76 (Supplementary Figure 2B, Supplementary Table 1.1). This change was more often a loss of enrichment rather than a gain, and this difference could not be directly attributed to a batch effect (Wilcoxon test, P = 0.45). This highlights that the time elapsed since antigen encounter might be a determining factor for the detection of antibody-bound peptide enrichment, which is in agreement with humoral studies showing that the prevalence of antibodies seemed to fade over time.63-65 Next, we studied whether genetically related individuals or those living in similar environments (co-housing) would show more similarity in antibody-bound peptide enrichment compared to unrelated individuals. To explore this, we used 26 family trios from the LLD population66 (note that most offspring are unlikely to currently cohouse with their parents as mean age = 37±10.1 years old). Mother–offspring, father–offspring and father–mother antibodybound peptide distances were significantly lower than those between unrelated individuals (P < 5x10-4, P = 0.013 and P < 5x10-4, respectively; 2,000 label permutations). However, no significant differences were found between family members although father–offspring pairs were, on average, more distant (Figure 1D). The role of common environment in shaping antibody repertoires is supported by the decreased father– mother distance, while offspring associations could indicate an important role for environment during early life, a common lifestyle, the effect of genetics, or all to some degree. Figure 1 | PhIP-Seq antibody-bound peptide profiles of 1,443 individuals representative of the Dutch population. A. Cohort characteristics. Lifelines-Deep is a population cohort from Northern Netherlands. In this work, we performed PhIP-Seq in 1,443 participants (including 26 trio families), 322 of whom have data from a second time point after 4 years. Other data layers include phenotypes (questionnaires and clinical measurements), genetics (imputed microarrays) and microbiome (bacterial taxonomic quantification). There is a higher proportion of females within the participants (57%). The age distribution is slightly left skewed, with a mean of 44.5 years (no significant sex differences). B. Prevalence of antibody-bound peptides in the population. X-axis depicts seroprevalence. Y-axis is the number of antibody-bound peptides with a given seroprevalence. C. Principal component analysis identified two clusters (color represents cluster labels after 2-means clustering) related to PC2, which is mainly driven by CMV peptides. D. Longitudinal samples taken 4 years apart in 322 participants are more closely related to the individual’s baseline than to other participants. E. 26 family trios show a lower distance between their antibody-bound peptide profiles than unrelated participants. Chapter 3
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