| 1. |
- Fagerholm, Rainer, et al.
(författare)
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NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:7, s. 844-53
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Tidskriftsartikel (refereegranskat)abstract
- NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.
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| 2. |
- Garcia-Closas, Montserrat, et al.
(författare)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Tidskriftsartikel (refereegranskat)abstract
- A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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| 3. |
- Fretts, Amanda M., et al.
(författare)
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Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes : a pooled analysis of prospective cohort studies
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : OXFORD UNIV PRESS. - 0002-9165 .- 1938-3207. ; 109:4, s. 1216-1223
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Tidskriftsartikel (refereegranskat)abstract
- Background: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.Objective: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.Methods: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.Results: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.Conclusions: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.
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| 4. |
- Imamura, Fumiaki, et al.
(författare)
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Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes : A pooled analysis of prospective cohort studies
- 2018
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15: 0 and 17: 0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, tri-glycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men ((pinteraction) < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.
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| 5. |
- Imamura, Fumiaki, et al.
(författare)
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Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes : A pooled analysis of prospective cohort studies
- 2020
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:6
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDe novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).Methods and findingsSeventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.ConclusionsConcentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.
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| 6. |
- Lankinen, Maria, et al.
(författare)
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A Healthy Nordic Diet Alters the Plasma Lipidomic Profile in Adults with Features of Metabolic Syndrome in a Multicenter Randomized Dietary Intervention
- 2016
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Ingår i: Journal of Nutrition. - New York, USA : Oxford University Press. - 0022-3166 .- 1541-6100. ; 146:4, s. 662-672
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known.OBJECTIVE: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome.METHODS: Men and women (n = 200) with features of metabolic syndrome [mean age: 55 y; body mass index (in kg/m(2)): 31.6] were randomly assigned to either a healthy Nordic (n = 104) or a control (n = 96) diet for 18 or 24 wk at 6 centers. Of the participants, 156 completed the study with plasma lipidomic measurements. The healthy Nordic diet consisted of whole grains, fruits, vegetables, berries, vegetable oils and margarines, fish, low-fat milk products, and low-fat meat. An average Nordic diet served as the control diet and included low-fiber cereal products, dairy fat-based spreads, regular-fat milk products, and a limited amount of fruits, vegetables, and berries. Lipidomic profiles were measured at baseline, week 12, and the end of the intervention (18 or 24 wk) by using ultraperformance liquid chromatography mass spectrometry. The effects of the diets on the lipid variables were analyzed with linear mixed-effects models. Data from centers with 18- or 24-wk duration were also analyzed separately.RESULTS: Changes in 21 plasma lipids differed significantly between the groups at week 12 (false discovery rate P < 0.05), including increases in plasmalogens and decreases in ceramides in the healthy Nordic diet group compared with the control group. At the end of the study, changes in lipidomic profiles did not differ between the groups. However, when the intervention lasted 24 wk, changes in 8 plasma lipids that had been identified at 12 wk, including plasmalogens, were sustained. There were no differences in changes in plasma lipids between groups with an intervention of 18 wk. By the dietary biomarker score, adherence to diet did not explain the difference in the results related to the duration of the study.CONCLUSIONS: A healthy Nordic diet transiently modified the plasma lipidomic profile, specifically by increasing the concentrations of antioxidative plasmalogens and decreasing insulin resistance-inducing ceramides. This trial was registered at clinicaltrials.gov as NCT00992641.
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| 7. |
- Lankinen, Maria, et al.
(författare)
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Effects of whole grain, fish and bilberries on serum metabolic profile and lipid transfer protein activities : a randomized trial (Sysdimet)
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We studied the combined effects of wholegrain, fish and bilberries on serum metabolic profile and lipid transfer protein activities in subjects with the metabolic syndrome.METHODS: Altogether 131 subjects (40-70 y, BMI 26-39 kg/m(2)) with impaired glucose metabolism and features of the metabolic syndrome were randomized into three groups with 12-week periods according to a parallel study design. They consumed either: a) wholegrain and low postprandial insulin response grain products, fatty fish 3 times a week, and bilberries 3 portions per day (HealthyDiet), b) wholegrain and low postprandial insulin response grain products (WGED), or c) refined wheat breads as cereal products (Control). Altogether 106 subjects completed the study. Serum metabolic profile was studied using an NMR-based platform providing information on lipoprotein subclasses and lipids as well as low-molecular-weight metabolites.RESULTS: There were no significant differences in clinical characteristics between the groups at baseline or at the end of the intervention. Mixed model analyses revealed significant changes in lipid metabolites in the HealthyDiet group during the intervention compared to the Control group. All changes reflected increased polyunsaturation in plasma fatty acids, especially in n-3 PUFAs, while n-6 and n-7 fatty acids decreased. According to tertiles of changes in fish intake, a greater increase of fish intake was associated with increased concentration of large HDL particles, larger average diameter of HDL particles, and increased concentrations of large HDL lipid components, even though total levels of HDL cholesterol remained stable.CONCLUSIONS: The results suggest that consumption of diet rich in whole grain, bilberries and especially fatty fish causes changes in HDL particles shifting their subclass distribution toward larger particles. These changes may be related to known protective functions of HDL such as reverse cholesterol transport and could partly explain the known protective effects of fish consumption against atherosclerosis.TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov NCT00573781.
