European Prospective Investigation Into Research Articles

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

P13-010-23 A Dietary Pattern Derived To Correlate With Estrogens and Risk of Endometrial Cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC) Study

P13-010-23 A Dietary Pattern Derived To Correlate With Estrogens and Risk of Endometrial Cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC) Study

P13-030-23 Ultra-Processed Food Consumption, Adiposity and Upper-Aerodigestive Tract Cancer Risk in the European Prospective Investigation Into Cancer Study: A Mediation Analysis

P13-030-23 Ultra-Processed Food Consumption, Adiposity and Upper-Aerodigestive Tract Cancer Risk in the European Prospective Investigation Into Cancer Study: A Mediation Analysis

Abstract MP11: Ultra-Processed Food Consumption and Cardiovascular Disease in the European Prospective Investigation Into Cancer and Nutrition Study

Introduction: Diets containing many ultra-processed foods (UPF) are linked to unfavourable health. UPF are defined by the NOVA classification as industrial food and drinks made from substances not used in domestic culinary preparations, such as hydrogenated fats, modified starches, and other food additives. There is evidence suggesting a link between UPF consumption and cardiovascular disease (CVD) incidence, but this association has not been tested in a large European cohort. Using data from the pan-European Prospective Investigation into Cancer and nutrition (EPIC) study, we assessed the hypothesis that higher consumption of UPF is associated with an increased risk of incident fatal and non-fatal CHD and stroke in the EPIC-Heart cohort. Methods: Case-cohort design nested in the EPIC cohort including 36,415 adults from Denmark, Germany, Italy, the Netherlands, Spain, Sweden, and the UK. Socio-demographic, lifestyle factors and usual dietary intake were assessed at time of recruitment (1992 - 2000) using country-specific validated questionnaires. Consumption of UPF was expressed in percentage of grams per day. CVD cases ascertainment varied across EPIC centres and included hospital admissions, linkage to registers, self-report and mortality data. Proportion of missing values ranged from 0.95% for smoking status to 14.2% for history of diabetes. We performed multiple imputation on all covariates with missing values. Cox proportional hazard models with age as the underlying time variable stratified by sex, centre and age were used to test the longitudinal association between UPF consumption and coronary heart disease (CHD) and stroke incidence adjusted for confounders. We applied prentice weights to our cox proportional hazard models to account for the case-cohort design. Results: The mean contribution of UPF to the overall diet in grams was 14.2% in men and 12.8% in women. After a median follow-up time of 9.7 years, it was documented 11,973 non-fatal and 2,281 fatal CHD events, and 6,765 non-fatal and 899 fatal stroke events. In models adjusted for education, smoking, physical activity, body mass index, height, diabetes, high blood pressure, alcohol, energy, and sodium intake, and the Mediterranean diet score, each 10% increase in the consumption of grams from UPF was associated with an increased risk of non-fatal CHD (HR 1.13, 95%CI 1.02 - 1.26), fatal CHD (HR 1.33, 95%CI 1.09 - 1.62) and fatal stroke (HR 1.40, 95%CI 1.07 - 1.85), but not with non-fatal stroke (HR 1.11, 95%CI 0.98 - 1.24). Complete-case analysis showed similar results. Conclusion: In this large prospective cross-European study we found that higher proportion of UPF in the diet was associated with an increased risk of non-fatal CHD and fatal CHD and stroke. These findings corroborate other large-scale cohort studies indicating that the increasing consumption of ultra-processed intake may contribute to higher CVD incidence.

Continuing Medical Education Questions: April 2023.

Article Title: Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition.

