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Background Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function. Objectives We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk. Methods We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics. Results Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n–6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: −0.12, −0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n–3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n–3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex. Conclusions Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention. [ABSTRACT FROM AUTHOR]

Background Flavonoid intake modifies the composition of the gut microbiome, which contributes to the metabolism of flavonoids. Few studies have examined the contribution of the gut microbiome to the health benefits associated with flavonoid intake. Objectives We aimed to examine associations between habitual intakes of flavonoid subclasses and MRI-determined visceral (VAT) and subcutaneous (SAT) adipose tissue. Uniquely, we also identified associations between the aforementioned measurements and gut microbiome composition sequenced from 16S ribosomal RNA genes. Methods We undertook cross-sectional analyses of 618 men and women (n  = 368 male), aged 25–83 y, from the PopGen cohort. Results Higher intake of anthocyanins was associated with lower amounts of VAT [tertile (T)3-T1:  −0.49 dm3; β: −8.9%; 95% CI: −16.2%, −1.1%; P  = 0.03] and VAT:SAT ratio (T3-T1: −0.04; β: −7.1%; 95% CI: −13.5%, −0.3%; P  = 0.03). Higher intakes of anthocyanin-rich foods were also inversely associated with VAT [quantile (Q)4-Q1: −0.39 dm3; β: −9.9%; 95% CI: −17.4%, −1.6%; P  = 0.02] and VAT:SAT ratio (Q4-Q1: −0.04; β: −6.5%; 95% CI: −13.3%, −0.9%; P  = 0.03). Participants with the highest intakes of anthocyanin-rich foods also had higher microbial diversity (Q4-Q1: β: 0.18; 95% CI: 0.06, 0.31; P  < 0.01), higher abundances of Clostridiales (Q4-Q1: β: 449; 95% CI: 96.3, 801; P  = 0.04) and Ruminococcaceae (Q4-Q1: β: 313; 95% CI: 33.6, 591; P  = 0.04), and lower abundance of Clostridium XIVa (Q4-Q1: β: −41.1; 95% CI: −72.4, −9.8; P  = 0.04). Participants with the highest microbial diversity, abundances of Clostridiales and Ruminococcaceae, and lower abundance of Clostridium XIVa had lower amounts of VAT. Up to 18.5% of the association between intake of anthocyanin-rich foods and VAT could be explained by the gut microbiome. Conclusions These novel data suggest that higher microbial diversity and abundance of specific taxa in the Clostridiales order may contribute to the association between higher intake of anthocyanins and lower abdominal adipose tissue. [ABSTRACT FROM AUTHOR]

Background It is unknown whether dietary quality modifies genetic association with body mass index (BMI). Objective This study examined whether dietary quality modifies genetic association with BMI. Design We calculated 3 diet quality scores including the Alternative Healthy Eating Index 2010 (AHEI-2010), the Alternative Mediterranean Diet score (AMED), and the Dietary Approach to Stop Hypertension (DASH) diet score. We examined the interactions of a genetic risk score (GRS) based on 97 BMI-associated variants with the 3 diet quality scores on BMI in 30,904 participants from 3 large cohorts. Results We found significant interactions between total GRS and all 3 diet scores on BMI assessed after 2-3 y, with an attenuated genetic effect observed in individuals with healthier diets (AHEI: P-interaction = 0.003; AMED: P = 0.001; DASH: P = 0.004). For example, the difference in BMI (kg/m²) per 10-unit increment of the GRS was smaller among participants in the highest tertile of AHEI score compared with those in the lowest tertile (0.84; 95% CI: 0.72, 0.96 compared with 1.14; 95% CI: 0.99, 1.29). Results were consistent across the 3 cohorts with no significant heterogeneity. The interactions with diet scores on BMI appeared more significant for central nervous system GRSs (P < 0.01 for 3 diet scores) than for non-central nervous system GRSs (P > 0.05 for 3 diet scores). Conclusions A higher diet quality attenuated genetic predisposition to obesity. These findings underscore the importance of maintaining a healthful diet for the prevention of obesity, particularly for those individuals with a strong genetic predisposition to obesity. This trial was registered with the Clinical Trial Registry as NCT03577639. [ABSTRACT FROM AUTHOR]

