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Hypertension (HTN) is a well-established risk factor for cardiovascular diseases (CVDs), including ischemic heart disease, stroke, heart failure, and atrial fibrillation. The prevalence of HTN, as well as mortality rates attributable to HTN, continue to increase, particularly in the United States and among Black populations. The risk of HTN involves a complex interaction of genetics and modifiable risk factors, including dietary patterns. In this regard, there is accumulating evidence that links dietary intake of red meat with a higher risk of poorly controlled blood pressure and HTN. However, research on this topic contains significant methodological limitations, which are described in the review. The report provided below also summarizes the available research reports, with an emphasis on processed red meat consumption and how different dietary patterns among certain populations may contribute to HTN-related health disparities. Finally, this review outlines potential mechanisms and provides recommendations for providers to counsel patients with evidence-based nutritional approaches regarding red meat and the risk of HTN, as well as CVD morbidity and mortality.

Background & Aims: A genome-wide significant association between anti–Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest anti–H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori–eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with anti–H pylori IgG titers (rs12233670; β = −0.267 ± SE 0.034; P = 4.42 × 10−15) presented with high heterogeneity and failed replication. Anti–H pylori IgG titers declined within 2–4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between anti–H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti–H pylori IgG titers on therapy, clearance, and antibody decay. H pylori–mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.

Background and AimsCardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits.Methods and ResultsWe conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high-density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N=356,574–456,823). Multiple loci reached genome-wide levels of significance (N=145-333) for each trait, but only four loci (in/nearVEGFA, GRB14-COBLL1, KLF14, andRGS19-OPRL1)were associated with risk across all seven traits (P−8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses.GRB14-COBLL1showed the most consistent replication, revealing nominally significant associations (PConclusionsOur analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.

Purpose Since avocado consumption has been linked to a possible reduction in inflammation, we investigated associations between avocado consumption and markers of inflammation in a population-based multi-ethnic cohort [Multi-Ethnic Study of Atherosclerosis (MESA)]. Methods We used a food frequency questionnaire (FFQ) at MESA exam 1 to capture avocado/guacamole consumption. To calculate daily servings of avocado/guacamole, we used both frequency and serving size data from the FFQ. We classified participants into three consumer groups: rare or never (daily serving ≤ 0.03), medium (0.03 Results Among 5794 MESA participants, the average age and BMI were 62.25 y ± 10.26 and 28.28 ± 5.41 kg/m2, respectively, and 48% of the sample were men. Participants self-reported as Hispanic (22.30%), Caucasian (39.92%), African-American (25.39%), and Chinese (12.39%). Over 60% had higher than a high school education and 40% made $50,000 or more a year. Regarding avocado/guacamole consumption, 79% were categorized as rare or never, 12% as medium, and 9% as heavy. When adjusted for relevant confounders, there were no significant differences among the three consumer groups for any inflammatory marker. Conclusion In this cross-sectional study, we did not find that consumption of avocado/guacamole was associated with levels of inflammatory markers.

RationaleInflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have anti-inflammatory properties and may benefit lung health.ObjectivesInvestigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in adults of diverse races/ethnicities from general population cohorts.MethodsComplementary study designs: (1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1and FVC measures in the National Heart, Lung, and Blood Institute 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 ResultsThe longitudinal study found that higher omega-3 fatty acid concentrations were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for docosahexaenoic acid (DHA). One standard deviation higher DHA was associated with an attenuation of 1.8 mL/year for FEV1(95% confidence interval [CI] 1.3–2.2) and 2.4 mL/year for FVC (95% CI 1.9–3.0). One standard deviation higher DHA was also associated with a 9% lower incidence of spirometry-defined airway obstruction (95% CI 0.86–0.97). DHA associations persisted across sexes, smoking histories, and Black, white and Hispanic participants, with the largest magnitude associations in former smokers and Hispanics. The MR study showed positive associations of genetically predicted omega-3 fatty acids with FEV1and FVC, with statistically significant findings across multiple MR methods.ConclusionsThe longitudinal and MR studies provide evidence supporting beneficial effects of higher circulating omega-3 fatty acids, especially DHA, on lung health.

