We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric ...acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 95% CI 0.87, 1.16). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.
Studies of the relation between polyunsaturated fatty acids and risk of atrial fibrillation have been inconclusive. The risk of atrial fibrillation may depend on the interaction between n-3 and n-6 ...polyunsaturated fatty acids as both types of fatty acids are involved in the regulation of systemic inflammation.
We investigated the association between dietary intake of long chain polyunsaturated fatty acids (individually and in combination) and the risk of atrial fibrillation with focus on potential interaction between the two types of polyunsaturated fatty acids.
The risk of atrial fibrillation in the Diet, Cancer and Health Cohort was analyzed using the pseudo-observation method to explore cumulative risks on an additive scale providing risk differences. Dietary intake of long chain polyunsaturated fatty acids was assessed by food frequency questionnaires. The main analyses were adjusted for the dietary intake of n-3 α-linolenic acid and n-6 linoleic acid to account for endogenous synthesis of long chain polyunsaturated fatty acids. Interaction was assessed as deviation from additivity of absolute association measures (risk differences).
Cumulative risks in 15-year age periods were estimated in three strata of the cohort (N = 54,737). No associations between intake of n-3 or n-6 long chain polyunsaturated fatty acids and atrial fibrillation were found, neither when analyzed separately as primary exposures nor when interaction between n-3 and n-6 long chain polyunsaturated fatty acids was explored.
This study suggests no association between intake of long chain polyunsaturated fatty acids and risk of atrial fibrillation.
Marine n-3 polyunsaturated fatty acids (PUFA) may have beneficial effects in relation to atrial fibrillation (AF) with promising data from experimental animal studies, however, results from studies ...in humans have been inconsistent. This review evaluates the mechanisms of action of marine n-3 PUFA in relation to AF based on experimental data and provides a status on the evidence obtained from observational studies and interventional trials. In conclusion, there is growing evidence for an effect of marine n-3 PUFA in prevention and treatment of AF. However, further studies are needed to establish which patients are more likely to benefit from n-3 PUFA, the timing of treatment, and dosages.
Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.
Plasma ...phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation SD 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.
These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.
BACKGROUND: Evidence suggests that asthma is rooted in the intrauterine environment and that intake of marine n-3 polyunsaturated fatty acids (n-3 PUFAs) in pregnancy may have immunomodulatory ...effects on the child. OBJECTIVE: Our aim was to examine whether increasing maternal intake of n-3 PUFAs in pregnancy may affect offspring risk of asthma. DESIGN: In 1990, a population-based sample of 533 women with normal pregnancies were randomly assigned 2:1:1 to receive four 1-g gelatin capsules/d with fish oil providing 2.7 g n-3 PUFAs (n = 266); four 1-g, similar-looking capsules/d with olive oil (n = 136); or no oil capsules (n = 131). Women were recruited and randomly assigned around gestation week 30 and asked to take capsules until delivery. Among 531 live-born children, 528 were identified in registries and 523 were still alive by August 2006. Diagnoses from the International Coding of Diseases version 10 were extracted from a mandatory registry that recorded diagnoses reported from hospital contacts. RESULTS: During the 16 y that passed since childbirth, 19 children from the fish oil and olive oil groups had received an asthma-related diagnosis; 10 had received the diagnosis allergic asthma. The hazard rate of asthma was reduced by 63% (95% CI: 8%, 85%; P = 0.03), whereas the hazard rate of allergic asthma was reduced by 87% (95% CI: 40%, 97%; P = 0.01) in the fish oil compared with the olive oil group. CONCLUSION: Under the assumption that intake of olive oil in the dose provided here was inert, our results support that increasing n-3 PUFAs in late pregnancy may carry an important prophylactic potential in relation to offspring asthma.
Aims/hypothesis
The gut incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have a major role in the pathophysiology of type 2 diabetes. Specific ...genetic and dietary factors have been found to influence the release and action of incretins. We examined the effect of interactions between seven incretin-related genetic variants in
GIPR
,
KCNQ1
,
TCF7L2
and
WFS1
and dietary components (whey-containing dairy, cereal fibre, coffee and olive oil) on the risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study.
Methods
The current case-cohort study included 8086 incident type 2 diabetes cases and a representative subcohort of 11,035 participants (median follow-up: 12.5 years). Prentice-weighted Cox proportional hazard regression models were used to investigate the associations and interactions between the dietary factors and genes in relation to the risk of type 2 diabetes.
Results
An interaction (
p
= 0.048) between
TCF7L2
variants and coffee intake was apparent, with an inverse association between coffee and type 2 diabetes present among carriers of the diabetes risk allele (T) in rs12255372 (GG: HR 0.99 95% CI 0.97, 1.02 per cup of coffee; GT: HR 0.96 95% CI 0.93, 0.98); and TT: HR 0.93 95% CI 0.88, 0.98). In addition, an interaction (
p
= 0.005) between an incretin-specific genetic risk score and coffee was observed, again with a stronger inverse association with coffee in carriers with more risk alleles (0–3 risk alleles: HR 0.99 95% CI 0.94, 1.04; 7–10 risk alleles: HR 0.95 95% CI 0.90, 0.99). None of these associations were statistically significant after correction for multiple testing.
Conclusions/interpretation
Our large-scale case-cohort study provides some evidence for a possible interaction of
TCF7L2
variants and an incretin-specific genetic risk score with coffee consumption in relation to the risk of type 2 diabetes. Further large-scale studies and/or meta-analyses are needed to confirm these interactions in other populations.
Exposure during fetal life may have long-lasting health consequences for the child. Cohorts with biological material are necessary to investigate the possible biological mechanisms behind this ...potential early programming of disease. The Aarhus Birth Cohort Biobank was established in 2008 as an amendment to an ongoing research database, the Aarhus Birth Cohort. It aims to provide the opportunity to investigate the role of genetic factors, environmental exposures and lifestyles in pregnancy on the risk of disease in the offspring. All pregnant women who plan to give birth at Aarhus University Hospital, Skejby, and the fathers-to-be are invited to participate in the Aarhus Birth Cohort Biobank. Blood samples (mother 54 ml, father 4 ml) are drawn at the time of the routine ultrasound scanning in gestational week 12. At the same time, the women fill out a detailed questionnaire on medical and lifestyle factors. Immediately after birth, blood (10 ml) from the umbilical cord and umbilical cord tissue are sampled. Samples from the mothers are separated into plasma, buffy coat, erythrocyte suspension and serum before freezing at -80°C. Samples of whole blood are also stored, from both the mother and the father. Plasma, buffy coat, erythrocyte suspension and tissue from the umbilical cord are stored at -80°C. All researchers can apply for access to the database. For more details, see www.ab-biobank.dk or tbh@dadlnet.dk.
Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while ...NFKB1 activates the transcription of pro‐inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log‐additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.
What's new?
Variations in immune genes appear to play an important role in determining susceptibility to gastric cancer linked to Helicobacter pylori colonization of gastric mucosa. However, little is known about the influence of variation on anatomical localization and histological subtype of this malignancy. The results of this study first confirm that NOD2 and CD14, which encode proteins that recognize H. pylori lipopolysaccharide and peptidoglycan, are significantly associated with gastric cancer risk and second indicate that NOD2 associates with noncardia and CD14 with cardia gastric cancer. The differential effects of variation on the anatomical localization of disease warrant further investigation.
Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccaride and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while ...NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. SNPs in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1284 matched controls from the EPIC cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p=0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p=0.0003) and CD14 with cardia GC (p=0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.
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