Introduction: Previous cohort studies have reported relationships of active commuting, walking, and cycling with mortality. No studies have separately examined commuter and recreational cycling and how changes in cycling are related to mortality.Methods: Prospective cohort study among individuals who were between 50 and 65years and living in Denmark at the baseline examination between 1993 and 1997. Commuter/recreational cycling and changes in cycling were investigated in analytic samples of 28,204 and 15,272 participants, respectively. Participants were asked to provide information on cycling habits and other risk factors for mortality at baseline and 5years later and were followed for risk of death until July 2013. Data were analyzed in 2018.Results: Cycling between 1 and 60 minutes per week was associated with lower risk of all-cause mortality, with an appertaining multivariable adjusted hazard ratio of 0.76 (95% CI=0.69, 0.83) for recreational cycling and 0.78 (95% CI=0.63, 0.96) for commuter cycling when compared with no cycling. Compared with those who never cycled, the hazard ratio for those who initiated cycling was 0.78 (95% CI=0.67, 0.90) and the hazard ratio for those who consistently cycled was 0.77 (95% CI=0.71, 0.84), whereas the hazard ratio for those who stopped cycling was 0.98 (95% CI=0.87, 1.11).Conclusions: Initiation of, or continued engagement in, cycling late in mid-life is associated with a lower risk of all-cause mortality. It may be suggested that national and local governments prioritize resources to promote cycling. [ABSTRACT FROM AUTHOR]

Background: Polyunsaturated fatty acids (PUFAs) are associated with a lower risk of multiple diseases. Fatty acid desaturase 1 gene (FADSl) polymorphisms and dietary PUFA intake are both established determinants of circulating PUFA proportions. Objective: We explored the joint effects of FADSl polymorphisms and dietary PUFA intake on circulating PUFA proportions. Design: We studied 2288 participants from a nested case-control study of coronary artery disease among participants who provided blood samples in the Nurses' Health Study and the Health Professionals Follow-Up Study. Dietary PUFA intake was obtained from semiquantitative food-frequency questionnaires. FADSl rs174546 was genotyped by using the Affymetrix 6.0 platform, and circulating PUFA proportions were measured with gas-liquid chromatography. Linear regression models were used to examine the associations between rs174546 and circulating proportions of each fatty acid. Gene-diet interactions were tested by including a cross-product term of dietary intake of each PUFA by rs174546 genotype in the linear regression models. Results: After adjustment for sex and ancestry, each copy of the C allele of rs174546 was associated with higher circulating pro-portions of arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and lower proportions of linoleic acid and a-linolenic acid. The magnitude of positive association between higher consumption of dietary EPA or DHA and circulating pro-portions of EPA increased with each copy of the rs174546_T allele (P-interaction = 0.01 and 0.007, respectively). Each 1-SD increment in EPA intake was associated with an average 3.7% increase in circulating EPA proportions among participants with the rs174546_CC genotype and an average 7.8% increase among participants with the TT genotype. Conclusions: Carriers of the T allele at FADSl rs174546 may need higher doses of dietary EPA and DHA to achieve the same circulating proportions of EPA as carriers of the C allele. The implications of these findings on disease risk and dietary guidelines require further study. [ABSTRACT FROM AUTHOR]

Alcohol consumption increases circulating high-density lipoprotein cholesterol (HDL-C), but HDL protein cargo may better reflect HDL function. This study examined the associations between alcohol intake and HDL subspecies containing or lacking apoC3, apoE, and apoJ in a well-phenotyped cohort. We performed a cross-sectional analysis of 2092 Cardiovascular Health Study participants aged 70 or older with HDL subspecies measured in stored specimens from 1998 to 1999. Associations between alcohol intake and apoA1 defined HDL subspecies lacking or containing apoC3, apoE, and apoJ, and circulating levels of total apoA1, apoC3, apoE, and apoJ were examined. HDL subspecies lacking and containing apoC3, apoE, and apoJ were all positively associated with alcohol intake, with ∼1% per additional drink per week or ∼7% per additional drink per day (subspecies without the apolipoproteins, P ≤ 2 × 10-9, subspecies with the apolipoproteins, P ≤ 3 × 10-5). Total apoA1 was also directly associated with alcohol consumption, with a 1% increase per additional drink per week (P = 1 × 10-14). Total apoC3 blood levels were 0.5% higher per additional drink per week (P = 0.01), but the association was driven by a few heavily drinking men. Alcohol intake was positively associated with HDL subspecies lacking and containing apoC3, apoE, or apoJ, and with total plasma apoA1. ApoC3 was directly, albeit not as robustly associated with alcohol intake. HDL protein cargo is crucial for its anti-atherosclerotic functions, but it remains to be determined whether HDL subspecies play a role in the putative association between limited alcohol intake and lower risk of coronary heart disease. [ABSTRACT FROM AUTHOR]