Abstract 10476: Impact of C-Reactive Protein Levels on Lipoprotein(a)-Associated Coronary Artery Disease and Aortic Stenosis Risk in Apparently Healthy Individuals

Introduction: Elevated Lipoprotein(a) (Lp[a]) levels are strongly and linearly associated with coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies in primary and secondary prevention settings revealed that Lp(a) and other CAD risk factors such as C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS risk is unknown. Methods: We investigated the long-term associations of Lp(a) with CAD and CAVS according to CRP levels in the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk study. Lp(a) and CRP levels were measured in 18,459 participants who were followed for 20 years. During the follow-up, 3915 and 418 participants had incident CAD and CAVS, respectively. Results: As presented in Figure 1, in comparison to individuals with low Lp(a) levels (<30 mg/dL) and low CRP levels (<2.0 mg/dL), those with elevated Lp(a) (>30 mg/dL) and low CRP levels (<2.0 mg/dL) and those with elevated Lp(a) (>30 mg/dL) and elevated CRP levels (>2.0 mg/dL) had a higher CAD risk (hazard ratio [HR] = 1.38 [95% CI, 1.28-1.49] and 1.93 [95% CI, 1.74-2.13] , respectively), and a higher CAVS risk (HR = 1.46 [95% CI, 1.08-1.98] and 1.87 [95% CI, 1.40-2.49], respectively). Conclusions: Results of this study confirm the joint association of high Lp(a) and CRP levels on incident CAD and extend these joint associations to valvular diseases such as CAVS. Lowering Lp(a) levels may warrant further investigation in the prevention of CAD and CAVS, especially in the context of systemic inflammation.

Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition.

We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort. We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile. Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

Retinol and Retinol Binding Protein 4 Levels and Cardiometabolic Disease Risk.

Background:Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function.Methods:We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data.Results:The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVD<0.001; P interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratioper SD [95% CI]: CVD, 0.71 [0.56–0.90]; T2D, 0.81 [0.70–0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06–1.64]; T2D, 1.15 [0.98–1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers’ interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III.Conclusions:Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk.

Association of Accelerometer-Measured Sedentary Accumulation Patterns With Incident Cardiovascular Disease, Cancer, and All-Cause Mortality.

BackgroundEmerging evidence suggests accruing sedentary behavior (SB) in relatively more prolonged periods may convey additional cardiometabolic risks, but few studies have examined prospective outcomes. We examined the association of SB accumulation patterns with incident cardiovascular disease (CVD), cancer, and all‐cause mortality (ACM).Methods and ResultsData were from 7671 EPIC‐Norfolk (European Prospective Investigation Into Cancer and Nutrition–Norfolk) cohort middle‐ to older‐aged adults who wore accelerometers on the right hip for 4 to 7 days. Cox proportional hazards regression modeled associations between 2 measures of SB accumulation and incident CVD, cancer, and ACM. These were usual SB bout duration (the midpoint of each individual’s SB accumulation curve, fitted using nonlinear regression) and alpha (hybrid measure of bout frequency and duration, with higher values indicating relatively shorter bouts and fewer long bouts). Models were adjusted for potential confounders, then further for 24‐hour time‐use compositions. During mean follow‐up time of 6.4 years, 339 ACM, 1106 CVD, and 516 cancer events occurred. Elevated rates of incident cancer and ACM were seen with more prolonged SB accumulation (lower alpha, higher usual SB bout duration) but not CVD. For usual SB bout duration and alpha, respectively, the confounder‐adjusted hazard ratios per SD of the exposure were 1.12 (95% CI, 1.02–1.23) and 0.88 (95% CI, 0.79–0.98) with incident cancer and 1.16 (95% CI, 1.07–1.26) and 0.80 (95% CI, 0.72–0.89) with ACM (all P<0.05). Further adjustment for 24‐hour time use weakened associations with ACM for usual bout duration (hazard ratio, 1.06; 95% CI, 0.97–1.16; P=0.209) and partially for alpha (hazard ratio, 0.87; 95% CI, 0.77–0.99; P=0.029).ConclusionsAccruing SB in longer bout durations was associated with higher rates of incident cancer and ACM but not with incident CVD, with some evidence of direct SB accumulation effects independent of 24‐hour time use. Findings provide some support for considering SB accumulation as an adjunct target of messaging to “sit less and move more.”

