Associations Between Flavonoid Intake and Subclinical Atherosclerosis: The MESA.

BACKGROUND: Flavonoids may play a role in mitigating atherosclerotic cardiovascular diseases, with evidence suggesting effects may differ between vascular beds. Studies examining associations with subclinical markers of atherosclerosis between subpopulations with different underlying risks of atherosclerosis are lacking. METHODS: Among 5599 participants from the MESA (Multi-Ethnic Study of Atherosclerosis), associations between dietary flavonoid intakes (estimated from a food frequency questionnaire) and subclinical measures of atherosclerosis (ankle-brachial index, carotid plaques and intima-media thickness, and coronary artery calcification) were examined using repeated measures models. Exposures and outcomes were measured at exam 1 (2000-2002) and exam 5 (2010-2011). Stratified analyses and interaction terms were used to explore effect modification by time, sex, race/ethnicity, and smoking status. RESULTS: In the analytic population, at baseline, ≈46% were males with a median age of 62 (interquartile range, 53-70) years and total flavonoid intakes of 182 (interquartile range, 98-308) mg/d. After multivariable adjustments, participants with the highest (quartile 4) versus lowest (quartile 1) total flavonoid intakes had 26% lower odds of having an ankle-brachial index <1 (odds ratio, 0.74 [95% CI, 0.60-0.92]) and 18% lower odds of having a carotid plaque (odds ratio, 0.82 [95% CI, 0.69-0.99]), averaged over exams 1 and 5. Moderate (quartile 3) to high (quartile 4) intakes of flavonols, flavanol monomers, and anthocyanins were associated with 19% to 34% lower odds of having an ankle-brachial index <1 and 18% to 20% lower odds of having carotid plaque. Participants with the highest intakes of anthocyanins (quartile 4) at baseline had a marginally slower rate of carotid plaque progression than those with moderate intakes (quartiles 2 and 3). There were no significant associations with intima-media thickness or coronary artery calcification. Observed associations did not differ by sex, race/ethnicity, or smoking status. CONCLUSIONS: In this multi-ethnic population, higher dietary flavonoid intakes were associated with lower odds of peripheral and carotid artery atherosclerosis. Increasing intakes of healthy, flavonoid-rich foods may protect against atherosclerosis in the peripheral and carotid arteries.

Polygenic scores and Mendelian randomization identify plasma proteins causally implicated in Alzheimer's disease.

Background: An increasing body of evidence suggests that neuroinflammation is one of the key drivers of late-onset Alzheimer's disease (LOAD) pathology. Due to the increased permeability of the blood-brain barrier (BBB) in older adults, peripheral plasma proteins can infiltrate the central nervous system (CNS) and drive neuroinflammation through interactions with neurons and glial cells. Because these inflammatory factors are heritable, a greater understanding of their genetic relationship with LOAD could identify new biomarkers that contribute to LOAD pathology or offer protection against it. Methods: We used a genome-wide association study (GWAS) of 90 different plasma proteins (n = 17,747) to create polygenic scores (PGSs) in an independent discovery (cases = 1,852 and controls = 1,990) and replication (cases = 799 and controls = 778) cohort. Multivariate logistic regression was used to associate the plasma protein PGSs with LOAD diagnosis while controlling for age, sex, principal components 1-2, and the number of APOE-e4 alleles as covariates. After meta-analyzing the PGS-LOAD associations between the two cohorts, we then performed a two-sample Mendelian randomization (MR) analysis using the summary statistics of significant plasma protein level PGSs in the meta-analysis as an exposure, and a GWAS of clinically diagnosed LOAD (cases = 21,982, controls = 41,944) as an outcome to explore possible causal relationships between the two. Results: We identified four plasma protein level PGSs that were significantly associated (FDR-adjusted p < 0.05) with LOAD in a meta-analysis of the discovery and replication cohorts: CX3CL1, hepatocyte growth factor (HGF), TIE2, and matrix metalloproteinase-3 (MMP-3). When these four plasma proteins were used as exposures in MR with LOAD liability as the outcome, plasma levels of HGF were inferred to have a negative causal relationship with the disease when single-nucleotide polymorphisms (SNPs) used as instrumental variables were not restricted to cis-variants (OR/95%CI = 0.945/0.906-0.984, p = 0.005). Conclusion: Our results show that plasma HGF has a negative causal relationship with LOAD liability that is driven by pleiotropic SNPs possibly involved in other pathways. These findings suggest a low transferability between PGS and MR approaches, and future research should explore ways in which LOAD and the plasma proteome may interact.

