Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes.

BACKGROUND: Consistent evidence suggests diabetes-protective effects of dietary fiber intake. However, the underlying mechanisms, particularly the role of gut microbiota and host circulating metabolites, are not fully understood. We aimed to investigate gut microbiota and circulating metabolites associated with dietary fiber intake and their relationships with type 2 diabetes (T2D). METHODS: This study included up to 11 394 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Diet was assessed with two 24-hour dietary recalls at baseline. We examined associations of dietary fiber intake with gut microbiome measured by shotgun metagenomics (350 species/85 genera and 1958 enzymes; n=2992 at visit 2), serum metabolome measured by untargeted metabolomics (624 metabolites; n=6198 at baseline), and associations between fiber-related gut bacteria and metabolites (n=804 at visit 2). We examined prospective associations of serum microbial-associated metabolites (n=3579 at baseline) with incident T2D over 6 years. RESULTS: We identified multiple bacterial genera, species, and related enzymes associated with fiber intake. Several bacteria (eg, Butyrivibrio, Faecalibacterium) and enzymes involved in fiber degradation (eg, xylanase EC3.2.1.156) were positively associated with fiber intake, inversely associated with prevalent T2D, and favorably associated with T2D-related metabolic traits. We identified 159 metabolites associated with fiber intake, 47 of which were associated with incident T2D. We identified 18 of these 47 metabolites associated with the identified fiber-related bacteria, including several microbial metabolites (eg, indolepropionate and 3-phenylpropionate) inversely associated with the risk of T2D. Both Butyrivibrio and Faecalibacterium were associated with these favorable metabolites. The associations of fiber-related bacteria, especially Faecalibacterium and Butyrivibrio, with T2D were attenuated after further adjustment for these microbial metabolites. CONCLUSIONS: Among United States Hispanics/Latinos, dietary fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for T2D. These findings advance our understanding of the role of gut microbiota and microbial metabolites in the relationship between diet and T2D.

Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, and Cardiovascular Disease Risk in US Hispanics and Latinos: Results From HCHS/SOL.

BACKGROUND: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults. METHODS: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14 172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US exposure. We evaluated associations of dietary acculturation with incident CVD across ≈7 years of follow-up (n=211/14 172 cases/total) and gut microbiota (n=2349; visit 2, 2014 to 2017). Serum metabolites associated with both dietary acculturation-related gut microbiota (n=694) and incident CVD (n=108/5256 cases/total) were used as proxy measures to assess the association of diet-related gut microbiome with incident CVD. RESULTS: We identified an empirical US-oriented dietary acculturation score that increased with US exposure. Higher dietary acculturation score was associated with higher risk of incident CVD (hazard ratio per SD, 1.33 [95% CI, 1.13-1.57]), adjusted for sociodemographic, lifestyle, and clinical factors. Sixty-nine microbial species (17 enriched from diverse species, 52 depleted mainly from fiber-utilizing Clostridia and Prevotella species) were associated with dietary acculturation, driven by lower intakes of whole grains, beans, and fruits and higher intakes of refined grains. Twenty-five metabolites, involved predominantly in fatty acid and glycerophospholipid metabolism (eg, branched-chain 14:0 dicarboxylic acid** and glycerophosphoethanolamine), were associated with both diet acculturation-related gut microbiota and incident CVD. Proxy association analysis based on these metabolites suggested a positive relationship between diet acculturation-related microbiome and risk of CVD (r=0.70, P<0.001). CONCLUSIONS: Among US Hispanic and Latino adults, greater dietary acculturation was associated with elevated CVD risk, possibly through alterations in gut microbiota and related metabolites. Diet and microbiota-targeted interventions may offer opportunities to mitigate CVD burdens of dietary acculturation.

Subclinical Atherosclerosis Across the Menopausal Transition in Women With and Without HIV.

The menopausal transition is a pivotal time of cardiovascular risk, but knowledge is limited in HIV. We studied longitudinal carotid artery intima-media thickness (CIMT) in the Women's Interagency HIV Study (2004-2019; 979 women/3247 person-visits; 72% with HIV). Among women with HIV only, those who transitioned had greater age-related CIMT progression compared to those remaining premenopausal (difference in slope = 1.64 µm/year, P = .002); and CIMT increased over time in the pretransition (3.47 µm/year, P = .002) and during the menopausal transition (9.41 µm/year, P < .0001), but not posttransition (2.9 µm/year, P = .19). In women with HIV, menopause may accelerate subclinical atherosclerosis as measured by CIMT.

Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations.