Plasma Industrial and Ruminant Trans Fatty Acids and Incident Type 2 Diabetes in the EPIC-Potsdam Cohort

OBJECTIVEAlthough dietary intake of trans fatty acid (TFA) is a major public health concern because of the associated increase in the risk of cardiovascular events, it remains unclear whether TFAs also influence risk of type 2 diabetes (T2D) and whether industrial TFAs (iTFAs) and ruminant TFAs (rTFAs) exert the same effect on health.RESEARCH DESIGN AND METHODSTo investigate the relationship of 7 rTFAs and iTFAs, including 2 conjugated linoleic acids (CLAs), plasma phospholipid TFAs were measured in a case-cohort study nested within the European Prospective Investigation Into Cancer and Nutrition–Potsdam cohort. The analytical sample was a random subsample (n = 1,248) and incident cases of T2D (n = 801) over a median follow-up of 6.5 years. Using multivariable Cox regression models, we examined associations of TFAs with incident T2D.RESULTSThe TFA subtypes were intercorrelated with each other, with other fatty acids, and with different food sources. After controlling for other TFAs, the iTFAs (18:1n-6t, 18:1n-9t, 18:2n-6,9t) were not associated with diabetes risk. Some rTFA subtypes were inversely associated with diabetes risk: vaccenic acid (18:1n-7t; hazard ratio [HR] per SD 0.72; 95% CI 0.58–0.89) and t10c12-CLA (HR per SD 0.81; 95% CI 0.70–0.94), whereas c9t11-CLA was positively associated (HR per SD 1.39; 95% CI 1.19–1.62). Trans-palmitoleic acid (16:1n-7t) was not associated with diabetes risk when adjusting for the other TFAs (HR per SD 1.08; 95% CI 0.88–1.31).CONCLUSIONSThe TFAs’ conformation plays an essential role in their relationship to diabetes risk. rTFA subtypes may have opposing relationships to diabetes risk. Previous observations for reduced diabetes risk with higher levels of circulating trans-palmitoleic acid are likely due to confounding.

Positive Associations of Dietary Intake and Plasma Concentrations of Vitamin E with Skeletal Muscle Mass, Heel Bone Ultrasound Attenuation and Fracture Risk in the EPIC-Norfolk Cohort.

The prevalence of sarcopenia, frailty and fractures is increasing. Prevention options are limited, but dietary factors including vitamin E have the potential to confer some protection. This study investigated cross-sectional associations between dietary and plasma concentrations of vitamin E with indices of skeletal muscle mass (SMM) (n = 14,179 and 4283, respectively) and bone density (n = 14,694 and 4457, respectively) and longitudinal fracture risk (n = 25,223 and 7291, respectively) in European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk participants, aged 39–79 years at baseline. Participants completed a health and lifestyle questionnaire, a 7-day diet diary (7dDD) and had anthropometric measurements taken. Fat-free mass (as a SMM proxy) was measured using bioimpedance and bone density was measured using calcaneal broadband ultrasound attenuation (BUA) and incident fractures over 18.5 years of follow-up. Associations between indices of SMM, BUA and fracture risk were investigated by quintiles of dietary vitamin E intake or plasma concentrations. Positive trends in SMM indices and BUA were apparent across dietary quintiles for both sexes, with interquintile differences of 0.88–1.91% (p < 0.001), and protective trends for total and hip fracture risk. Circulating plasma α- and γ-tocopherol results matched the overall dietary findings. Dietary vitamin E may be important for musculoskeletal health but further investigation is required to fully understand the relationships of plasma tocopherols.

Plasma Sulfur Amino Acids and Risk of Cerebrovascular Diseases: A Nested Case-Control Study in the EPIC-Norfolk Cohort.

B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular diseases. Nested within the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk cohort, we established a case-control study with 480 incident cases of cerebrovascular diseases and 480 controls matched by age, sex, and year of baseline examination (1993-1997). Using baseline plasma samples, we assayed sulfur-containing compounds including methionine, homocysteine, cystathionine, cysteine, glutathione, and taurine with liquid chromatography-tandem mass spectrometry. We examined the association of concentrations of each of the compounds and the ratio of methionine to homocysteine (representing activity of one-carbon metabolism) with risk of incident cerebrovascular diseases, adjusted for potential confounders. Plasma methionine and the methionine/homocysteine ratio were inversely associated with risk of cerebrovascular diseases, with odds ratios per 1 SD of 0.83 (95% CI, 0.72-0.96) and 0.82 (95% CI, 0.71-0.95), respectively. The association of methionine remained significant after adjustment for homocysteine. None of the other examined compounds was significantly associated with incident cerebrovascular diseases. These findings suggest that greater availability of methionine, an essential amino acid, may play a role in the prevention of cerebrovascular diseases and explain the previously recognized link between elevated homocysteine and stroke. Further research is needed to determine causation and the potential of circulating methionine as a target in cerebrovascular disease prevention.