Genetic Architecture and Analysis Practices of Circulating Metabolites in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Circulating metabolite levels partly reflect the state of human health and diseases, and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally-diverse samples. We provided recommendations for outlier and imputation handling to process metabolite data, as well as a general analytical framework. We further performed a pooled analysis following our practical recommendations and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus - metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes, but also novel genes (such as GAB3 and VSIG4 located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such as FADS2 , D2HGDH , SUGP1 , UTG2B17 , strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

Association of aortic valve calcium with dementia and stroke: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Calcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: AVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1-99, 100-299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR). RESULTS: Overall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04-1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14-2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors. CONCLUSIONS: After multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors.

Lac-Phe mediates the effects of metformin on food intake and body weight.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

Refinement of a published gene-physical activity interaction impacting HDL-cholesterol: role of sex and lipoprotein subfractions.

Large-scale gene-environment interaction (GxE) discovery efforts often involve compromises in the definition of outcomes and choice of covariates for the sake of data harmonization and statistical power. Consequently, refinement of exposures, covariates, outcomes, and population subsets may be helpful to establish often-elusive replication and evaluate potential clinical utility. Here, we used additional datasets, an expanded set of statistical models, and interrogation of lipoprotein metabolism via nuclear magnetic resonance (NMR)-based lipoprotein subfractions to refine a previously discovered GxE modifying the relationship between physical activity (PA) and HDL-cholesterol (HDL-C). This GxE was originally identified by Kilpeläinen et al., with the strongest cohort-specific signal coming from the Women's Genome Health Study (WGHS). We thus explored this GxE further in the WGHS (N = 23,294), with follow-up in the UK Biobank (UKB; N = 281,380), and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 4,587). Self-reported PA (MET-hrs/wk), genotypes at rs295849 (nearest gene: LHX1), and NMR metabolomics data were available in all three cohorts. As originally reported, minor allele carriers of rs295849 in WGHS had a stronger positive association between PA and HDL-C (pint = 0.002). When testing a range of NMR metabolites (primarily lipoprotein and lipid subfractions) to refine the HDL-C outcome, we found a stronger interaction effect on medium-sized HDL particle concentrations (M-HDL-P; pint = 1.0×10-4) than HDL-C. Meta-regression revealed a systematically larger interaction effect in cohorts from the original meta-analysis with a greater fraction of women (p = 0.018). In the UKB, GxE effects were stronger both in women and using M-HDL-P as the outcome. In MESA, the primary interaction for HDL-C showed nominal significance (pint = 0.013), but without clear differences by sex and with a greater magnitude using large, rather than medium, HDL-P as an outcome. Towards reconciling these observations, further exploration leveraging NMR platform-specific HDL subfraction diameter annotations revealed modest agreement across all cohorts in the interaction affecting medium-to-large particles. Taken together, our work provides additional insights into a specific known gene-PA interaction while illustrating the importance of phenotype and model refinement towards understanding and replicating GxEs.

Frequency of Treatment Failure of UTIs in Children With Congenital Urinary Tract Anomalies.

