The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection

We have identified statistically significant SNPs influencing susceptibility to diarrhea due to Entamoeba histolytica infection at the locus encoding the transcription factor CREM (10p11.21; rs58000832, P=6.1x10-9; rs2148483, P=9.6x10-8) using genome wide association studies (GWAS). Considering undernutrition increases susceptibility to enteric infection, we investigated if CREM locus variants were also associated with nutritional status. Genetic analysis on birth cohorts of Bangladeshi children demonstrated that risk alleles of rs58000832 and rs2148483 were associated with lower weight-for-age z-scores at 12 months of age (rs2148483: 0.188 reduction in WAZ, P= 0.014; rs58000832: 0.135 reduction in WAZ, P= 0.001), independent of E. histolytica diarrhea. Small intestinal transcriptome data from children homozygous for the rs2148483 risk allele compared to heterozygotes demonstrated enrichment of mitochondrial function and catabolism among upregulated genes and enrichment of B-cell activation and adaptive immune pathways among downregulated genes, consistent with dual roles of the CREM locus in immunity and metabolism. Full body deletion and/or intestinal epithelial cell (IEC)-specific deletion of CREM in mice produced decreased body weight. Transcriptome analysis of cecal tissue from E. histolytica challenged mice also showed upregulation of metabolic processes in both full body and IEC-specific deletion mice. Processes with downregulated genes in full body deletion mice were enriched for myeloid cell activation and chemotaxis while immune process changes were absent when deletion was limited to IECs. These data suggest that CREM modulates both metabolism and immune function at mucosal sites. Overall design: To determine the role of CREM mediated transcription in the cecum, we have conducted RNA-seq on both full body (CREM fl/fl CRE-ER) and intestinal epithelium specific (CREM fl/fl Vil-CRE) CREM deletion mouse models. Each tissue deletion model was compared to same sex litter mates without CRE recombinase