Opposing Associations of NT-proBNP With Risks of Diabetes and Diabetes-Related Complications.

OBJECTIVECirculating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a classic diagnostic and prognostic marker for heart failure. However, it is inversely associated with diabetes risk. We aimed to investigate relationships of NT-proBNP with risk of diabetes-related complications in initially healthy individuals.RESEARCH DESIGN AND METHODSWe performed a case-cohort study within the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort including a random subcohort (n = 1,294) and incident cases of type 2 diabetes (n = 649) and cardiovascular diseases (n = 478). Incident cases of type 2 diabetes (n = 545) were followed up for microvascular (n = 133) and macrovascular (n = 50) complications. Plasma NT-proBNP was measured at baseline in initially healthy participants.RESULTSIn multivariable models, NT-proBNP was linearly inversely associated with incident type 2 diabetes with a hazard ratio (HR) (95% CI) per doubling in NT-proBNP of 0.91 (0.86, 0.98). The association was only observable in women (0.80 [0.72, 0.90]) compared with men (0.98 [0.91, 1.07]). Among people with incident diabetes, NT-proBNP was positively associated with diabetes complications: overall, 1.31 (1.13, 1.53); microvascular complications, 1.20 (1.01, 1.43); and macrovascular complications, 1.37 (1.03, 1.83).CONCLUSIONSAlthough higher NT-proBNP levels are associated with lower diabetes risk, NT-proBNP is a biomarker for vascular complications in people who develop diabetes independent of potential confounders. Thus, NT-proBNP might be informative to monitor risk for diabetes-related microvascular and macrovascular complications, which should be further explored in future prospective studies.

Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease–Free Survival, and Mortality Risk

Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial. To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk. In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the LPA locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019. Genetically determined and measured Lp(a) levels. Parental life span, health span, and all-cause mortality. In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between LPA single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]). The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels.

Chili Pepper Consumption and Mortality in Italian Adults

BackgroundChili pepper is a usual part of a traditional Mediterranean diet. Yet epidemiological data on the association between chili pepper intake and mortality risk are scarce, with a lack of studies from Mediterranean populations. ObjectivesThis study sought to examine the association between chili pepper consumption and risk of death in a large sample of the adult Italian general population, and to account for biological mediators of the association. MethodsLongitudinal analysis was performed on 22,811 men and women enrolled in the Moli-sani Study cohort (2005 to 2010). Chili pepper intake was estimated by the EPIC (European Prospective Investigation Into Cancer) Food Frequency Questionnaire and categorized as none/rare consumption, up to 2 times/week, >2 to ≤4 times/week, and >4 times/week. ResultsOver a median follow-up of 8.2 years, a total of 1,236 deaths were ascertained. Multivariable hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality among participants in the regular (>4 times/week) relative to none/rare intake were 0.77 (95% confidence interval [CI]: 0.66 to 0.90) and 0.66 (95% CI: 0.50 to 0.86), respectively. Regular intake was also inversely associated with ischemic heart disease (HR: 0.56; 95% CI: 0.35 to 0.87) and cerebrovascular (HR: 0.39; 95% CI: 0.20 to 0.75) death risks. The association of chili pepper consumption with total mortality appeared to be stronger in hypertension-free individuals (p for interaction = 0.021). Among known biomarkers of CVD, only serum vitamin D marginally accounted for such associations. ConclusionsIn a large adult Mediterranean population, regular consumption of chili pepper is associated with a lower risk of total and CVD death independent of CVD risk factors or adherence to a Mediterranean diet. Known biomarkers of CVD risk only marginally mediate the association of chili pepper intake with mortality.