Peer reviewed: True, Funder: University of New South Wales; FundRef: http://dx.doi.org/10.13039/501100001773, OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate

Purpose of Review To examine the evidence that the dietary quality of children changed between the period preceding the COVID-19 pandemic and the first year during the pandemic. Recent Findings A systematic review of the evidence for dietary changes occurring as a result of the pandemic-related restrictions, in Part I of this article, yielded 38 original research articles. These articles had conflicting results, some describing improvements in overall quality and some describing deteriorations. As a whole the studies were characterized by a low study quality, and children were poorly represented. Taken together, these studies do not provide enough evidence to draw conclusions about whether dietary habits changed or not as a result of the pandemic. However, in a wider, narrative review of the psychosocial changes occurring as a result of the COVID-19 pandemic, and the known associations of these factors with a dietary intake in Part II, we conclude that there is a reason to expect that the dietary quality of children might have been adversely affected by the COVID-19 pandemic. Summary One the one hand, the literature fails to provide conclusive evidence on changes in the dietary quality of children resulting from the COVID-19 pandemic. On the other hand, the broader literature supports the hypothesis that children’s dietary quality will have declined during the pandemic. Taken together, we urgently need more high-quality research on children’s changes in dietary intake occurring over the pandemic. This will provide important information on whether any potential long-term consequences of such changes, if they exist, need to be examined and ameliorated.

BackgroundHeterogeneity in the long-term metabolic response to dietary macronutrient composition can be partially explained by genetic factors. However, few studies have demonstrated reproducible gene-diet interactions (GDIs), likely due in part to measurement error in dietary intake estimation as well as insufficient capture of rare genetic variation. Discovery analyses in ancestry-diverse cohorts that include rare genetic variants from whole-genome sequencing (WGS) could help identify genetic variants modifying the effects of dietary macronutrient composition on glycemic phenotypes.ObjectiveWe aimed to identify macronutrient GDIs across the genetic frequency spectrum associated with continuous glycemic traits in genetically and culturally diverse cohorts.MethodsWe analyzed N=33,187 diabetes-free participants from 10 cohorts in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program with WGS, self-reported diet, and glycemic traits (fasting glucose [FG], insulin [FI], and hemoglobin A1c [HbA1c]). We fit multivariable-adjusted linear mixed models for the main effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and for its interactions with genetic variants genome-wide. Tests were performed for both common variants and gene-based rare variant sets in each cohort followed by a combined cohort meta-analysis.ResultsIn main effect models, participants consuming more calories from carbohydrate at the expense of fat had modestly lower glycemic trait values (β per 250 kcal substitution for FG: −0.030 mmol/L, p=2.7×10−6; lnFI: −0.008 log(pmol/L), p=0.17; HbA1c: −0.013 %, p=0.025). In GDI analyses, a common African ancestry-enriched variant (rs79762542; 78 kb upstream of the FRAS1 gene) reached study-wide significance (p = 1.14×10−8) indicating a higher HbA1c with greater proportion of calories from carbohydrate vs. fat among minor allele carriers only. This interaction was replicated in the UK Biobank cohort. Simulations revealed that there is (1) a substantial impact of measurement error on statistical power for GDI discovery at these sample sizes, especially for rare genetic variants, and (2) over 150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error.ConclusionsOur analysis identified a potential genetic interaction modifying the dietary macronutrient-HbA1c association while highlighting the importance of precise exposure measurement and significantly increased sample size to identify additional similar effects.

Previous studies have suggested that infants high in negative affect have higher levels of adiposity, arising in part via changes in nutrition (e.g., “feeding to soothe”). Few studies have examined whether positive affect shows similar or inverse associations with adiposity. The current study examined cross-sectional and longitudinal relationships between adiposity and observations of positive affect in both a social and a non-social context, using data from infants at four (n = 125) and 12 (n = 80) months of age. Our analyses did not find any cross-sectional associations between positive affect and adiposity (all p > 0.05). However, in the longitudinal analyses, positive affect in a non-social context, when observed at four months of age, was positively associated with weight-for-length at 12 months of age (zWFL; ß = 1.49, SE = 0.67, p = 0.03), while positive affect observed at four months of age in a social context was inversely associated with body fat percentage at 12 months of age (ß = −11.41, SE = 5.44, p = 0.04). These findings provide preliminary evidence that the p positive affect is related to adiposity in infancy and suggest that the direction of association (i.e., direct or inverse) may be specific to the context in which positive affect is measured. Future research should examine the role of nutritional status in any relationships between adiposity and emotion at this early stage.

