Abstract A056: Relationship among nutrient, metabolite, sex, and inflammatory genotype and phenotype as risk factors of colorectal cancer in rural residents

Abstract Systemic inflammation is a significant risk factor and a hallmark of colorectal cancer (CRC) and poor prognosis. We examined whether sex and rs1205 genotype moderate the indirect effect of gut microbiota choline metabolism on C-reactive protein (CRP), a marker of inflammation, through Trimethylamine N-Oxide (TMAO) metabolite. Gut microbiota metabolizes nutrients, such as dietary choline, an essential nutrient found in various foods, including eggs and meat, to form its metabolite, TMAO. Researchers found higher serum level of TMAO in healthy males than healthy females. In addition, a recent meta-analysis indicated the association of high level of TMAO metabolites with increase in CRP concentrations. CRP gene rs1205 polymorphism, particularly its major C allele, is associated with higher serum levels of CRP and presence of low-grade chronic inflammation. However, complex relationships among diet, metabolites, sex, and inflammatory genotype and phenotype are not known. The secondary analysis was performed using baseline data from the HeartHealth study. Participants included rural-dwelling Kentuckians (N=274); majority were female (75%). Blood samples were analyzed for the serum levels of CRP. We genotyped participants for the rs1205 polymorphism (CC vs. CT/TT). Choline intake was assessed using a web-based Food Frequency Questionnaire. TMAO was extracted from plasma and analyzed via high-performance liquid chromatography with electrospray ionization tandem mass spectrometry. The multiplicatively moderated mediation analysis was conducted using PROCESS macro for SPSS (Ver. 4.3; Model=11). The TMAO and CRP were log-transformed. We used age, body mass index, education, financial status, marital status, and insurance status as covariates. We found a significant three-way interaction among choline (X), rs1205 genotypes (Z), and sex (W) [B=.0026, t(260)=2.572, P=.011], indicating that the moderating effect of sex on the effect of choline on CRP depended on rs1205 genotypes (R2=.190; P<.001). There was a significantly positive association between choline and CRP in females compared to males in the rs1205 CT/TT genotype group [θ XW→Y |(Z=CT/TT)=.0012; F(1;260) =3.947; P=.048]. In contrast, the association was not statistically significantly moderated by sex in the rs1205 CC genotype group. The index of moderated mediation was .0003 (95% bootstrap confidence interval: <.0001-.0010). Our findings provide initial evidence that CRP-related genetic variation and sex moderate an association between diet and CRP. Females with high choline diet and CRP rs1205 CT/TT genotype may be at higher risk of a low-grade chronic inflammatory status. The findings indicate a complex interaction between inflammatory genotype and sex in the relationship of nutrients and metabolites with systemic inflammation. Understanding these associations may inform tailored anti-inflammatory dietary interventions to reduce CRC risks among rural residents. Citation Format: JungHee NMN. Kang, Debra K. Moser, Andrew J. Morris, Lori Ann. Morford, Ilhem Messaoudi, Hollie Raynor, Lovoria B. Williams, Terry A. Lennie, Gia Mudd-Martin. Relationship among nutrient, metabolite, sex, and inflammatory genotype and phenotype as risk factors of colorectal cancer in rural residents [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A056.