OBJECTIVES: Children with certain congenital anomalies of the kidney and urinary tract and neurogenic bladder (CAKUT/NGB) are at higher risk of treatment failure for urinary tract infections (UTIs) than children with normal genitourinary anatomy, but the literature describing treatment and outcomes is limited. The objectives of this study were to describe the rate of treatment failure in children with CAKUT/NGB and compare duration of antibiotics between those with and without treatment failure. METHODS: Multicenter retrospective cohort of children 0 to 17 years old with CAKUT/NGB who presented to the emergency department with fever or hypothermia and were diagnosed with UTI between 2017 and 2018. The outcome of interest was treatment failure, defined as subsequent emergency department visit or hospitalization for UTI because of the same pathogen within 30 days of the index encounter. Descriptive statistics and univariates analyses were used to compare covariates between groups. RESULTS: Of the 2014 patient encounters identified, 482 were included. Twenty-nine (6.0%) of the 482 included encounters had treatment failure. There was no difference in the mean duration of intravenous antibiotics (3.4 ± 2.5 days, 3.5 ± 2.8 days, P = .87) or total antibiotics between children with and without treatment failure (10.2 ± 3.8 days, 10.8 ± 4.0 days, P = .39) Of note, there was a higher rate of bacteremia in children with treatment failure (P = .04). CONCLUSIONS: In children with CAKUT/NGB and UTI, 6.0% of encounters had treatment failure. Duration of antibiotics was not associated with treatment failure. Larger studies are needed to assess whether bacteremia modifies the risk of treatment failure.

Increased Plasma Branched Short-Chain Fatty Acids and Improved Glucose Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Short-chain fatty acids (SCFAs) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched SCFAs (BSCFAs; isobutyrate, isovalerate, and methylbutyrate) is largely unknown. In a cohort of 219 non-Hispanic White participants and 126 African American participants, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, and lipid traits, and other SCFAs. We observed a bimodal distribution of BSCFAs, with 25 individuals having high levels (H-BSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared with the L-BSCFA group (16% vs. 49%; P = 0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFAs. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose levels were lower and the disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial C-peptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Lac-Phe mediates the anti-obesity effect of metformin.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin's effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformin's anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformin's effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

Associations between avocado intake and measures of glucose and insulin homeostasis in Hispanic individuals with and without type 2 diabetes: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BACKGROUND AND AIMS: To investigate associations between avocado intake and glycemia in adults with Hispanic/Latino ancestry. METHODS AND RESULTS: The associations of avocado intake with measures of insulin and glucose homeostasis were evaluated in a cross-sectional analysis of up to 14,591 Hispanic/Latino adults, using measures of: average glucose levels (hemoglobin A1c; HbA1c), fasting glucose and insulin, glucose and insulin levels after an oral glucose tolerance test (OGTT), and calculated measures of insulin resistance (HOMA-IR, and HOMA-%ß), and insulinogenic index. Associations were assessed using multivariable linear regression models, which controlled for sociodemographic factors and health behaviors, and which were stratified by dysglycemia status. In those with normoglycemia, avocado intake was associated with a higher insulinogenic index (ß = 0.17 ± 0.07, P = 0.02). In those with T2D (treated and untreated), avocado intake was associated with lower hemoglobin A1c (HbA1c; ß = -0.36 ± 0.21, P = 0.02), and lower fasting glucose (ß = -0.27 ± 0.12, P = 0.02). In the those with untreated T2D, avocado intake was additionally associated with HOMA-%ß (ß = 0.39 ± 0.19, P = 0.04), higher insulin values 2-h after an oral glucose load (ß = 0.62 ± 0.23, P = 0.01), and a higher insulinogenic index (ß = 0.42 ± 0.18, P = 0.02). No associations were observed in participants with prediabetes. CONCLUSIONS: We observed an association of avocado intake with better glucose/insulin homeostasis, especially in those with T2D.

Association Between Alcohol Consumption and Ectopic Fat in the Multi-Ethnic Study of Atherosclerosis.