Introduction Production of very low-density lipoprotein (VLDL) is increased in states of metabolic syndrome, leading to hypertriglyceridemia. However, metabolic syndrome is often associated with non-alcoholic fatty liver disease, which leads to liver fibrosis and inflammation that may decrease VLDL production. In this study, we aim to determine the interactive impact on VLDL profiles from insulin resistance, impairment in liver synthetic function and inflammation. Methods We examined cross-sectional associations of insulin sensitivity, inflammation, and liver synthetic function with VLDL particle (VLDL-P) concentration and size among 1,850 older adults in the Cardiovascular Health Study. Results Indices for high insulin sensitivity and low liver synthetic function were associated with lower concentrations of VLDL-P. In addition, insulin resistance preferentially increased concentration of large VLDL and was associated with mean VLDL size. Indices for inflammation however demonstrated a nonlinear relationship with both VLDL-P concentration and VLDL size. When mutually adjusted, one standard deviation (SD) increment in Matsuda index and C-reactive protein (CRP) were associated with 4.9 nmol/L (− 8.2 to − 1.5, p = 0.005) and 6.3 nmol/L (− 11.0 to − 1.6, p = 0.009) lower VLDL-P concentration respectively. In contrast, one-SD increment in factor VII, a marker for liver synthetic function, was associated with 16.9 nmol/L (12.6–21.2, p < 0.001) higher VLDL-P concentration. Furthermore, a one-SD increment in the Matsuda index was associated with 1.1 nm (− 2.0 to − 0.3, p = 0.006) smaller mean VLDL size, whereas CRP and factor VII were not associated with VLDL size. Conclusion Insulin sensitivity, inflammation and markers for liver synthetic function differentially impact VLDL-P concentration and VLDL size. These results underscore the complex effects of insulin resistance and its complications on VLDL production. [ABSTRACT FROM AUTHOR]

Background: Research targeting glycosylated hemoglobin A1c (HbA1c) to <6.5% to prevent coronary heart disease (CHD) events has conflicting results. We previously observed the haptoglobin (Hp) Hp2-2 genotype is associated with a ∼10-fold increased CHD risk among individuals with HbA1c ≥6.5%, and thus might be useful in identifying those at high risk of CHD who would benefit from maintaining HbA1c <6.5%.Objectives: This study sought to model whether HbA1c ≥ 6.5% in the Hp2-2 genotype is associated with CHD in a prospective case-control study nested within the Health Professionals Follow-Up Study (HPFS).Methods: HbA1c concentration and Hp genotype were determined for 695 incident cases of CHD from 1994 to 2010 and matched control participants. Logistic regression models calculated relative risk (RR) and 95% CI, for the first and second halves of follow-up, adjusting for confounding variables. A dataset from the Nurses' Health Study served as a replication cohort.Results: The prevalence of the Hp2-2 genotype in HPFS was 39%. Compared with HbA1c <6.5%, the RR of CHD for HbA1c ≥6.5% for the Hp2-2 genotype over full follow-up was 3.07 (95% CI: 1.37 to 6.86) to 3.88 (95% CI: 1.31 to 11.52) during the first half of follow-up and 2.16 (95% CI: 0.61 to 7.61) in the second half. The corresponding RRs for the Hp1-1 + Hp2-1 genotypes were: full follow-up, 2.19 (95% CI: 1.14 to 4.24); first half, 1.60 (95% CI: 0.73 to 3.53); and second half, 4.72 (95% CI: 1.26 to 17.65).Conclusions: In 2 independent cohorts, the risk of CHD associated with HbA1c ≥6.5% is pronounced in the Hp2-2 genotype, particularly in early cases. The Hp2-2 genotype may identify individuals at greatest CHD risk from hyperglycemia. [ABSTRACT FROM AUTHOR]

