models. The shaded region is the 95 % confidence interval on the fitted values. Differences in total IgG glycosylation between participants from five different populations (B). Each box represents interquartile range (25^th to 75^th percentiles). Lines inside the boxes represent the median values, while lines outside the boxes represent the 10^th and 90^th percentiles. Dots indicate outliers.

Figure 2

Levels of derived IgG1 Fc glycan traits across 27 different populations collected worldwide. Each box represents interquartile range (25^th to 75^th percentiles) with median values drawn as the middle line. Whiskers outside the boxes represent the 10^th and 90^th percentiles, while dots indicate outliers.

Figure 3

Relationship between IgG1 Fc galactosylation levels with development indices. Relationship between IgG1 Fc monogalactosylation (A) and relationship between IgG1 Fc agalactosylation (B) with United Nations’ development indices for a specific country of residence. HDI = Human Development Index; SDG = health-related Sustainable Development Goals index; MDG = health-related Millennium Development Goals index.