Background and aimsThe DASH diet conveys protection against type 2 diabetes mellitus (T2D) Via plant-based and non-plant-based recommendations. Research has not identified which glucose homeostasis pathways are improved. We examined associations between adherence to a DASH diet and six glucose homeostasis traits, probing whether associations could be attributed to the plant-based (DASH-P) and/or non-plant based (DASH-NP) components.Methods and resultsWe included data from 295 adults without T2D (age 59.3±9.00 years; 63.46% non-Hispanic White and 36.54% African American, self-reported race ancestry) participating in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). An oral glucose tolerance test (OGTT) yielded fasting plasma glucose, insulin, C-peptide, and insulin secretion, sensitivity, and disposition index. Habitual dietary intake was assessed by food frequency questionnaire (FFQ). Associations between DASH components and glucose homeostasis traits were examined, controlling for demographics, body mass index (BMI), physical activity, and energy intake. For significant associations, the models were repeated with scores for DASH-P and DASH-NP as predictors in the same model. DASH and DASH-P scores were inversely associated with fasting plasma glucose (DASH:β=-0.036±0.012,P=0.005; DASH-P: β=-0.04±0.017,P=0.002), and positively associated with insulin sensitivity (DASH:β=0.022±0.012,P=0.042; DASH-P:=0.036±0.015,P=0.014). The DASH score was also associated with disposition index (β=0.026±0.013,P=0.038), but this association did not reach significance with DASH-P (β=0.035±0.018,P=0.051). No associations were observed with DASH-NP score (all P>0.05).ConclusionsDASH diet is associated with improvement in specific glucose homeostasis traits, likely arising from increased plant-based foods. Such research may help tailor future dietary advice to specific metabolic risk, and to food groups most effective at improving these.

The pathophysiology underlying pseudotumor cerebri syndrome (PTCS) is complex and not well understood. There are clear differences between PTCS in adults and pediatrics. Few and isolated case reports have suggested that adrenal function may be involved, yet no large cohort study has examined this relationship.We conducted a retrospective single-center study of children who presented with a diagnosis of PTCS and had cortisol testing measured between January 2010 and September 2019. We included all subjects meeting the revised PTCS diagnostic criteria after the chart review. Based on morning, random or 1-μg cosyntropin stimulated cortisol levels, adrenal functioning was classified as: (1) insufficient (peak cortisol16 μg/dL and AM cortisol5 μg/dL), (2) at risk (peak cortisol 16-20 μg/dL, AM cortisol 5-13 μg/dL, or random13 μg/dL), or (3) sufficient (peak cortisol20 μg/dL and AM or random cortisol13 μg/dL).A total of 398 individuals were reviewed, and 64 were included for analysis. Of these, 40.6% were men, of mixed race and ethnicity with a mean age of 10.5 (SD 4.7) years. Of these, 23% and 52% had insufficient or at-risk cortisol levels. The majority of those in the insufficient (70%) or at-risk (80%) groups were exposed to topical, nasal, or inhaled glucocorticoids but not systemic. Only 60% and 12% of those with PTCS with insufficient or at-risk cortisol testing, respectively, underwent definitive testing with a stimulation test.Glucocorticoid use and hypocortisolism are prevalent in PTCS and need consideration as a potential underlying cause. Most children had insufficient or at-risk cortisol levels, and many did not undergo further testing/workup. Children who present with PTCS, particularly young, males should be evaluated for adrenal insufficiency and its risk factors, including nonsystemic steroids. Prospective studies are necessary to further evaluate the effect of cortisol in relation to pediatric PTCS.

Aim To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). Materials and methods The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. Results After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. Conclusions The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.

Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n = 431,167) and the Global Lipids Genetics Consortium (n = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (n = 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C–lowering medications.

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole metagenome shotgun sequencing with taxonomic profiling. We examined associations between 36 butyrate-producing taxa (7 genera, 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, body mass index, and race. Genus Coprococcus was associated with higher insulin sensitivity (β=0.14, P=0.002) and disposition index (β=0.12, P=0.012) and a lower rate of dysglycemia (odds ratio 0.91, 95% confidence interval (CI) 0.85-0.97, P=0.0025); in contrast, Flavonifractor was associated with lower insulin sensitivity (β=-0.13, P=0.004) and disposition index (β=-0.11, P=0.04) and higher prevalence of dysglycemia (OR 1.22, 95% CI 1.08-1.38, P=0.0013). Species-level analyses found 10 bacteria associated with beneficial directions of effects and two bacteria with adverse associations on insulin homeostasis and dysglycemia. While most butyrate-producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria, suggesting that microbiome-directed therapeutic measures to prevent or treat diabetes should be targeted to specific butyrate-producing taxa rather than all butyrate producers.