Background: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health. Objective: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers. Design: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts. Results: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 x 10-15), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 x 10-6) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 x 10-5). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans. Conclusions: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Inflammation is a risk factor for coronary heart disease (CHD). A common deletion-allele in the promoter region of NFKB1 results in lower protein levels of the NF-κB p50 subunit. Recent evidence suggests that the NF-κB p50 dimer has anti-inflammatory effects. We aimed to investigate the association of the functional ATTG NFKB1 insertion/deletion variant with risk of CHD in three independent prospective studies of generally healthy men and women. Methods and results: The NFKB1 ins/del polymorphism was genotyped in studies of CHD nested within the Diet, Cancer and Health (DCH) study, the Health Professionals Follow-up (HPFS) and the Nurses’ Health (NHS) studies, totaling 1008, 428 and 439 cases, respectively. The minor allele frequency in the combined sample was 0.38 among controls. In a pooled analysis, the relative risk (RR) among heterozygous men and women was 1.22 (95% CI: 1.07–1.40), compared to the most common ins/ins genotype. The RR among homozygotes was 1.20 (95% CI: 0.94–1.53). There was no evidence of an allele-dosage effect, and in a dominant model the RR among del-allele carriers was 1.22 (95% CI: 1.07–1.39). The risk was similar in women and men (RR was 1.20 in women and 1.23 in men, respectively). The NFKB1 variant was not associated with plasma lipid levels, but del-carriers had lower levels of C-reactive protein. Conclusions: The NFKB1 promoter variant, previously shown to cause partial depletion of NF-κB p50, was associated with a higher risk of CHD in three independent prospective studies of generally healthy Caucasians. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the predictive value of acute coronary syndrome (ACS) diagnoses, including unstable angina pectoris, myocardial infarction, and cardiac arrest, in the Danish National Patient Registry. Study Design and Setting: We identified all first-time ACS diagnoses in the Danish National Patient Registry among participants in the Danish cohort study “Diet, Cancer and Health” through the end of 2003. We retrieved and reviewed medical records based on current European Society of Cardiology criteria for ACS. Results: We reviewed hospital medical records of 1,577 out of 1,654 patients (95.3%) who had been hospitalized with a first-time ACS diagnosis. The overall positive predictive value for ACS was 65.5% (95% confidence interval [CI]=63.1–67.9%). Stratification by subdiagnosis and hospital department produced significantly higher positive predictive values for myocardial infarction diagnoses (81.9%; 95% CI=79.5–84.2%) and among patients who received an ACS diagnosis in a ward (80.1%; 95% CI=77.7–82.3%). Conclusion: The ACS diagnoses contained in hospital discharge registries should be used with caution. If validation is not possible, restricting analyses to patients with myocardial infarction and/or patients discharged from wards might be a useful alternative. [Copyright &y& Elsevier]

Background: Lipoprotein lipase (LPL) has a prominent role in the metabolism of triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C) and is a potential interesting target for the development of antiatherogenic treatment. To provide deeper insight into the role of natural variation in this gene, we investigated the association between the LPL S447X variant with lipids and risk of coronary heart disease (CHD) in 3 independent, prospective studies. Methods: The S447X variant was genotyped in case-control studies of incident CHD nested within the Nurses'' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Danish Diet, Cancer and Health (DCH) study, totaling 245, 258, and 962 cases, respectively. Results: S447X carriers tended to have lower TG and higher HDL-C concentrations than noncarriers. The S447X variant was associated with a lower risk of CHD in the NHS; the association was weaker in the HPFS and not statistically significant in the DCH women and men. The pooled relative risk per minor allele was 0.74 (0.56-1.00). There was a suggestion that the associations of the S447X variant with plasma lipids and CHD risk were more pronounced in obese individuals in the NHS study, but this finding was not consistent across the studies. Conclusions: The LPL S447X variant tended to be associated with lower TG and higher HDL-C levels, and lower risk of CHD in all 3 cohorts. Lipoprotein lipase is an attractive target for clinical intervention, but studies are needed to clarify whether greater benefit from this variant may be conferred in some subgroups. [Copyright &y& Elsevier]

The article discusses research, titled "Long-Term Dietary Flavonoid Intake and Risk of Alzheimer's Disease and Related Dementias in the Framingham Offspring Cohort," by E. Shishtar, G. T. Rogers, J. B. Blumberg and colleagues, that was published within the issue. Topics covered include risk factors and diseases of old age, potential of flavonoids to reduce the risk of dementia, and flavonoid subclasses such as flavonols, anthocyanins, and flavonoid polymers.

