Circulating sphingolipids and colorectal cancer risk in African American adults

Background: Obesity‑related metabolic dysfunction may promote colorectal carcinogenesis through sphingolipid pathways. Ceramides and related species regulate insulin resistance, inflammation, and intestinal stem‑cell proliferation; however, prospective data linking circulating sphingolipids to colorectal cancer (CRC) are limited, particularly in African Americans. Methods: We conducted a nested case-control study within the Southern Community Cohort Study (SCCS) including 373 African American CRC cases and 373 matched control participants. Targeted lipidomic analysis quantified 165 sphingolipids including 78 ceramides, 36 sphingomyelins, 30 neutral glycosphingolipids, 14 glycerophosphocholines, 4 sphingoid base‑1‑phosphates, 4 sphingoid base homologs, and one ceramide‑1‑phosphate. Conditional logistic regression estimated odds ratios (OR) and 95% CI per standard deviation (SD), adjusting for age, sex, number of aliquot freeze-thaw cycles, education, body mass index, smoking status, physical activity, energy intake, fiber intake, red/processed meat intake, and alcohol intake. Results: Participants were aged 54±9 years, and 55% were female. In fully adjusted models, several very‑long‑chain ceramides and one sphingomyelin showed statistically significant inverse associations with CRC risk with adjustment for multiple comparisons at FDR q<0.05, including Cer(d16:1/23:0), Cer(d16:1/22:0), Cer(d17:1/22:0), Cer(d17:1/23:0), Cer(d18:2/23:0), and SM(d16:1/23:0) (OR per SD range 0.76 to 0.80, p range 0.001 to 0.009). Some long-chain dihydroceramides and ceramides previously linked to metabolic diseases were positively associated with CRC, though results did not reach statistical significance (e.g., dhCer(d18:0/18:0), OR 1.15, 95% CI 0.98-1.35; Cer(d18:1/18:0), OR 1.08, 95% CI 0.92-1.26). Conclusions: Pre‑diagnostic very‑long‑chain ceramide species showed protective associations with CRC incidence in African Americans. Findings highlight potential metabolically actionable pathways for CRC prevention. Acknowledgement: U01CA202979 and U01CA272529