AIMS/HYPOTHESIS: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European. METHODS: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations. RESULTS: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development. CONCLUSIONS/INTERPRETATION: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations. DATA AVAILABILITY: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS ).

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Association of Gut Microbiota With Objective Sleep Measures in Women With and Without Human Immunodeficiency Virus Infection: The IDOze Study.

BACKGROUND: Poor sleep health is an underrecognized health challenge, especially for people with human immunodeficiency virus (HIV). Gut microbiota related to sleep are underinvestigated. METHODS: The IDOze microbiota substudy included 190 women (114 with HIV and 76 without HIV). Wrist actigraphy measured total sleep duration, sleep efficiency, number of wake bouts, wake after sleep onset, fragmentation index, and sleep timing. 16S rRNA gene sequencing identified gut microbial genera. Analysis of compositions of microbiomes with bias correction was used to investigate cross-sectional associations between gut microbiota and sleep. Abundances of sleep-related gut microbial genera were compared between women with and without HIV. RESULTS: Enrichment of 7 short-chain fatty acid-producing genera (eg, Butyricimonas, Roseburia, and Blautia) was associated with lower fragmentation index. Enrichment of 9 genera (eg, Dorea) was associated with lower sleep efficiency and/or more wake after sleep onset. Enrichment of proinflammatory Acidaminococcus was associated with late sleep midpoint and offset time. These associations were largely consistent regardless of HIV status. The abundance of Butyricimonas was lower among women with HIV compared to those without HIV. CONCLUSIONS: Seventeen genera were identified to be associated with sleep continuity or timing. Butyricimonas, a potentially beneficial genus associated with sleep continuity, was less abundant among women with HIV.

Interplay between diet, circulating indolepropionate concentrations and cardiometabolic health in US populations.

OBJECTIVES: To identify indolepropionate (IPA)-predicting gut microbiota species, investigate potential diet-microbiota interactions, and examine the prospective associations of circulating IPA concentrations with type 2 diabetes (T2D) and coronary heart disease (CHD) risk in free-living individuals. DESIGN: We included 287 men from the Men's Lifestyle Validation Study, a substudy of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of faecal samples and two blood samples. Diet was assessed using 7-day diet records. Associations between plasma concentrations of tryptophan metabolites and T2D CHD risk were examined in 13 032 participants from Nurses' Health Study (NHS), NHSII and HPFS. RESULTS: We identified 17 microbial species whose abundance was significantly associated with plasma IPA concentrations. A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fibre intake and a higher microbial species score consisting of the 17 species (p-interaction<0.01). Dietary and plasma concentrations of tryptophan and most kynurenine pathway metabolites were positively associated with T2D risk (HRQ5 vs Q1 ranged from 1.17 to 1.46) while a significant inverse association was found for IPA (HRQ5 vs Q1 (95% CI) 0.70 (0.56 to 0.88)). No associations were found in CHD for any plasma tryptophan metabolites. CONCLUSIONS: Specific microbial species and dietary fibre jointly predicted significantly higher circulating IPA concentrations at higher tryptophan intake. Dietary and plasma tryptophan, as well as its kynurenine pathway metabolites, demonstrated divergent associations from those for IPA, which was significantly predictive of lower risk of T2D.

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10-10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

Identification of Dietary Supplements Associated with Blood Metabolites in the Hispanic Community Health Study/Study of Latinos Cohort Study.

BACKGROUND: Metabolomics approaches have been widely used to define the consumption of foods but have less often been used to study exposure to dietary supplements. OBJECTIVES: This study aimed to identify dietary supplements associated with metabolite levels and to examine whether these metabolites predicted incident diabetes risk. METHODS: We studied 3972 participants from a prospective cohort study of 18-74-y-old Hispanic/Latino adults. At a baseline examination, we ascertained use of dietary supplements using recall methods and concurrently, a serum metabolomic panel. After adjustment for potential confounders, we identified dietary supplements associated with metabolites. We then examined the association of these metabolites with incident diabetes at the 6-y study examination. RESULTS: We observed a total of 110 dietary supplement-metabolite associations that met the criteria for statistical significance adjusted for age, sex, field center, Hispanic/Latino background, body mass index, diet, smoking, physical activity, and number of medications (adjusted P < 0.05). This included 13 metabolites uniquely associated with only one dietary supplement ingredient. Vitamin C had the most associated metabolites (n = 15), including positive associations with oxalate, tartronate, threonate, and isocitrate, which were each in turn protective for the risk of incident diabetes. Vitamin C was also associated with higher N-acetylvaline level, which was an unfavorable diabetes risk factor. Other findings related to branched chain amino acid related compounds including α-hydroxyisovalerate and 2-hydroxy-3-methylvalerate, which were inversely associated with thiamine or riboflavin intake and also predicted higher diabetes risk. Vitamin B12 had an inverse association with γ-glutamylvaline, levels of which were positively associated with the risk of diabetes. CONCLUSIONS: Our data point to potential metabolite changes associated with vitamin C and B vitamins, which may have favorable metabolic effects. Knowledge of blood metabolites that can be modified by dietary supplement intake may aid understanding the health effects of dietary supplements and identify potential biological mediators.