Background: Intake of whole grains is inversely associated with risk of diabetes and ischemic heart disease in observational studies. The lower risk associated with high whole-grain intakes may be mediated through improvements in glycemic control, lipid profiles, or reduced inflammation. Objective: The aim was to examine whether the intake of whole grains, bran, and germ is related to homocysteine, plasma markers of glycemic control (fasting insulin, hemoglobin A1c, C-peptide, and leptin), lipids (total cholesterol, triacylglycerol, HDL cholesterol, and LDL cholesterol), and inflammation (C-reactive protein, fibrinogen, and interleukin 6). Design: This was a cross-sectional study of the relations of whole grains, bran, and germ intakes with homocysteine and markers of glycemic control, lipids, and inflammation in 938 healthy men and women. Results: Whole-grain intake was inversely associated with homocysteine and markers of glycemic control. Compared with participants in the bottom quintile of whole-grain intake, participants in the highest quintile had 17%, 14%, 14%, and 11% lower concentrations of homocysteine (P < 0.01), insulin (P = 0.12), C-peptide (P = 0.03), and leptin (P=0.03), respectively. Inverse associations were also observed with total cholesterol (P = 0.02), HDL cholesterol (P=0.05), andLDLcholesterol (P=0.10). Whole-grain intake was not associated with the markers of inflammation. Whole-grain intake was most strongly inversely associated with markers of glycemic control in this population. Conclusion: The results suggest a lower risk of diabetes and heart disease in persons who consume diets high in whole grains. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested that a daily intake of 3 servings of whole-grain foods is associated with a reduced risk of coronary heart disease (CHD). However, methods for the assessment of whole-grain intake differ. Furthermore, any additional effects of added bran and germ, which are components of whole grains, have not been reported. Objective: The objective was to evaluate the association of wholegrain, bran, and germ intakes (with the use of new quantitative measures) with the incidence of CHD. Design: This was a prospective cohort study of 42 850 male health professionals aged 40-75 y at baseline in 1986 who were free from cardiovascular disease, cancer, and diabetes. Daily whole-grain, bran, and germ intakes were derived in grams per day from a detailed semiquantitative dietary questionnaire. Results: During 14 y of follow-up, we documented 1818 incident cases of CHD. After cardiovascular disease risk factors and the intakes of bran and germ added to foods were controlled for, the hazard ratio of CHD between extreme quintiles of whole-grain intake was 0.82 (95% CI: 0.70, 0.96; P for trend = 0.01). The hazard ratio of CHD in men with the highest intake of added bran was 0.70 (95% CI: 0.60, 0.82) compared with men with no intake of added bran (P for trend ≤ 0.001). Added germ was not associated with CHD risk. Conclusion: This study supports the reported beneficial association of whole-grain intake with CHD and suggests that the bran component of whole grains could be a key factor in this relation. [ABSTRACT FROM AUTHOR]

Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk. • The association of hemostatic factor levels with dementia risk is unclear. • We evaluated hemostatic factors from 1992/1993 and dementia risk over 5.4 years. • No evidence of linear associations between hemostatic factors and dementia risk. • Higher levels of factors measured at median age 73 may not reflect dementia risk. [ABSTRACT FROM AUTHOR]

A letter to the editor is shown in response to the study "Intakes of Fish and Polyunsaturated Fatty Acid (PUFA) Consumption in Relation to Risks of Developing Mild-to-Severe Cognitive Impairment Risks."

Abstract: The ATP-binding cassette transporter A-1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein (HDL) metabolism and atherogenesis. We investigated whether common ABCA1 variants, previously reported to have phenotypic effects in humans, were associated with plasma lipids and CHD in a prospective study of coronary heart disease (CHD) in healthy women. Three polymorphisms in the promoter region (−565C/T, −191G/C, and −17C/G) and two in the coding region (I883M and R1587K) were genotyped in the Nurses’ Health Study. During 8 years of follow-up, 249 incident cases of CHD were identified and matched to controls (1:2) on age and smoking. The I883M variant was associated with higher HDL-cholesterol levels among younger women. Nearly complete linkage disequilibrium was observed between −565C/T and −191G/C and their less common alleles predicted a lower risk of CHD (odds ratio of CHD per −191C allele: 0.8; 95% CI, 0.6–1.0). Neither the −17C/G SNP nor the 2 the coding polymorphisms were associated with risk of CHD. The −565C/T and the −191G/C variants were inversely associated with risk of CHD among healthy women, without pronounced effects on plasma lipids. [Copyright &y& Elsevier]

Background: Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection.Objectives: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population.Methods: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death.Results: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02).Conclusions: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults. [ABSTRACT FROM AUTHOR]

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function. [ABSTRACT FROM AUTHOR]