Background The relationship between alcohol consumption and ectopic fat distribution, both known factors for cardiovascular disease, remains understudied. Therefore, we aimed to examine the association between alcohol consumption and ectopic adiposity in adults at risk for cardiovascular disease. Methods and Results In this cross-sectional analysis, we categorized alcohol intake among participants in MESA (Multi-Ethnic Study of Atherosclerosis) as follows (drinks/day): <1 (light drinking), 1 to 2 (moderate drinking), >2 (heavy drinking), former drinking, and lifetime abstention. Binge drinking was defined as consuming ≥5 drinks on 1 occasion in the past month. Visceral, subcutaneous, and intermuscular fat area, pericardial fat volume, and hepatic fat attenuation were measured using noncontrast computed tomography. Using multivariable linear regression, we examined the associations between categories of alcohol consumption and natural log-transformed fat in ectopic depots. We included 6756 MESA participants (62.1±10.2 years; 47.2% women), of whom 6734 and 1934 had chest computed tomography (pericardial and hepatic fat) and abdominal computed tomography (subcutaneous, intermuscular, and visceral fat), respectively. In adjusted analysis, heavy drinking, relative to lifetime abstention, was associated with a higher (relative percent difference) pericardial 15.1 [95% CI, 7.1-27.7], hepatic 3.4 [95% CI, 0.1-6.8], visceral 2.5 [95% CI, -10.4 to 17.2], and intermuscular 5.2 [95% CI, -6.6 to 18.4] fat but lower subcutaneous fat -3.5 [95% CI, -15.5 to 10.2]). The associations between alcohol consumption and ectopic adiposity exhibited a J-shaped pattern. Binge drinking, relative to light-to-moderate drinking, was also associated with higher ectopic fat. Conclusions Alcohol consumption had a J-shaped association with ectopic adiposity. Both heavy alcohol intake and binge alcohol drinking were associated with higher ectopic fat.

Untargeted metabolomic analysis investigating links between unprocessed red meat intake and markers of inflammation.

BACKGROUND: Whether red meat consumption is associated with higher inflammation or confounded by increased adiposity remains unclear. Plasma metabolites capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so they can help clarify diet-health relationships. OBJECTIVE: To identify whether any metabolites associated with red meat intake are also associated with inflammation. METHODS: A cross-sectional analysis of observational data from older adults (52.84% women, mean age 63 ± 0.3 y) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food-frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, homocysteine, and tumor necrosis factor alpha, and untargeted proton nuclear magnetic resonance (1H NMR) metabolomic features. Associations between these variables were examined using linear regression models, adjusted for demographic factors, lifestyle behaviors, and body mass index (BMI). RESULTS: In analyses that adjust for BMI, neither processed nor unprocessed forms of red meat were associated with any markers of inflammation (all P > 0.01). However, when adjusting for BMI, unprocessed red meat was inversely associated with spectral features representing the metabolite glutamine (sentinel hit: ß = -0.09 ± 0.02, P = 2.0 × 10-5), an amino acid which was also inversely associated with CRP level (ß = -0.11 ± 0.01, P = 3.3 × 10-10). CONCLUSIONS: Our analyses were unable to support a relationship between either processed or unprocessed red meat and inflammation, over and above any confounding by BMI. Glutamine, a plasma correlate of lower unprocessed red meat intake, was associated with lower CRP levels. The differences in diet-inflammation associations, compared with diet metabolite-inflammation associations, warrant further investigation to understand the extent that these arise from the following: 1) a reduction in measurement error with metabolite measures; 2) the extent that which factors other than unprocessed red meat intake contribute to glutamine levels; and 3) the ability of plasma metabolites to capture individual differences in how food intake is metabolized.

Associations between Avocado Intake and Lower Rates of Incident Type 2 Diabetes in US Adults with Hispanic/Latino Ancestry.