BackgroundVitamin D inadequacy affects almost 50% of adults in the United States and is associated with numerous adverse health effects. Vitamin D concentration [25(OH)D] is a complex trait with genetic and environmental predictors that work in tandem to influence 25(OH)D and may determine how much vitamin D intake is required to reach an optimal 25(OH)D concentration. To date, there has been little investigation into how genetics and environment interact to affect 25(OH)D.ObjectiveInteractions between continuous measures of a polygenic score (PGS) and vitamin D intake (PGS*intake) or available ultra-violet (UV) radiation (PGS*UV) were evaluated separately in individuals of African or European ancestry.MethodsMega-analyses were performed using three independent cohorts (N=9,668; African ancestry n=1,099; European ancestry n=8,569). Interaction terms and joint effects (main and interaction terms) were tested using one-degree of freedom (DF) and 2-DF models, respectively. All models controlled for age, sex, body mass index (BMI), cohort, and dietary intake/available UV. Additionally, in participants achieving Institute of Medicine (IOM) vitamin D intake recommendations, 25(OH)D was evaluated by level of genetic risk of 25(OH)D deficiency.ResultsThe 2-DF PGS*intake, 1-DF PGS*UV and 2-DF PGS*UV results were statistically significant in participants of European ancestry (p=3.3×10−18, 2.1×10−2, and 2.4×10−19, respectively), but not in those of African ancestry. In European-ancestry participants who reached IOM vitamin D intake guidelines, the percent of participants achieving adequate 25(OH)D (>20ng/ml) increased as genetic risk decreased (72% vs 89% in the highest vs lowest risk categories; p=0.018).ConclusionsAvailable UV radiation and vitamin D intake interact with genetics to influence 25(OH)D. Individuals with higher genetic risk of deficiency may require more vitamin D exposure to maintain optimal 25(OH)D concentrations. Overall, the results showcase the importance of incorporating both environmental and genetic factors into analyses, as well as the potential for gene-environment interactions to inform personalized dosing of vitamin D.Sources of SupportARICThe Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions.Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E. Boerwinkle).MESAMESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491.The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226.Funding support for the Vitamin D dataset was provided by grant HL096875WHIThe WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI.WHI PAGE is funded through the NHGRI Population Architecture Using Genomics and Epidemiology (PAGE) network (Grant Number U01 HG004790). Assistance with phenotype harmonization, SNP selection, data cleaning, meta-analyses, data management and dissemination, and general study coordination, was provided by the PAGE Coordinating Center (U01HG004801-01).Funding support for WHI GARNET was provided through the NHGRI Genomics and Randomized Trials Network (GARNET) (Grant Number U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004424). The datasets used for the analyses described in this manuscript were obtained from dbGaP athttp://www.ncbi.nlm.nih.gov/sites/entrez?db=gapthrough dbGa Paccession phs000200.v11.p3.Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278.OtherKEH was supported by an NLM training grant to the Computation and Informatics in Biology and Medicine Training Program (NLM 5T15LM007359). Computational resources were supported by a core grant to the Center for Demography and Ecology at the University of Wisconsin-Madison (P2C HD047873).JM was supported by the Department of Ophthalmology and Visual Sciences, and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences from the Research to Prevent Blindness, and by National Institutes of Health, National Eye Institute grants R01 EY016686, R01 EY025292.

Introduction In observational studies, the association between the Dietary Approaches to Stop Hypertension (DASH) diet and incident heart failure has been inconsistent. It was hypothesized that higher DASH diet concordance has a protective effect on heart failure in a multi-ethnic cohort. Methods The Multi-Ethnic Study of Atherosclerosis cohort includes men and women of multiple ethnicities who were aged 45–84 years and free of clinical cardiovascular disease at baseline. Participants were recruited between 2000 and 2002 from six U.S. communities and followed for incident cardiovascular health events through 2015 for the purpose of this data set. Diet was measured using food-frequency questionnaires. Cox proportional hazards analysis was used to investigate the associations of the DASH diet concordance with incident heart failure in 2017–2018. Results During a median 13 years of follow-up, 179 of 4,478 participants developed heart failure, corresponding to a rate of 3.4 per 1,000 person years. Heart failure incidence rates did not vary significantly by DASH quintile for the population as a whole. In participants younger than 75 years, highest DASH concordance was associated with a lower risk of incident heart failure compared with those in the lowest quintile (hazard ratio=0.4, 95% CI=0.2, 0.9 vs all participants hazard ratio=1.0, 95% CI=0.2, 0.9) after adjusting for demographics, energy consumption, and known cardiovascular confounders. Conclusions This study supports the hypothesis that DASH is beneficial in heart failure prevention within the individuals aged less than 75 years subgroup, an idea that to date was substantiated only by much smaller studies or in less diverse patient populations.