Background and aims Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene ( AHSG ) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). Methods Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992–1993. Results Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele ( P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00–1.26) for rs2248690 and 1.02 (0.91–1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70–1.00) for rs2248690 and 0.97 (95% CI: 0.82–1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93–1.34) and 1.06 (0.93–1.20) for rs2248690 and rs4917, respectively ( p heterogeneity 0.005 and 0.0048). Conclusion Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to investigate into the biologically plausible interaction between the common haptoglobin (Hp) polymorphism rs#72294371 and glycosylated hemoglobin (HbA1c) on risk of coronary heart disease (CHD). Background: Studies of the association between the Hp polymorphism and CHD report inconsistent results. Individuals with the Hp2-2 genotype produce Hp proteins with an impaired ability to prevent oxidative injury caused by elevated HbA1c. Methods: HbA1c concentration and Hp genotype were determined for 407 CHD cases matched 1:1 to controls (from the NHS [Nurses'' Health Study]) and in a replication cohort of 2,070 individuals who served as the nontreatment group in the ICARE (Prevention of Cardiovascular Complications in Diabetic Patients With Vitamin E Treatment) study, with 29 CHD events during follow-up. Multivariate models were adjusted for lifestyle and CHD risk factors as appropriate. A pooled analysis was conducted of NHS, ICARE, and the 1 previously published analysis (a cardiovascular disease case-control sample from the Strong Heart Study). Results: In the NHS, Hp2-2 genotype (39% frequency) was strongly related to CHD risk only among individuals with elevated HbA1c (≥6.5%), an association that was similar in the ICARE trial and the Strong Heart Study. In a pooled analysis, participants with both the Hp2-2 genotype and elevated HbA1c had a relative risk of 7.90 (95% confidence interval: 4.43 to 14.10) for CHD compared with participants with both an Hp1 allele and HbA1c <6.5% (p for interaction = 0.004), whereas the Hp2-2 genotype with HbA1c <6.5% was not associated with risk (relative risk: 1.34 [95% confidence interval: 0.73 to 2.46]). Conclusions: Hp genotype was a significant predictor of CHD among individuals with elevated HbA1c. [Copyright &y& Elsevier]

Abstract: Background: The use of specific COX-2 inhibitors in cancer prevention has been associated with higher risk of acute coronary syndrome (ACS) and myocardial infarction. The aim of this study was to investigate if the polymorphisms COX2 T8473C (rs5275), and COX2 A-1195G (rs689466), which modify the enzyme levels of COX-2, were associated with risk of ACS and if alcohol intake, smoking, and use of NSAID would modify the associations. We also wanted to investigate associations with blood lipid levels. Methods: A case–cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals aged 55–64 at recruitment 1993–1997. Results: Male variant allele carriers of COX-2 T8473C were at lower risk of ACS (IRR=0.75, CI=0.61–0.93, p =0.008) than homozygous wildtype carriers. There were no statistically significant interactions between genotypes and alcohol intake, smoking and NSAID use in relation to risk of ACS. Among males, there was interaction between COX-2 T8473C and alcohol in relation to total cholesterol, non-HDL cholesterol and LDL levels (p for interaction: 0.003, 0.007 and 0.01, respectively), such that variant allele carriers with low alcohol intake had the lowest lipid levels. No statistically significant associations were observed in females. Conclusion: This study suggests that genetically determined COX-2 levels are associated with risk of ACS and blood lipid levels among males. No consistent associations were found for females. [Copyright &y& Elsevier]

Abstract: Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. E-Cadherin is an adhesion molecule that is thought to be involved in GC. Germline mutations in the E-Cadherin gene (CDH1) have been identified in hereditary diffuse GC. Also, a promoter polymorphism at position −160 C/A has been suggested to lead to transcriptional down regulation and has been shown to affect GC risk in some studies. However, very little information exists on the GC risk association of other CDH1 polymorphisms and it is unclear whether any associations may be different by GC anatomical sites or histological types. Thus, a case–control study (cases=245/controls=950) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort was conducted to assess the GC risk association of eight CDH1 gene polymorphisms. None of the CDH1 polymorphisms or haplotypes analysed were associated with GC risk and no differences of effect were observed by Helicobacter pylori infection status. However, three CDH1 polymorphisms in the same haplotype block, including the CDH1−160C/A, interacted with smoking to increase GC risk in smokers but not in never smokers. These findings should be confirmed in larger independent studies. [Copyright &y& Elsevier]