Marine n-3 fatty acid intake, glutathione s-transfrases (GST) polymorphisms and colorectal cancer risk: the Singapore Chinese Health Study

The role of marine n-3 polyunsaturated fatty acids (PUFAs) in colorectal carcinogenesis has been investigated in many epidemiological studies; however, the epidemiological evidence is inconclusive. A potential explanation is due to competing products of n-3 PUFAs metabolism. Anti-inflammatory eicosanoids, products of n-3 PUFAs metabolism through cyclooxygenase (COX) enzymes, could inhibit inflammatory responses, which have a protective effect against colorectal cancer. Alternatively, malondialdehyde (MDA) and 4-hydroxy-2-hexenal (4-HHE), lipid peroxidation products of marine n-3 PUFAs, could be mutagenic. It has been suggested that glutathione S-transferases (GSTs) are involved in removing lipid peroxidation products. Therefore, we investigated whether GST genotypes (i.e., GSTT1, GSTM1) modified the marine n-3 PUFAs-colorectal cancer association using a nested case-control study within the Singapore Chinese Health Study. With 469 incident colorectal cancer cases and 1,167 noncases, we observed the effect modification of combined GSTT1 and GSTM1 positive genotypes with marine n-3 PUFAs on colorectal cancer (p for interaction < 0.01), and with the ratio of marine n-3 to n-6 PUFAs on colorectal cancer (p for interaction = 0.01). An inverse association of marine n-3 PUFAs with colorectal cancer was observed among those with high activity GST genotypes (i.e., combined GSTM1 and GSTT1 positive genotype) [Odds ratio (OR) for Q4 vs. Q1 = 0.57, 95% CI = 0.32-1.01, p for trend <0.05]; however, a positive association was observed among those with one or more GST null genotypes [OR for Q4 vs. Q1 = 1.49, 95% CI = 1.00-2.23, p for trend = 0.01]. Among those with one or more GST null genotypes, a positive association was also shown for the ratio of marine n-3 to n-6 PUFAs and colorectal cancer [OR for Q4 vs. Q1 = 1.64, 95% CI = 1.09-2.37, p for trend < 0.01], although no statistically significant association was observed for high activity GST genotypes. Our results suggest the role of GSTT1 and GSTM1 in the association between marine n-3 PUFAs and colorectal cancer. This finding provided a point to consider GST genotypes in the marine n-3 PUFAs-colorectal cancer association in the population. It is important for further public health intervention program to consider this interaction while intervening on the population

Comparing Pathological Risk Factors for Dementia between Cognitively Normal Japanese and Americans

The Alzheimer’s Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E (APOE) genotype. Brain vascular disease burden and brain Aβ burden were measured using white matter lesions (WMLs) and 11C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aβ standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aβ SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aβ burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aβ burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings

Vascular burden, brain beta-amyloid, and soy isoflavones: informing dementia prevention programs

Dementia is now challenging the U.S. health system with its increasing prevalence and huge disease burden. Unfortunately, no cure for dementia is currently available. Therefore, the prevention of dementia is of high public health relevance. This dissertation takes a combination of epidemiological approaches to inform dementia prevention. The first paper examined the association between arterial stiffness and dementia. With a 15-year follow-up, arterial stiffness was associated with increased risk of all-cause dementia among older adults. This finding emphasizes the vascular burden in the development of dementia. The second paper compared three biomarkers of beta-amyloid deposition, brain vascular burden, and neurodegeneration, which are important dementia pathologies, between Japanese and Americans. Japanese are known to have elevated vascular burden which is related to their high-salt intake. Yet, the Japanese diet also contains high intake of marine omega-3 fatty acids and soy isoflavones which are thought to be protective against brain damage. A comparison of these biomarkers between cognitively normal elderly men and women in Japan and the U.S., showed that Japanese had significantly higher amount of white matter lesions, but lower brain beta-amyloid than U.S. Caucasian older adults. This finding lent support to this concept of multiple pathologies in the expression of dementia. Considering the uniqueness of Japanese diet, this difference could be due to dietary factors. The third paper, a systematic review and meta-analysis of randomized controlled trials, showed that intervention group of soy isoflavones had greater improvement in cognitive function than control group, especially in the domain of memory. The implications of these findings for dementia prevention strategies have substantial public health significance. First, these results point to the fact that dementia involves a combination of multiple pathologies: brain beta-amyloid deposition, brain vascular burden, and neurodegeneration. Second, strategies that can improve arterial stiffness, such as reducing blood pressure and increasing physical activity, may reduce or delay the onset of dementia. The finding of lower beta-amyloid burden in Japanese suggests that the Japanese lifestyle, especially diet, may be protective against amyloid deposition. Additionally, soy isoflavones might be beneficial to cognitive function. This information should be considered in future dementia prevention programs

Effect of High-Dose Marine Omega-3 Fatty Acids on Atherosclerosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

A recent randomized controlled trial (RCT), the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), reported that high-dose marine omega-3 fatty acids (OM3) significantly reduce cardiovascular disease (CVD) outcomes, yet the mechanisms responsible for this benefit remain unknown. To test the hypothesis that high-dose OM3 is anti-atherosclerotic, we performed a systematic review and meta-analysis of RCT of high-dose OM3 on atherosclerosis. The protocol of this systematic review was registered with PROSPERO (CRD42019125566). PubMed, Embase, Cochran Central Register for Controlled Trials, and Clinicaltrials.gov databases were searched using the following criteria: adult participants, high-dose OM3 (defined as &ge;3.0 g/day, or in Japan 1.8 g/day and purity &ge;90%) as the intervention, changes in atherosclerosis as the outcome, and RCTs with an intervention duration of &ge;6 months. A random-effects meta-analysis was used to pool estimates across studies. Among the 598 articles retrieved, six articles met our criteria. Four RCTs evaluated atherosclerosis in the coronary and two in the carotid arteries. High-dose OM3 significantly slowed the progression of atherosclerosis (standardized mean difference &minus;1.97, 95% confidence interval &minus;3.01, &minus;0.94, p &lt; 0.001). The results indicate that anti-atherosclerotic effect of high-dose OM3 is one potential mechanism in reducing CVD outcomes demonstrated in the REDUCE-IT trial