Background and Purpose— Dietary sodium reduction with concurrent increase in potassium intake is a current public health priority to reduce risk of cardiovascular events. This study explored associations between the spot urine sodium-to-potassium ratio and cardiovascular events in the MESA (Multi-Ethnic Study of Atherosclerosis) longitudinal cohort. Methods— The MESA is a prospective cohort study of 6814 adults from 4 ethnic groups (European-, Asian-, African- and Hispanic-American) with a mean age of 62 (±10.2) years and an average of 11.7 (±2.2) years of follow-up. Participants were free of clinical cardiovascular disease at baseline. Spot urine sodium and potassium excretion, as a marker of dietary intake, was collected at baseline. The impact of urinary sodium-to-potassium ratio on adjudicated cardiovascular events was assessed using Cox proportional hazards models. Results— Only 39% of MESA participants had a urinary sodium-to-potassium ratio ≤1, and these participants experienced only 74 of the 236 strokes. A sodium-to-potassium ratio >1 was associated with a hazard ratio of 1.47 (95% CI,1.07–2.00) for risk of stroke, adjusting for age, sex, race, cardiovascular risk factors, socio-demographic characteristics, body size, and kidney function. Conclusions— The spot urine sodium-to-potassium ratio (measurable in routine care) is associated with stroke. A urine sodium-to-potassium ratio of ≤1, may be related to a clinically relevant reduction in stroke risk and is a feasible target for health interventions.

ImportanceEvidence linking low-carbohydrate diets (LCDs) to mortality is limited among multiethnic populations.ObjectiveTo evaluate the association between LCDs and mortality by race and ethnicity.Design, Setting, and ParticipantsThe Multi-Ethnic Study of Atherosclerosis is a large, population-based prospective cohort study of adults aged 45 to 84 years recruited from 6 US communities. A total of 6109 participants without baseline cardiovascular disease were included in this analysis. Baseline data were collected from July 2000 to August 2002, with follow-up completed by December 2017. The data were analyzed between May 2021 and April 2022.ExposuresFood frequency questionnaires were used to assess dietary intake. From these data, overall LCD scores were calculated from the percentages of energy intake from carbohydrates, fats, and proteins. Animal-based (emphasizing saturated fat and animal protein) and vegetable-based (emphasizing monounsaturated fat and vegetable protein) LCD scores were also calculated.Main Outcomes and MeasuresAll-cause and cause-specific mortality over a median follow-up of 15.9 years (IQR, 14.3-16.6 years).ResultsAmong the 6109 participants (mean [SD] age, 62.3 [10.3] years; 3190 women [52.2%]; 1623 African American [26.6%], 701 Chinese American [11.5%], 1350 Hispanic [22.1%], and 2435 non-Hispanic White [39.8%]), there were 1391 deaths. Overall, LCD scores were not associated with mortality, but when analyses were stratified by race and ethnicity, a lower risk of all-cause and non-CV mortality was observed among Hispanic participants with moderate carbohydrate intake. Specifically, the hazard ratios for total mortality for overall LCD scores were 0.58 (95% CI, 0.40-0.84) for quintile 2, 0.67 (95% CI, 0.45-0.98) for quintile 3, 0.60 (95% CI, 0.41-0.87) for quintile 4, and 0.83 (95% CI, 0.57-1.21) for quintile 5, with quintile 1 as the reference group. A similar association was observed for animal-based (but not vegetable-based) LCD scores. In contrast, no significant associations were found between LCD scores and mortality risk in the other racial and ethnic groups.Conclusions and RelevanceIn this cohort study of multiethnic US adults, LCD score was not associated with mortality in the whole population. However, moderate carbohydrate intake was associated with a lower risk of mortality among Hispanic participants. These findings suggest that the association between carbohydrate intake and mortality may differ according to race and ethnicity. Dietary guidelines considering these differences may be necessary.

