Citations

AbstractBackground: The MTHFR C677T TT genotype is associated with a 15% to 18% reduction in colorectal cancer risk, but it is not clear if other variants of the gene are associated with colorectal cancer risk.Methods: We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and colorectal cancer risk using a large family-based case-control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry. We assessed 22 TagSNPs, selected based on pairwise r2 >95%, using the Haploview Tagger and genotyped the TagSNPs on the Illumina GoldenGate or Sequenom platforms. The association between single nucleotide polymorphisms and colorectal cancer was assessed using log-additive, codominant, and recessive models.Results: From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased colorectal cancer risk overall [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.63-1.04; and OR, 0.82; 95% CI, 0.64-1.07, respectively]. The 677 TT genotype was associated with a decreased risk of microsatellite-stable/microsatellite-low tumors (OR, 0.69; 95% CI, 0.49-0.97) and an increased risk of microsatellite-high tumors (OR, 2.22; 95% CI, 0.91-5.43; Pinteraction = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (Pinteraction = 0.02). No other single nucleotide polymorphism was associated with risk overall or within subgroups.Conclusion: The 677 TT and 1298 CC genotypes may each be associated with a decrease in colorectal cancer risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to colorectal cancer risk. Cancer Epidemiol Biomarkers Prev; 19(1); 89–100

Abstract Introduction: Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer (CRC). Reports have suggested that these associations may differ by tumor molecular subtype, with stronger associations for microsatellite unstable (MSI-H) tumors. Methods: We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings) recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption, and CRC. Associations were assessed using conditional logistic regression, treating sibship as the matching factor. Results: Although there were no statistically significant associations between any smoking variable and CRC overall, smoking did confer an increased risk of certain types of CRC. We observed an association between pack-years of smoking and rectal cancer [odds ratio (OR), 1.85; 95% confidence interval (CI), 1.23-2.79 for >40 pack-years versus nonsmokers; Ptrend = 0.03], and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR, 1.94; 95% CI, 1.09-3.46 for >30 years of smoking versus nonsmokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR, 1.21; 95% CI, 1.03-1.44 for 12+ drinks per week versus nondrinkers), with more marked increases in risk for MSI-L CRC (OR, 1.85; 95% CI, 1.06-3.24) and rectal cancer (OR, 1.48; 95% CI, 1.08-2.02). Conclusions: We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering tumor phenotype in studies of risk factors for CRC. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2745–50)

OBJECTIVE Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the “athlete paradox.” The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity. RESEARCH DESIGN AND METHODS We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic-euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states. RESULTS MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5–10% lower body weights compared with wild-type littermates, whereas food consumption was not different. CONCLUSIONS DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic “remodeling” of skeletal muscle coupled with insulin sensitization.