Individualized Prediction of Follicular Lymphoma Risk Using a Combination of Blood t(14;18) Frequency Years before Diagnosis and a Polygenic Risk Score (PRS) of 9 SNPs Associated with Follicular Lymphoma Susceptibility

Introduction: The risk of developing a follicular lymphoma (FL) begins to be better understood with the identification in large epidemiological studies of familial predisposition, some occupational exposures and genetic factors. Genome wide-association studies (GWAS) identified constitutional single nucleotide polymorphisms (SNPs) at risk of FL in HLA region (rs12195582), in 11q23.3 (near CXCR5), in 11q24.3 (near ETS1), in 3q28 (near LPP), in 18q21.33 (near BCL2), and 8q24 (near PVT1); three suggestive loci are localized at 17q25.3 (near CYBC1), 3q13.33 (CD86), 18q12.3 (SLC14A2) (Skibola, Am J Hum Genet. 2014). High t(14;18) frequency in blood years before diagnosis from healthy individuals was also defined as a predictive biomarker for FL (Roulland, J Clin Oncol 2014). It is currently unknown whether any relationship exists between inherited genetic variants associated with FL susceptibility and t(14;18) frequency and if the combination of the two biomarkers could be useful for a better stratification of risk of FL development in healthy individuals. Methods: We used quantitative PCR assays to estimate t(14;18) frequency in prediagnostic blood samples from 105 individuals that were obtained on average 6.4 years before FL diagnosis (pre-FL group) together with 236 age and gender-matched individuals (control group) that were issued from the participants in the EPIC cohort ( European Prospective Investigation Into Cancer and Nutrition). Constitutional DNA was analyzed for the genotyping of the nine SNPs associated with FL risk (HLA, rs12195582; CXCR5, rs4938573; ETS1, rs4937362; LPP, rs6444305; BCL2, rs17749561; PVT1, rs13254990; CYBC1, rs3751913; CD86, rs2681416; SLC14A2, rs11082438). Genotyping were performed in duplicate using TaqMan® assays on Fluidigm platform. The nine SNPs were analyzed individually and combined in a polygenic risk score (PRS). PRS is a weighted average of the number of risk alleles with the weights being the log of the odds-ratio (OR) reported in the FL GWAS (Skibola, Am J Hum Genet. 2014). A model for FL risk was developed using multivariable logistic regression. Predictive ability was assessed by area under Receiver Operating Characteristic (ROC) curve, with 10-fold cross-validation. This work is supported by the French NCI (INCA, PRT-K16-167). Results: t(14;18) frequency as a log-transformed continuous variable is predictive of FL risk (OR: 1.50; 95%CI: 1.29-1.78, P&lt;0.001); PRS is also strongly associated with FL risk (OR: 3.31; 95%CI: 2.01-5.62, P&lt;0.001). Age at screening (OR: 0.98; 95%CI: 0.95-1.01, P=0.24) did not influence FL risk. A weak but statistically significant correlation between t(14; 18) frequency and PRS was observed (Pearson correlation=0.18, P=0.002). In multivariable analysis, both PRS (OR: 2.84, 95%CI: 1.66-4.99, P&lt;0.001) and t(14;18) frequency (OR: 1.45, 95%CI: 1.18-1.84, P&lt;0.001) remained statistically significant. No departure from log-linear effect was observed in the modeling nor statistical interaction between PRS and log-transformed t(14;18), confirming that t(14; 18) frequency and genetic markers (PRS) were two independent factors of FL risk. Sensitivity analyses showed that these results were not influenced by the delay between the date of the screening and the FL diagnosis. Combining t(14;18) frequency and the PRS in a prediction model allowed the identification of some individuals at very high risk of developing FL and a shiny web application was developed to provide an easy-to-use tool to obtain individualized risk predictions for new patients (Figure). Area under ROC curve (AUC) showed that the model that integrated t(14;18) frequency and PRS (AUC: 0.69, 95%CI: 0.62-0.76) had a better prediction of FL risk than t(14;18) frequency (AUC: 0.62, 95%CI: 0.55-0.70) and PRS alone (AUC: 0.68, 95%CI: 0.61-0.75). Conclusions: Genetic variants combined in PRS and t(14;18) frequency allowed the identification of individuals at high-risk of FL development and provided a better way, when these two biomarkers were combined, to discriminate healthy individuals from pre-FL cases many years before malignant transformation. These findings could be used for screening test of populations with some environmental exposures positively associated with FL development in epidemiological studies and may contribute in the future to monitoring or early intervention. Figure Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria.

