Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly marked by central nervous system (CNS) neuronal loss and amyloid plaques. FAM222A, encoding an amyloid plaque core protein, is an AD brain atrophy susceptibility gene that mediates amyloid-β aggregation. However, the expression interplay between FAM222A and other AD-related pathway genes is unclear. Objective: Our goal was to study FAM222A’s whole-genome co-expression profile in multiple tissues and investigate its interplay with other AD-related genes. Methods: We analyzed gene expression correlations in Genotype-Tissue Expression (GTEx) tissues to identify FAM222A co-expressed genes and performed functional enrichment analysis on identified genes in CNS system. Results: Genome-wide gene expression profiling identified 673 genes significantly correlated with FAM222A (p <  2.5×10–6) in 48 human tissues, including 298 from 13 CNS tissues. Functional enrichment analysis revealed that FAM222A co-expressed CNS genes were enriched in multiple AD-related pathways. Gene co-expression network analysis for identified genes in each brain region predicted other disease associated genes with similar biological function. Furthermore, co-expression of 25 out of 31 AD-related pathways genes with FAM222A was replicated in brain samples from 107 aged subjects from the Aging, Dementia and TBI Study. Conclusion: This gene co-expression study identified multiple AD-related genes that are associated with FAM222A, indicating that FAM222A and AD-associated genes can be active simultaneously in similar biological processes, providing evidence that supports the association of FAM222A with AD.

Background: The pharmacologic targeting of polyamines and prostaglandin E2 (PGE2) has proven efficacy for colorectal adenoma prevention. However, the contribution of these analytes as biomarkers of drug response has not been investigated. Methods: We analyzed the relationships between rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment, and risk of adenoma within the context of a phase IIb/III trial of combination difluoromethylornithine (DFMO) plus sulindac for the prevention of colorectal adenoma. Results: We detected no differences in the change in PGE2 levels between the two groups for any time points, but we show a statistically significant decrease in spermidine:spermine levels and in putrescine levels in the DFMO/sulindac group at 12 and 36 months compared to the placebo arm. When we asked whether or not change in polyamine or putrescine levels was associated with adenoma recurrence in the treatment arm only, we found no difference in the rate of metachronous events by change in polyamine or PGE2 levels in the treatment arm. We also found no evidence that polyamine or PGE2 levels were associated with risk of adenoma when we restricted the analysis to the placebo arm only. Of interest, we found that participants with low baseline spermidine:spermine levels who received DFMO/sulindac achieved a significantly greater benefit from treatment (RR = 0.15, 95% CI = 0.06 to 0.40) than those with high baseline spermidine:spermine receiving drug (RR = 0.50, 95% CI = 0.27 to 0.92). Conclusions: DFMO/sulindac significantly suppressed the production of rectal mucosal polyamines, but the magnitude of change was not predictive of response to intervention. This was likely due to the large effect of DFMO/sulindac on adenoma recurrence. We found no evidence in the placebo arm that baseline polyamine or PGE2 were associated with the risk of developing adenoma. The modulating effect of baseline spermidine:spermine levels on metachronous adenoma, in those individuals receiving the drug combination, provides evidence of differential agent-effectiveness by steady-state polyamine levels that should be investigated in future studies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A29.