The Gut Microbiome, Microbial Metabolites, and Cardiovascular Disease in People Living with HIV.

PURPOSE OF REVIEW: To synthesize recent evidence relating the gut microbiome and microbial metabolites to cardiovascular disease (CVD) in people living with HIV (PLWH). RECENT FINDINGS: A few cross-sectional studies have reported on the gut microbiome and cardiovascular outcomes in the context of HIV, with no consistent patterns emerging. The largest such study found that gut Fusobacterium was associated with carotid artery plaque. More studies have evaluated microbial metabolite trimethylamine N-oxide with CVD risk in PLWH, but results were inconsistent, with recent prospective analyses showing null effects. Studies of other microbial metabolites are scarce. Microbial translocation biomarkers (e.g., lipopolysaccharide binding protein) have been related to incident CVD in PLWH. Microbial translocation may increase CVD risk in PLWH, but there is insufficient and/or inconsistent evidence regarding specific microbial species and microbial metabolites associated with cardiovascular outcomes in PLWH. Further research is needed in large prospective studies integrating the gut microbiome, microbial translocation, and microbial metabolites with cardiovascular outcomes in PLWH.

Gut Microbiota, Plasma Metabolomic Profiles, and Carotid Artery Atherosclerosis in HIV Infection.

BACKGROUND: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection. METHODS: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up. RESULTS: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus, were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09-1.64] and 1.24 [1.02-1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines. CONCLUSIONS: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition.

INTRODUCTION: We studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations. METHODS: We tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n = 2222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n = 1365) and African (n = 478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function. RESULTS: Six metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar-related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet. DISCUSSION: Several diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities. HIGHLIGHTS: Metabolites associated with cognitive function in Puerto Rican adults were recently identified. We demonstrate the generalizability of these associations across diverse race/ethnicities. Most identified metabolites are related to sugars. Mendelian Randomization (MR) provides weak evidence for a causal effect of ribitol on cognitive function. Beta-cryptoxanthin and other metabolites highlight the importance of a healthy diet.

The IDOze Study: The Link Between Sleep Disruption and Tryptophan-Kynurenine Pathway Activation in Women With Human Immunodeficiency Virus.

BACKGROUND: Poor sleep is associated with human immunodeficiency virus (HIV), particularly among women with HIV (WWH), although mechanisms are unclear. We explored cross-sectional associations between sleep disruption and tryptophan-kynurenine (T/K) pathway activation, measured by the kynurenine-to-tryptophan ratio (K:T). METHODS: HIV-uninfected women (HIV-) and WWH aged 35-70 years and on stable antiretroviral therapy were included. Sleep metrics were measured using wrist actigraphy. Plasma T/K pathway metabolites were measured using liquid chromatography-tandem mass spectrometry. Multivariate linear regression models examined relationships between K:T and actigraphy-based sleep metrics by HIV status. RESULTS: WWH (n = 153) and HIV- women (n = 151) were demographically similar. Among WWH, median CD4 was 751 cells/µL; 92% had undetectable HIV RNA. Compared to HIV- women, WWH had higher K:T (P < .001) and kynurenine (P = .01) levels but similar tryptophan levels (P = .25). Higher K:T was associated with more wake bouts (P = .001), more time awake after sleep onset (P = .01), and lower sleep efficiency (P = .03) in WWH only. CONCLUSIONS: HIV infection was associated with T/K pathway activation; this activation was associated with poorer sleep efficiency and more fragmented sleep. While longitudinal studies are needed to elucidate the directionality of these associations, these findings may help identify treatments to reduce sleep disruption in WWH by targeting residual inflammation and T/K pathway activation.

Menopause Is Associated With Immune Activation in Women With HIV.