ApoB/apoA-I Ratio and Lp(a) Associations With Aortic Valve Stenosis Incidence: Insights From the EPIC-Norfolk Prospective Population Study.

BackgroundApolipoprotein B/apolipoprotein A‐I (apoB/apoA‐I) ratio and lipoprotein(a) (Lp[a]) are associated with aortic valve stenosis (AVS) disease progression. Clinical characteristics such as age, sex, and presence of concomitant coronary artery disease may strongly modify these associations; however, these effects have not been well defined in longitudinal studies. We set out to assess these associations between apoB/apoA‐I ratio, Lp(a), and AVS incidence in a large population study.Methods and ResultsWe analyzed data from 17 745 participants (mean age, 59.2±9.1 years; men, 44.9%) in the EPIC‐Norfolk (European Prospective Investigation Into Cancer in Norfolk Prospective Population Study) population study in whom apoB/apoA‐I and Lp(a) levels were measured. Participants were identified as having incident AVS if they were hospitalized or died with AVS as an underlying cause. After a median follow‐up of 19.8 years (17.9–21.0 years) there were 403 (2.2%) incident cases of AVS. The hazard ratio for AVS risk was 1.30 (95% CI, 1.19–1.41; P<0.001) per SD increase in apoB/apoA‐I. Adjusting for age, sex, and coronary artery disease, there was no significant association between apoB/apoA‐I and AVS incidence (hazard ratio, 1.06; 95% CI, 0.97–1.17 [P=0.215]). Elevated Lp(a) (>50 mg/dL) remained an independent risk factor for AVS after adjustment for age, sex, low‐density lipoprotein cholesterol, and concomitant coronary artery disease (hazard ratio, 1.70; 95% CI, 1.33–2.19 [P<0.001]).ConclusionsIn this population study, apoB/apoA‐I ratio was associated with risk of AVS incidence, especially in younger and female participants and those without concomitant coronary artery disease. Lp(a) was an independent risk factor for AVS incidence. Interventional trials are needed to investigate whether modulating apoB/apoA‐I or lowering Lp(a) can prevent or slow down AVS.

Risk for Heart Failure: The Opportunity for Prevention With the American Heart Association’s Life’s Simple 7

ObjectivesThe aim of this study is to determine whether combinations of specific Life’s Simple 7 (LS7) components are associated with reduced risk for heart failure (HF). BackgroundThe American Heart Association recommends the concept of LS7: healthy behaviors that have been shown to reduce cardiovascular disease. MethodsA total of 37,803 participants from the EPIC-NL (European Prospective Investigation Into Cancer and Nutrition–Netherlands) cohort were included (mean age: 49.4 ± 11.9 years, 74.7% women). The LS7 score ranged from 0 to 14 and was calculated by assigning 0, 1, or 2 points for smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose. An overall ideal score (11 to 14 points) was present in 23.2% of participants, an intermediate score (9 or 10 points) in 35.3%, and an inadequate score (0 to 8 points) in 41.5%. ResultsOver a median follow-up period of 15.2 years (interquartile range: 14.1 to 16.5 years), 690 participants (1.8%) developed HF. In Cox proportional hazards models, ideal and intermediate LS7 scores were associated with reduced risk for HF compared with the inadequate category (hazard ratio: 0.45 [95% confidence interval (CI): 0.34 to 0.60] and hazard ratio: 0.53 [95% CI: 0.44 to 0.64], respectively). Our analyses show that combinations with specific LS7 components, notably glucose, body mass index, smoking, and blood pressure, are associated with a lower incidence of HF. ConclusionsA healthy lifestyle, as reflected in an ideal LS7 score, was associated with a 55% lower risk for HF compared with an inadequate LS7 score. Preventive strategies that target combinations of specific LS7 components could have a significant impact on decreasing incident HF in the population at large.