Background/Purpose: Hispanic/Latinos in the US are at increased risk for type 2 diabetes (T2D). Data suggest that avocado intake is associated with better glycemic control, but whether this translates to protection from T2D has not been studied. The goal of the current analyses was to examine whether consuming avocados at baseline is associated with lower incident T2D over a six-year period, compared to not consuming avocados at baseline. Subjects/Methods: Using data from a large population of US adults with Hispanic ancestry, without known or unknown T2D at baseline (N=6,159), participants were classified as avocado consumers (N=983) or non-consumers (N=5,176) based on the mean of two 24-hour dietary recalls. Cox proportional hazard models estimated the association of avocado consumption with incident T2D (N=656 cases) over a six-year follow-up period, in the population as a whole, and separately in those with normoglycemia vs. prediabetes at baseline. A set of three sequential models were run: the first controlling only for sociodemographic factors ("minimally adjusted" models), the second for these and health behaviors ("fully adjusted" models), and a third for both sets of covariates and also body mass index (BMI; "fully adjusted + BMI" models). Results: In the population as a whole, avocado intake at baseline was associated with reduced incident T2D in both the minimally adjusted (hazard ratio [HR] (+/- 95% confidence intervals [CIs]): 0.70 (0.52 - 0.94), P=.04) and the fully adjusted models (HR: 0.72 (0.54-0.97), P=.03). This association was observed in both those with prediabetes and with normoglycemia at baseline, but only reached significance in those with prediabetes (minimally adjusted model: HR: 0.68 (0.48-0.97), P=.03; fully adjusted model: HR: 0.69 (0.48-0.98), P=.04), not in those with normoglycemia (minimally adjusted model: HR: 0.86 (0.45-1.65), P=.65; fully adjusted model: HR: 0.80 (0.41-1.55), P=.50). In models which additionally controlled for BMI ("fully adjusted + BMI model"), the associations were slightly attenuated (overall population: HR: 0.79 (0.59-1.06), P=.60; normoglycemia: HR: 0.83 (0.42-1.64), P=.60; prediabetes: HR= 0.75 (0.54 - 1.05), P=0.09). Conclusions: In our longitudinal analyses, adults with Hispanic / Latino ancestry who consumed avocado were less likely to develop T2D than those who did not consume avocado at baseline, especially if they had prediabetes at baseline.

Associations between Metabolomic Biomarkers of Avocado Intake and Glycemia in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Avocado consumption is linked to better glucose homeostasis, but small associations suggest potential population heterogeneity. Metabolomic data capture the effects of food intake after digestion and metabolism, thus accounting for individual differences in these processes. OBJECTIVES: To identify metabolomic biomarkers of avocado intake and to examine their associations with glycemia. METHODS: Baseline data from 6224 multi-ethnic older adults (62% female) included self-reported avocado intake, fasting glucose and insulin, and untargeted plasma proton nuclear magnetic resonance metabolomic features (metabolomic data were available for a randomly selected subset; N = 3438). Subsequently, incident type 2 diabetes (T2D) was assessed over an ∼18 y follow-up period. A metabolome-wide association study of avocado consumption status (consumer compared with nonconsumer) was conducted, and the relationship of these features with glycemia via cross-sectional associations with fasting insulin and glucose and longitudinal associations with incident T2D was examined. RESULTS: Three highly-correlated spectral features were associated with avocado intake at metabolome-wide significance levels (P < 5.3 ∗ 10-7) and combined into a single biomarker. We did not find evidence that these features were additionally associated with overall dietary quality, nor with any of 47 other food groups (all P > 0.001), supporting their suitability as a biomarker of avocado intake. Avocado intake showed a modest association only with lower fasting insulin (ß = -0.07 +/- 0.03, P = 0.03), an association that was attenuated to nonsignificance when additionally controlling for body mass index (kg/m2). However, our biomarker of avocado intake was strongly associated with lower fasting glucose (ß = -0.22 +/- 0.02, P < 2.0 ∗ 10-16), lower fasting insulin (ß = -0.17 +/- 0.02, P < 2.0 ∗ 10-16), and a lower incidence of T2D (hazard ratio: 0.68; 0.63-074, P < 2.0 ∗ 10-16), even when adjusting for BMI. CONCLUSIONS: Highly significant associations between glycemia and avocado-related metabolomic features, which serve as biomarkers of the physiological impact of dietary intake after digestion and absorption, compared to modest relationships between glycemia and avocado consumption, highlights the importance of considering individual differences in metabolism when considering diet-health relationships.

Genome-wide association studies and fine-mapping identify genomic loci for n-3 and n-6 polyunsaturated fatty acids in Hispanic American and African American cohorts.

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10-8, we confirmed association of the FADS signal and found evidence of two additional signals (in DAGLA and BEST1) within 200 kb of the originally reported FADS signal. Outside of the FADS region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including TMX2, SLC29A2, ANKRD13D and POLD4, and spanning a > 9 Mb region on chromosome 11 (57.5 Mb ~ 67.1 Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV1 (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV1 and FVC. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.