Supplemental Digital Content is available in the text., Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16–3.07] mg/dL per allele; P

Insulin resistance and insufficient insulin secretion lead to type 2 diabetes. A role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in 224 non-Hispanic White and 129 African Americans individuals from MILES (mean age 59, 62% female). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Logistic regression models (controlling for age, sex, race, and BMI) examined the individual contributions of these traits separately, as well as the joint contribution of insulin sensitivity, clearance, and secretion, to early dysglycemia (prediabetes plus newly diagnosed diabetes; 46% of cohort). Models used standardized predictors such that odds ratios (OR) represent the change in odds of dysglycemia per standard deviation change. Model performance was assessed via Akaike’s Information Criterion (AIC) and area under the receiver operator characteristic curves (AUROC). In separate models, dysglycemia was associated with insulin sensitivity (OR 0.2; 0.14-0.30; P Disclosure A. Wood: None. E. T. Jensen: None. G. Ramesh: None. Z. Arzumanyan: None. K. Lam: None. A. Bertoni: None. J. I. Rotter: None. Y. Chen: None. M. O. Goodarzi: None. Funding National Institutes of Health (R01DK109588)

Background: The metabolites associated with a Mediterranean-style (AMED) diet may give insight into why AMED is robustly associated with protection against CVD. Previous investigations seeking to identify these have been limited by the use of modest sample sizes and targeted assays. Methods: Using samples from the Multi-Ethnic Study of Atherosclerosis (MESA), we conducted untargeted 1 H NMR spectroscopy (600 MHz) with internal and external annotation on the sera of ~3,698 participants, ages 45-84, who were free from overt CVD. We included data on baseline dietary intake (self-reported), and all incident CVD events (excluding stroke) over a 10-year period. From >100,000 spectral features, 845 significant associations (P-6 ) were identified via linear regression, and reduced to a putative list of 46 via elastic net regularized models. Hierarchical clustering identified 11 feature groups, from which cluster scores were constructed. The ‘mediate’ package in R used bootstrapping (1000 simulations) to partition the association between AMED and incident CVD into the effects of dietary intake on CVD which are mediated by the metabolomic cluster scores (the “indirect” / mediated effects) and those effects which are not (“direct effects”). All association analyses controlled for age, sex, ethnicity, data collection site and daily caloric intake. Results: AMED score was associated with reductions in the incidence of CVD (HR=0.95; 95% CI: 0.91 - 0.99; P=0.02). All metabolomic cluster scores were associated with AMED (all P-06 ; Table 1 ), with 6 significantly associated with incident CVD (all P-4 ) in the expected direction given their associations with AMED score. Four of these six significantly mediated the association of AMED score with incident CVD (PTable 1 ). Conclusions: These preliminary data suggest that specific molecules, if replicated in other studies, hold promise to identify the underlying pathways by which an AMED diet offers protection against CVD.

Introduction: Quality and quantity of skeletal muscle decrease with age, largely due to adipose tissue infiltration, and are important determinants of metabolic health. To inform efforts to slow aging-related decline in muscle mass and prevent myosteatosis, a better understanding of the biological determinants of muscle atrophy and quality is needed. We used targeted lipidomics to identify, with a greater specificity, lipoproteins associated with muscle and intermuscular adipose tissue (IMAT) area (quantity) and density (quality) of the total abdominal, locomotion, and stabilization muscles in the Multi-Ethnic Study of Atherosclerosis. Hypothesis: Lower density lipoproteins will be positively associated with muscle and IMAT quantity, but negatively associated with quality. Methods: At visit one, 105 serum lipoproteins were measured by Bruker lipoprotein subclass analysis with 1 H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm 2 ) and density (Hounsfield units) were estimated 2.6 years, on average, after visit 1 for the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, and rectus abdominis) muscles from computed-tomography scans at the L4/L5 spinal junction. We identified lipoproteins associated with body composition using linear regression adjusting for age, gender, race, diet, physical activity, lipid-lowering medication, and multiple comparisons using a 1% false discovery rate. Results: Participants (N=947) were 44-84 years old (mean: 63), 51% men, 40% White, 16% Black, 16% Chinese American, and 27% Hispanic American. Among 105 lipoproteins, 24 were associated with total muscle area, whereas none were associated with muscle density. When examining specific muscle groups, 25 lipoproteins were associated with stabilization muscle area, driven by the oblique muscles. As for total IMAT area, there were 27 associations with lipoproteins. Specifically, 27 lipoproteins were associated with stabilization muscle IMAT area, driven by oblique and rectus abdominis muscles. Last, 39 lipoproteins were associated with total IMAT density, with 28 and 33 associated with locomotion and stabilization (driven by obliques) IMAT density, respectively. Higher VLDL: cholesterols, free cholesterols, phospholipids, and triglycerides and lower HDL: cholesterols and free cholesterols were associated with higher muscle area and IMAT area, but lower IMAT density (

