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Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2024)

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.

    Cover page: Dairy and Milk Intake, Genetic Predispositions, and Circulating Proteins: Unveiling the Multifaceted Landscape of Colorectal Cancer Risk and Progression
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2020)

    Background

    Circulating glycemic traits (GTs) have been considered a risk factor for breast cancer, but studies using GT-associated genetic variants as an instrumental variable are limited and inconclusive.

    Methods

    Our Mendelian Randomization analysis used the most recent genome-wide datasets focusing on European women.

    Results

    Of 44 single-nucleotide polymorphisms (SNPs) with GTs, 38 fasting-glucose and 6 fasting-insulin SNPs showed heterogeneous associations with breast cancer, without significant directional pleiotropy observed.

    Conclusion

    Our findings indicate a null association between genetically determined GTs and breast cancer risk among European women. Our findings may contribute to more complete characterizing of metabolic pathways in GTs and breast cancer.
      Cover page: The Role of Genetically Determined Glycemic Traits in Breast Cancer: A Mendelian Randomization Study
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2024)
      Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPHs potential role in CRC prevention.
        Cover page: Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2021)
        Immune-related etiologic pathways to influence invasive breast cancer risk may interact with lifestyle factors, but the interrelated molecular genetic pathways are incompletely characterized. We used data from the Women's Health Initiative Database for Genotypes and Phenotypes Study including 16,088 postmenopausal women, a population highly susceptible to inflammation, obesity, and increased risk for breast cancer. With 21,784,812 common autosomal single-nucleotide polymorphisms (SNP), we conducted a genome-wide association (GWA) gene-environment interaction (G × E) analysis in six independent GWA Studies for proinflammatory cytokines [IL6 and C-reactive protein (CRP)] and their gene-lifestyle interactions. Subsequently, we tested for the association of the GWA SNPs with breast cancer risk. In women overall and stratified by obesity status (body mass index, waist circumference, and waist-to-hip ratio) and obesity-related lifestyle factors (exercise and high-fat diet), 88 GWA SNPs in 10 loci were associated with proinflammatory cytokines: 3 associated with IL6 (1 index SNP in MAPK1 and 1 independent SNP in DEC1); 85 with CRP (3 index SNPs in CRPP1, CRP, RP11-419N10.5, HNF1A-AS1, HNF1A, and C1q2orf43; and two independent SNPs in APOE and APOC1). Of those, 27 in HNF1A-AS1, HNF1A, and C1q2orf43 displayed significantly increased risk for breast cancer. We found a number of novel top markers for CRP and IL6, which interacted with obesity factors. A substantial proportion of those SNPs' susceptibility influenced breast cancer risk. Our findings may contribute to better understanding of genetic associations between pro-inflammation and cancer and suggest intervention strategies for women who carry the risk genotypes, reducing breast cancer risk. PREVENTION RELEVANCE: The top GWA-SNPs associated with pro-inflammatory biomarkers have implications for breast carcinogenesis by interacting with obesity factors. Our findings may suggest interventions for women who carry the inflammatory-risk genotypes to reduce breast cancer risk.
          Cover page: Genome-wide Association Analysis of Proinflammatory Cytokines and Gene–lifestyle Interaction for Invasive Breast Cancer Risk: The WHI dbGaP StudyCreative Commons 'BY-ND' version 4.0 license
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