BACKGROUND: Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown. METHODS: In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1) were measured at 674 person-visits spanning ≤2 years. RESULTS: Menopause (post- vs premenopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (ß = 161.89 ng/mL; 95% confidence interval [CI], 18.37-305.41 and 65.48 ng/mL, 95% CI, 6.64-124.33, respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI, 16.63-484.79; P = .04), but not in premenopausal or postmenopausal periods. CONCLUSIONS: In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during menopausal transition warrant further investigation.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Healthful eating patterns, serum metabolite profile and risk of diabetes in a population-based prospective study of US Hispanics/Latinos.

AIMS/HYPOTHESIS: We aimed to evaluate associations of multiple recommended dietary patterns (i.e. the alternate Mediterranean diet [aMED], the Healthy Eating Index [HEI]-2015 and the healthful Plant-based Diet Index [hPDI]) with serum metabolite profile, and to examine dietary-pattern-associated metabolites in relation to incident diabetes. METHODS: We included 2842 adult participants free from diabetes, CVD and cancer during baseline recruitment of the Hispanic Community Health Study/Study of Latinos. Metabolomics profiling of fasting serum was performed using an untargeted approach. Dietary pattern scores were derived using information collected by two 24 h dietary recalls. Dietary-pattern-associated metabolites were identified using multivariable survey linear regressions and their associations with incident diabetes were assessed using multivariable survey Poisson regressions with adjustment for traditional risk factors. RESULTS: We identified eight metabolites (mannose, γ/ß-tocopherol, N1-methylinosine, pyrraline and four amino acids) that were inversely associated with all dietary scores. These metabolites were detrimentally associated with various cardiometabolic risk traits, especially insulin resistance. A score comprised of these metabolites was associated with elevated risk of diabetes (RRper SD 1.54 [95% CI 1.29, 1.83]), and this detrimental association appeared to be attenuated or eliminated by having a higher score for aMED (pinteraction = 0.0001), HEI-2015 (pinteraction = 0.020) or hPDI (pinteraction = 0.023). For example, RR (95% CI) of diabetes for each SD increment in the metabolite score was 1.99 (1.44, 2.37), 1.67 (1.17, 2.38) and 1.08 (0.86, 1.34) across the lowest to the highest tertile of aMED score, respectively. CONCLUSIONS/INTERPRETATION: Various recommended dietary patterns were inversely related to a group of metabolites that were associated with elevated risk of diabetes. Adhering to a healthful eating pattern may attenuate or eliminate the detrimental association between metabolically unhealthy serum metabolites and risk of diabetes.

Metabolome-wide association study of estimated glomerular filtration rates in Hispanics.

Circulating metabolites are by-products of endogenous metabolism or exogenous sources and may inform disease states. Our study aimed to identify the source of variability in the association of metabolites with estimated glomerular filtration rate (eGFR) in Hispanics/Latinos with low chronic kidney disease prevalence by testing the association of 640 metabolites in 3,906 participants of the Hispanic Community Health Study/Study of Latinos. Metabolites were quantified in fasting serum through non-targeted mass spectrometry analysis. eGFR was regressed on inverse normally transformed metabolites in models accounting for study design and covariates. To identify the source of variation on eGFR associations, we tested the interaction of metabolites with lifestyle and clinical risk factors, and results were integrated with genotypes to identify metabolite genetic regulation. The mean age was 46 years, 43% were men, 22% were current smokers, 47% had a Caribbean Hispanic background, 19% had diabetes and the mean cohort eGFR was 96.4 ml/min/1.73 m2. We identified 404 eGFR-metabolite associations (False Discovery Rate under 0.05). Of these, 69 were previously reported, and 79 were novel associations with eGFR replicated in one or more published studies. There were significant interactions with lifestyle and clinical risk factors, with larger differences in eGFR-metabolite associations within strata of age, urine albumin to creatinine ratio, diabetes and Hispanic/Latino background. Several newly identified metabolites were genetically regulated, and variants were located at genomic regions previously associated with eGFR. Thus, our results suggest complex mechanisms contribute to the association of eGFR with metabolites and provide new insights into these associations.

Chronic Stress, Genetic Risk, and Obesity in US Hispanic/Latinos: Results From the Hispanic Community Health Study/Study of Latinos.