Hispanic populations have higher rates of obesity, elevated triglycerides, and a greater prevalence of diabetes. Long chain polyunsaturated fatty acids (LC-PUFAs) and LC-PUFA metabolites have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS cluster accounts for a large part of the interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind (AI) ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation, plasma phospholipid levels of LC-PUFAs, anthropometric measures, and circulating metabolic and inflammatory biomarkers in 1,102 Hispanic American participants, representing six distinct ancestry populations from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between AI genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. We further replicated the association with circulating TGs in two additional Hispanic cohorts: the Hispanic Community Health Study/Study of Latinos and the Arizona Insulin Resistance Registry. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.

OBJECTIVE Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis. RESEARCH DESIGN AND METHODS For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance–weighted meta-analysis. RESULTS A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all P < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses. CONCLUSIONS Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.

Background: DNA methylation patterns associated with habitual diet have not been well studied. Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P −3 ). Hypermethylation of cg18181703 ( SOCS3 ) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality ( P =5.7×10 −15 ). Ten additional diet-associated CpGs were nominally associated with all-cause mortality ( P P −4 ). For example, hypermethylation of cg11250194 ( FADS2 ) was associated with lower triglyceride concentrations (MR, P =1.5×10 −14 ).and hypermethylation of cg02079413 ( SNORA54 ; NAP1L4 ) was associated with body mass index (corrected MR, P =1×10 −6 ). Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (OR=0.41[0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C, and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

OBJECTIVES: To assess associations between individual and total circulating n-3 fatty acids (FAs) with self-reported sleep duration and difficulty sleeping in the Fatty Acids and Outcome Research Consortium (FORCE). METHODS: De novo harmonized individual-level analyses were performed and pooled in 10 prospective studies (N = 22,717) with data on sleep duration and 7 studies (N = 9997) with data on difficulty initiating sleeping (DIS). Participant ages ranged from 35 to 96 years from 5 countries (Finland, Iceland, Sweden, Singapore, and the United States). Measured circulating FAs included alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and the sum of EPA, DPA and DHA. FAs were expressed as a % of total FAs. Self-reported sleep duration was categorized as short (8 hrs). DIS was categorized as yes or no (reference). Cross-sectional associations were assessed by multinomial logistic regression in each study with a standardized protocol including definitions for exposures, outcomes and covariates (demographics, health factors and dietary habits). Cohort-specific odds ratios (OR) per quintile (reference: Q1) of FAs were pooled with inverse-variance weighted meta-analysis. RESULTS: In pooled multivariate analysis, we found that participants with higher circulating n-3 FAs (Q5) had a lower risk of short and long sleep duration. For short sleep ORs (95% confidence intervals, CI) for Q5 were 0.87 (0.78–0.98) for EPA, 0.87 (0.77–0.97) for DPA, 0.83 (0.73–0.93) for DHA and 0.83 (0.74–0.93) for the sum of EPA, DPA and DHA, respectively. For long sleep ORs (95% CI) were 0.79 (0.64–0.97) for DHA, and 0.80 (0.65–0.98) for the sum of EPA, DPA and DHA. The only significant association observed for DIS was for Q3 of DHA, OR = 0.77, 95% CI = 0.63–0.96. CONCLUSIONS: In pooled de novo analyses across multiple cohorts, higher levels of n-3 FAs are associated with lower risk of suboptimal sleep (i.e., too little or too much sleep); These novel findings support the need for additional investigation of the temporal nature and causality of these relationships. FUNDING SOURCES: International Life Sciences Institute, North America.

