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Nthase which is involved in heme synthesis. A formal enrichment analysis
Nthase which is involved in heme synthesis. A formal enrichment analysis for GO terms revealed `bicarbonate transport’, `hemoglobin metabolic process’ and `hemoglobin complex’ as the top three enriched biological pathways (all P = 8.4 ?10-4, not significant after multiple testing correction, Table S7 in Additional file 2). In Ingenuity pathway analysis, `heme biosynthesis from uroporphyrinogen-III I’ was among the top five upregulated canonical pathways (P = 9.9 ?10-3, not significant after multiple testingcorrection), although results are based on only one gene (FECH) in this pathway (Table S8 in Additional file 2). Consequently, we hypothesized that the transcripts in the RBC module are reflective of erythrocyte development, since immature RBCs, reticulocytes, contain remnant mRNA [56] which is depleted during erythrocyte maturation. An increased hematopoiesis upon diet-induced obesity in rats has been observed, putatively through action of leptin in the bone marrow [57], whereas glycosylated hemoglobin shows an inverse relationship with erythrocyte survival [58]. A shift towards a larger proportion of immature RBCs upon weight gain would be consistent with these observations. In agreement with our findings, a small transcriptomics study of obesity reported the majority of the genes significantly upregulated in obesity to be related to reticulocytes [8]. The proportion of immature reticulocytes was shown to be elevated in cardiac disease patients [59]. In a transcriptomics study of participants from the Framingham heart study, a cluster of transcripts specific to CD71+ early erythroid cells was significantly upregulated in coronary heart disease (CHD) cases compared to controls [60]. This cluster, comprising 126 transcripts, showed a large overlap with the RBC module identified in our study, with nine of the above-mentioned core transcripts being contained in this cluster. Furthermore, Zhang et al. observed an PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26795252 increased RBC count and increased hemoglobin levels in obese but not in non-obese CHD patients as compared to healthy controls [61]. Also, the obese patients were more likely to have acute coronary syndrome, which the authors attribute to PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26100631 a potential role of RBCs in the development of plaque instability. Our results suggest that even in non-obese subjects, weight change is related to RBC development. Another, smaller, gene expression module (GenM14, comprising 17 transcripts) was negatively associated with BW (Figure 5, Table S6 in Additional file 2). GenM14 contained all 11 transcripts of the `lipid-leukocyte (LL) module’ previously buy Nutlin (3a) described as a leukocyte gene expression module strongly related to blood lipids [62] and a large number of serum metabolites including lipoprotein subclasses, lipids, glycoproteins and amino acids [13]. We therefore termed it the `LL-like module.’ The core of the LL-like module (module membership strength >0.8) comprised the LL genes HDC, GATA2, SLC45A3, MS4A2 and SPRYD5. Inouye et al. [62] discussed this module as being involved in basophil and mast cell-related immune response and allergy. For instance, the core gene HDC codes for a protein converting histidine to histamine, which is secreted by basophils and mast cells in response to IgE sensitization. Accordingly, when we applied Ingenuity pathway analysis to our data, `FC Epsilon RI Signaling’ (P = 1.1 ?10-4), `Histamine Biosynthesis’ (P = 9.1 ?10-4) and `Airway Inflammation in Asthma’Wahl et al. BMC Medicine (2015) 13:Page 12 ofGenM14 (LL-lik.