Consumption of Meat, Fish, Dairy Products, and Eggs and Risk of Ischemic Heart Disease.

There is uncertainty about the relevance of animal foods to the pathogenesis of ischemic heart disease (IHD). We examined meat, fish, dairy products, and eggs and risk for IHD in the pan-European EPIC cohort (European Prospective Investigation Into Cancer and Nutrition). In this prospective study of 409 885 men and women in 9 European countries, diet was assessed with validated questionnaires and calibrated with 24-hour recalls. Lipids and blood pressure were measured in a subsample. During a mean of 12.6 years of follow-up, 7198 participants had a myocardial infarction or died of IHD. The relationships of animal foods with risk were examined with Cox regression with adjustment for other animal foods and relevant covariates. The hazard ratio (HR) for IHD was 1.19 (95% CI, 1.06-1.33) for a 100-g/d increment in intake of red and processed meat, and this remained significant after exclusion of the first 4 years of follow-up (HR, 1.25 [95% CI, 1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR, 0.93 [95% CI, 0.89-0.98] per 100-g/d increment), cheese (HR, 0.92 [95% CI, 0.86-0.98] per 30-g/d increment), and eggs (HR, 0.93 [95% CI, 0.88-0.99] per 20-g/d increment); the associations with yogurt and eggs were attenuated and nonsignificant after exclusion of the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish, or milk. In analyses modeling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese, or eggs was associated with ≈20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-high-density lipoprotein cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-high-density lipoprotein cholesterol. Risk for IHD was positively associated with consumption of red and processed meat and inversely associated with consumption of yogurt, cheese, and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-high-density lipoprotein cholesterol and for red and processed meat with systolic blood pressure, which could mediate such effects.

Association of Chemerin Plasma Concentration With Risk of Colorectal Cancer

Inflammatory processes have been suggested to have an important role in colorectal cancer (CRC) etiology. Chemerin is a recently discovered inflammatory biomarker thought to exert chemotactic, adipogenic, and angiogenic functions. However, its potential link with CRC has not been sufficiently explored. To evaluate the prospective association of circulating plasma chemerin concentrations with incident CRC. Prospective case-cohort study based on 27 548 initially healthy participants from the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort who were followed for up to 16 years. Baseline study information and samples were collected between August 23, 1994, and September 25, 1998. Recruitment was according to random registry sampling from the geographical area of Potsdam, Germany, and surrounding municipalities. The last date of study follow-up was May 10, 2010. Statistical analysis was conducted in 2018. Incident CRC, colon cancer, and rectal cancer. Baseline chemerin plasma concentrations were measured by enzyme-linked immunosorbent assay. A random subcohort of 221 incident CRC cases and 2329 participants free of CRC with available blood sample measurements were included in the analysis. The participants' mean (SD) age was 50 (9) years, 62.1% were female, and 16.5% had a body mass index greater than 30. In multivariable-adjusted Cox proportional hazards regression models taking into account established CRC risk factors, higher chemerin concentrations were associated with a greater risk of CRC, with a hazard ratio (HR) of 1.81 (95% CI, 1.08-3.05; P for trend = .007) for the highest chemerin quartile vs the lowest. Analyses by cancer subsite indicated a stronger association with colon cancer (HR, 2.27; 95% CI, 1.18-4.34 for the highest quartile vs the lowest; P for trend = .005) compared with rectal cancer (HR, 1.27; 95% CI, 0.57-2.85; P for trend = .35). The association was particularly strong for proximal colon cancer (HR, 3.97; 95% CI, 1.51-10.50; P for trend = .001). This study found that the association between chemerin concentration and the risk of incident CRC was linear and independent of established CRC risk factors. Further studies are warranted to evaluate chemerin as a novel immune-inflammatory agent in colorectal carcinogenesis.