Background: The use of gonadotropins is a recent strategy for inducing puberty in adolescent males with hypogonadotropic hypogonadism (HH). Testosterone use has been discouraged in patients who desire to preserve fertility. Human chorionic gonadotropin (hCG) has been recommended for inducing puberty in HH; however, several clinicians administer hCG in combination with other gonadotropins. The benefits of using combination gonadotropin therapies (hCG+) over hCG monotherapy in pre-pubertal adolescent males with HH has not been clearly established. We performed a meta-analysis to assess the outcomes of hCG compared to hCG+ in terms of virilizing effects and testicular growth in peripubertal boys with HH. Methods: We evaluated for heterogeneity among studies. We calculated pooled means for the post-treatment mean testicular volume (MTV), testosterone (T) level, and penile length for the hCG monotherapy and hCG+ treatment groups. We performed a meta-regression analysis to examine the contribution of various factors to post-treatment outcomes including baseline T level, age, treatment duration, and study quality. Results: The meta-analysis included seven studies. All participants were prepubertal (age range: 13.3–25.9 years), with weighted mean treatment durations of 10.95 months for hCG monotherapy and 28.2 months for hCG. There was significant heterogeneity in baseline age (Q = 121.71; df = 1; P < 0.001) and T levels (Q = 436.74; df = 1; P < 0.001) between the two treatment groups. The hCG+ group had a larger post-treatment MTV, but it was not significantly different between the two groups (6.60 mL [95% CI, 3.18–10.02] for hCG monotherapy vs. 10.02 mL [95% CI, 8.30–11.75] for hCG+; P = 0.079). Post-treatment T levels differed significantly between the two groups (101.89 ng/dL [95% CI, 50.7–153.08] for hCG monotherapy vs. 424.10 ng/dL [95% CI, 304.59–543.62] for hCG+; P < 0.0001). A meta-regression analysis of post-treatment T levels showed that baseline age, baseline T level, and study grade did not contribute significantly to the difference between treatment groups. Treatment duration explained 3.04% of the difference between the two groups (P < 0.0001). After adjusting for treatment duration, the post-treatment T level remained significantly higher in the hCG+ group compared to the hCG monotherapy group. The hCG+ was also associated with better outcomes for post-treatment penile length, although these findings relied on data from only three studies. Conclusion: Our study indicates that hCG+ therapies provide potential benefits over hCG monotherapy for pubertal induction in males with HH, regarding T levels and penile growth, with no difference in testicular growth between treatments. Prospective pediatric studies are needed to assess the benefits of these therapies in patients with HH and, ultimately, to establish guidelines for gonadotropin therapy in the adolescent population.

Background Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain. Methods We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk. Results We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR. Conclusions We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

Background: Idiopathic intracranial hypertension (IIH) is a condition of elevated intracranial pressure without identifiable secondary causes. The childhood incidence is 0.7 per 100,000 and increases with age, obesity, and female gender. Few case reports in the literature, and our own experience, suggest there may be an association between IIH and adrenal insufficiency (AI) but the real extent is unknown. Aim: To describe the prevalence of AI in children presenting with IIH to a large pediatric referral center. Methods: Retrospective chart review identified all children who presented with IHH and had cortisol measured between January 2010 and September 2019. Based on morning, random or 1 mcg ACTH stimulated cortisol levels, adrenal functioning was classified as: (1) deficient (peak cortisol 20 μg/dl, AM or random cortisol >13 μg/dl). Descriptive data present mean (+/- standard deviation), and chi-squared (χ 2) tests of differences are used to examine differences between the adrenal functioning groups. Results: Participants (N=64) were 40.6% male, of mixed ancestry (61% non-Hispanic white; 19% African-American, 16% Hispanic White and 5% Asian), with a mean age of 10.8 (4.8) years. Cortisol levels were obtained at an average of 0.6 (1.9) years after diagnosis of IIH; 23% and 52% of patients had insufficient or at risk cortisol levels. The majority of those in the insufficient (70%) or at risk (80%) groups were exposed to topical, nasal or inhaled corticosteroids, but not systemic. Only 60% and 12 % of those with IIH and insufficient or at risk cortisol testing, respectively, underwent definitive testing with a stimulation test. Adrenal function did not differ by age, race/ethnicity, zBMI, nor prolong exposure to steroids (> 2 weeks), time between IIH diagnosis and cortisol testing (all P>.05). Those in the deficient group were less likely to be female (33%) than those in the at risk (61%; χ 2=3.07, df=1, P=.001) or sufficient (81%; χ 2=7.30, df=1, P.05) Conclusions: Steroid use and AI are common in IIH and need consideration as a cause of IIH development. Appropriate diagnosis and treatment of AI in children who present with IIH may lead to its resolution, significantly impacting clinical outcomes of these children. In our cohort, the majority had AI or at risk cortisol levels, and many did not undergo further testing. All young children who present with IIH should be evaluated for steroid exposure, including non-systemic steroids, and undergo evaluation for AI. Caution should be utilized in pediatric providers prescribing these medications. More prospective studies are required to evaluate the effects of steroid use in relation to IIH development.