UCLA

Background: Colorectal cancer (CRC) remains a significant global health challenge, influenced by both dietary factors and genetic predispositions. Dairy/milk consumption has been suggested to be involved in CRC pathogenesis, yet the underlying mechanisms, particularly in ethnically diverse populations, remain poorly understood. This research aims to unravel the complex relationships between dairy/milk consumption, genetic polymorphisms related to dairy/milk digestion, and the influence of circulating proteins on CRC risk and progression.

Objectives and Specific Aims: The study aims to: 1) Assess the association between dairy/milk intake (including lactose, calcium, and vitamin D) and CRC incidence and mortality across race/ethnicity; 2) Investigate the associations between genetic polymorphisms in LCT, MCM6, CASR, and VDR genes and CRC risk, including gene-diet interactions; 3) Explore the causal relationship between circulating proteins and CRC risk.

Methods: Data from the Multiethnic Cohort study, involving 215,634 participants, were analyzed for dietary associations. Genetic analyses involved candidate SNPs on a sub-cohort of 70,000 participants. Proteomic Mendelian Randomization (MR) analyses leveraged summary-level statistics from various GWAS studies.

Results: Higher consumption of dairy/milk and their key components was linked to a 13-17% reduced CRC risk. There was a weak association between dairy/milk intake and mortality among CRC patients. While no evident racial/ethnic heterogeneity was observed in incidence, significant differences were noted across racial/ethnic groups in mortality. No interaction was found between dairy/milk consumption and lactase persistence status. Several SNPs within LCT, MCM6, CASR, and VDR were associated with CRC risk across the different racial/ethnic groups. Elevated genetically determined lactase-phlorizin hydrolase levels were inversely associated with CRC risk. Four unique proteins (GREM1, LPH, PDE5A, LIMA1) were associated with CRC risk in the cis-MR analyses, while 15 additional proteins were identified in the analyses using all (cis+trans) protein quantitative trait loci.

Conclusions: This study highlights the protective effects of dairy/milk intake against CRC risk, the genetic factors influencing CRC susceptibility, and the potential role of circulating proteins in CRC carcinogenesis. These findings emphasize the importance of race/ethnicity-specific dietary guidelines and genetic risk stratification in CRC prevention, suggesting targeted public health interventions for effective CRC management.