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| 8. |
- Marklund, Matti, et al.
(författare)
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A Dietary Biomarker Approach Captures Compliance and Cardiometabolic Effects of a Healthy Nordic Diet in Individuals with Metabolic Syndrome.
- 2014
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 144:10, s. 1642-1649
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of compliance with dietary interventions is necessary to understand the observed magnitude of the health effects of the diet per se. To avoid reporting bias, different dietary biomarkers (DBs) could be used instead of self-reported data. However, few studies investigated a combination of DBs to assess compliance and its influence on cardiometabolic risk factors. The objectives of this study were to use a combination of DBs to assess compliance and to investigate how a healthy Nordic diet (ND) influences cardiometabolic risk factors in participants with high apparent compliance compared with the whole study population. From a recently conducted isocaloric randomized trial, SYSDIET (Systems Biology in Controlled Dietary Interventions and Cohort Studies), in 166 individuals with metabolic syndrome, several DBs were assessed to reflect different key components of the ND: canola oil (serum phospholipid α-linolenic acid), fatty fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], vegetables (plasma β-carotene), and whole grains (plasma alkylresorcinols). High-fat dairy intake (expectedly low in the ND) was reflected by serum pentadecanoic acid. All participants with biomarker data (n = 154) were included in the analyses. Biomarkers were combined by using a biomarker rank score (DB score) and principal component analysis (PCA). The DB score was then used to assess compliance. During the intervention, median concentrations of alkylresorcinols, α-linolenic acid, EPA, and DHA were >25% higher in the ND individuals compared with the controls (P < 0.05), whereas median concentrations of pentadecanoic acid were 14% higher in controls (P < 0.05). Median DB score was 57% higher in the ND compared with controls (P < 0.001) during the intervention, and participants were ranked similarly by DB score and PCA score. Overall, estimates of group difference in cardiometabolic effects generally appeared to be greater among compliant participants than in the whole study population (e.g., estimates of treatment effects on blood pressure and lipoproteins were ∼1.5- to 2-fold greater in the most compliant participants), suggesting that poor compliance attenuated the dietary effects. With adequate consideration of their limitations, DB combinations (e.g., DB score) could be useful for assessing compliance in intervention studies investigating cardiometabolic effects of healthy dietary patterns. The study was registered at clinicaltrials.gov as NCT00992641.
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| 9. |
- Marklund, Matti, et al.
(författare)
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Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
- 2019
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
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Tidskriftsartikel (refereegranskat)abstract
- Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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| 10. |
- Murphy, Rachel A, et al.
(författare)
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Omega-3 and omega-6 polyunsaturated fatty acid biomarkers and sleep : a pooled analysis of cohort studies On behalf of the Fatty Acids and Outcomes Research Consortium (FORCE).
- 2022
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Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press (OUP). - 0002-9165 .- 1938-3207. ; 115:3, s. 864-876
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: n-3 and n-6 polyunsaturated fatty acids (PUFAs) have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.OBJECTIVES: To assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were between 35 to 96 years old and from 5 nations. Circulating measures included alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), EPA + DPA + DHA, linoleic acid and arachidonic acid. Sleep duration (10 cohorts, N = 18,791) was categorized as short (≤6 hours), 7-8 hours (reference) or long (9 + hours). Difficulty falling sleeping (8 cohorts, N = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted odds ratios (ORs) per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.RESULTS: In pooled analysis adjusted for sociodemographics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. Comparing top vs. bottom quintiles, the multivariable-adjusted OR (95% confidence interval, CI) for long-sleep was 0.78 (0.65, 0.95) for DHA and for EPA + DPA + DHA, 0.76 (0.63, 0.93). Significant associations were not identified for ALA and n-6 PUFA with short sleep duration, or difficulty falling sleeping.CONCLUSIONS: Participants with higher levels of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relationship. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.
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