Dietary Sources of Linoleic Acid (LA) Differ by Race/Ethnicity in Adults Participating in the National Health and Nutrition Examination Survey (NHANES) between 2017-2018.

Linoleic acid (LA) is a primary n-6 polyunsaturated fatty acid (PUFA), which is of interest to nutritional professionals as it has been associated with health outcomes. However, as some LA-rich foods offer protection against chronic diseases such as CVD (e.g., fatty fish), while others increase risk (e.g., red meat), the individual foods contributing to LA intake may be an important factor to consider. Therefore, this analysis sought to examine whether there are racial/ethnic differences in the proportion of overall LA intake accounted for by individual food groups, via a cross-sectional analysis of 3815 adults participating in the National Health and Nutrition Examination Survey (NHANES; 2017-2018 cycle). Separate multivariable linear regressions models specified the proportion of overall LA intake attributable to each of the nine food groups (dairy, eggs, fat, fish, fruits and vegetables, grains, meat, nuts, and sweets) as the outcome, and race/ethnicity as the predictor, with age, gender, and socioeconomic status (SES) as covariates, in order to estimate whether there were mean differences by race/ethnicity in the proportion of overall LA intake attributable to each of these foods seperately. After a Bonferroni correction for multiple testing, eggs, grains, fruits and vegetables, meat, and fish each accounted for a different proportion of overall LA intake according to racial/ethnic grouping (all p < 0.006 after a Bonferroni correction). These findings indicate the food sources of LA in the diet differ by race/ethnicity, and warrant future investigations into whether this plays a role in health disparities.

Metabolomic Profile of the Healthy Eating Index-2015 in the Multiethnic Study of Atherosclerosis.

BACKGROUND: Poor diet quality is a risk factor for type 2 diabetes and cardiovascular disease. However, knowledge of metabolites marking adherence to Dietary Guidelines for Americans (2015 version) are limited. OBJECTIVES: The goal was to determine a pattern of metabolites associated with the Healthy Eating Index (HEI)-2015, which measures adherence to the Dietary Guidelines for Americans. METHODS: The analysis examined 3557 adult men and women from the longitudinal cohort Multiethnic Study of Atherosclerosis (MESA), without known cardiovascular disease and with complete dietary data. Fasting serum specimens and diet and demographic questionnaires were assessed at baseline. Untargeted 1H 1-dimensional nuclei magnetic resonance spectroscopy (600 MHz) was used to generate metabolomics and lipidomics. A metabolome-wide association study specified each spectral feature as outcomes, HEI-2015 score as predictor, adjusting for age, sex, race, and study site in linear regression analyses. Subsequently, hierarchical clustering defined the discrete groups of correlated nuclei magnetic resonance features associated with named metabolites, and the linear regression analysis assessed for associations with HEI-2015 total and component scores. RESULTS: The sample included 50% women with an mean age of 63 years, with 40% identifying as White, 23% as Black, 24% as Hispanic, and 13% as Chinese American. The mean HEI-2015 score was 66. The metabolome-wide association study identified 179 spectral features significantly associated with HEI-2015 score. The cluster analysis identified 7 clusters representing 4 metabolites; HEI-2015 score was significantly associated with all. HEI-2015 score was associated with proline betaine [ß = 0.12 (SE = 0.02); P = 4.70 × 10-13] and was inversely related to proline [ß = -0.13 (SE = 0.02); P = 4.45 × 10-14], 1,5 anhydrosorbitol [ß = -0.08 (SE = 0.02); P = 4.37 × 10-7] and unsaturated fatty acyl chains [ß = 0.08 (SE = 0.02); P = 8.98 × 10-7]. Intake of total fruit, whole grains, and seafood and plant proteins was associated with proline betaine. CONCLUSIONS: Diet quality is significantly associated with unsaturated fatty acyl chains, proline betaine, and proline. Further analysis may clarify the link between diet quality, metabolites, and pathogenesis of cardiometabolic disease.