OBJECTIVE: This study aimed to investigate whether the association of chronic stress with obesity is independent of genetic risk and test whether it varies by the underlying genetic risk. METHODS: The analysis included data from the Hispanic Community Health Study/Study of Latinos, a community-based study of Hispanic/Latinos living in four US communities (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). The sample consisted of 5336 women and 3231 men who attended the Hispanic Community Health Study/Study of Latinos second in-person examination, had measures of obesity, and chronic stress, and were genotyped. Chronic stress burden was assessed by an eight-item scale. An overall polygenic risk score was calculated based on the summary statistics from GIANT and UK BioBank meta-analysis of body mass index (BMI) genome-wide association studies. Mixed-effect models were used to account for genetic relatedness and sampling design, as well as to adjust for potential confounders. RESULTS: A higher number of chronic stressors were associated with both BMI ( ß [log odds] = 0.31 [95% confidence interval = 0.23-0.38]) and obesity ( ß [log odds] = 0.10 [95% confidence interval = 0.07-0.13]), after adjustment for covariates and genetic risk. No interactions were found between chronic stress and the genetic risk score for BMI or obesity. CONCLUSIONS: We did not find evidence for an interaction between chronic stress and polygenic risk score, which was not consistent with other publications that showed greater BMI or obesity in the groups with high stressors and elevated genetic risk.

Association of Sugar-Sweetened Beverage Consumption with Prediabetes and Glucose Metabolism Markers in Hispanic/Latino Adults in the United States: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BACKGROUND: Both the incidence of diabetes mellitus and consumption of sugar-sweetened beverages are high in the Hispanic/Latino population in the United States. The associations between consumption of sugar-sweetened beverages, artificially sweetened beverages, and 100% fruit juice with prediabetes and glucose metabolism markers in the diverse Hispanic/Latino population in the United States are unknown. OBJECTIVES: The objective of this study was to examine the cross-sectional associations between consumption of sugar-sweetened beverages, artificially sweetened beverages, and 100% fruit juice with prediabetes and glucose metabolism markers such as fasting glucose and insulin, 2-h oral-glucose-tolerance test, HOMA-IR, HOMA index for ß-cell function (HOMA-B), and glycated hemoglobin (HbA1c) among US Hispanic/Latino adults. METHODS: Using baseline data from the Hispanic Community Health Study/Study of Latinos (2008-2011), beverage consumption was ascertained using two 24-h dietary recalls and a food propensity questionnaire. Diabetes/prediabetes status was defined by self-report, antihyperglycemic medication use, and American Diabetes Association laboratory criteria. Among 9965 individuals without diabetes (5194 normoglycemia, 4771 prediabetes) aged 18-74 y, the associations of beverage consumption with prediabetes and glucose metabolism markers were analyzed using logistic and linear regressions, respectively, accounting for complex survey design. RESULTS: Compared with individuals who consumed <1 serving/d (<240 mL/d) of sugar-sweetened beverages, individuals who consumed >2 servings/d (>480 mL/d) had 1.3 times greater odds of having prediabetes (95% CI: 1.06, 1.61) and higher glucose metabolism markers including fasting glucose, fasting insulin, HOMA-IR, and HbA1c. Consumption of artificially sweetened beverages showed an inverse association with ß-cell function (HOMA-B). Intake of 100% fruit juice was not significantly associated with prediabetes nor with glucose metabolism markers. CONCLUSIONS: Among US Hispanic/Latino adults, higher sugar-sweetened beverage consumption was associated with increased odds of prediabetes and higher glucose metabolism markers. Public health initiatives to decrease sugar-sweetened beverage consumption could potentially reduce the burden of diabetes among Hispanics/Latinos in the United States.

Jointly modeling of sleep variables that are objectively measured by wrist actigraphy.

Recently developed actigraphy devices have made it possible for continuous and objective monitoring of sleep over multiple nights. Sleep variables captured by wrist actigraphy devices include sleep onset, sleep end, total sleep time, wake time after sleep onset, number of awakenings, etc. Currently available statistical methods to analyze such actigraphy data have limitations. First, averages over multiple nights are used to summarize sleep activities, ignoring variability over multiple nights from the same subject. Second, sleep variables are often analyzed independently. However, sleep variables tend to be correlated with each other. For example, how long a subject sleeps at night can be correlated with how long and how frequent he/she wakes up during that night. It is important to understand these inter-relationships. We therefore propose a joint mixed effect model on total sleep time, number of awakenings, and wake time. We develop an estimating procedure based upon a sequence of generalized linear mixed effects models, which can be implemented using existing software. The use of these models not only avoids computational intensity and instability that may occur by directly applying a numerical algorithm on a complicated joint likelihood function, but also provides additional insights on sleep activities. We demonstrated in simulation studies that the proposed estimating procedure performed well in estimating both fixed and random effects' parameters. We applied the proposed model to data from the Women's Interagency HIV Sleep Study to examine the association of employment status and age with overall sleep quality assessed by several actigraphy measured sleep variables.