Publications by authors named "Michael Y Tsai"

259 Publications

Maternal Proinflammatory Adipokines Throughout Pregnancy and Neonatal Size and Body Composition: A Prospective Study.

Curr Dev Nutr 2021 Oct 7;5(10):nzab113. Epub 2021 Sep 7.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research Epidemiology Branch, Bethesda, MD, USA.

Background: Increased maternal adiposity and inflammation have impacts on fetal growth.

Objectives: The purpose of this prospective study was to investigate the associations of 3 proinflammatory adipokines in pregnancy with neonatal anthropometry.

Methods: In a sample of 321 US pregnant women from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort (NCT00912132), plasma IL-6, fatty acid binding protein-4 (FABP4), and chemerin were measured in plasma samples collected at 10-14, 15-26, 23-31, and 33-39 weeks of gestation. Generalized linear models were used to estimate associations of adipokines with neonatal weight, thigh, and crown-heel length, and skinfolds at birth. Models adjusted for age, race/ethnicity, education, nulliparity, prepregnancy BMI, and weeks of gestation at blood collection.

Results: At each time point, higher IL-6 was associated with lower neonatal birthweight and thigh length. At 15-26 weeks of gestation, a 1 SD pg/mL increase in IL-6 was associated with -84.46 g lower neonatal birthweight (95% CI: -150.70, -18.22), -0.17 cm shorter thigh length (95% CI: -0.27, -0.07), -0.43 cm shorter crown-heel length (95% CI: -0.75, -0.10), and -0.75 mm smaller sum of skinfolds (95% CI: -1.19, -0.31), with similar associations at 23-31 and 33-39 weeks of gestation. There were no associations of FABP4 and chemerin with neonatal anthropometry.

Conclusions: Starting as early as 15 weeks of gestation, higher maternal IL-6 concentrations in pregnancy were associated with lower neonatal birthweight, thigh and crown-heel length, and skinfolds. These data provide insight into the relevance of maternal inflammatory markers with neonatal anthropometry.
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http://dx.doi.org/10.1093/cdn/nzab113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528696PMC
October 2021

Changes of Plasma Phospholipid Fatty Acids Profiles in Pregnancy in Relation to the Diagnosis and Treatment of Gestational Diabetes Mellitus.

Clin Chem 2021 Oct 11. Epub 2021 Oct 11.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: Plasma phospholipid fatty acids (FAs) in early and mid-pregnancy have been prospectively related to gestational diabetes mellitus (GDM) risk. Yet, changes of FAs following GDM diagnosis and treatment and their implications for glucose metabolism and control remain understudied.

Methods: From the Eunice Kennedy Shriver National Institute Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2802 pregnant women, we ascertained 85 GDM cases using the Carpenter and Coustan criteria and 85 non-GDM controls after exclusion. Using plasma collected before (23-31 weeks) and after GDM diagnosis (33-39 weeks), we quantified 25 saturated, poly- and monounsaturated FAs levels. We estimated the fold change of FAs before and after GDM diagnosis, using multiple linear mixed models adjusting for confounders.

Results: Eight FAs showed significant fold changes from the baseline values (23-31 weeks) among GDM cases as compared to women without GDM. Five FAs showed reduced fold changes [myristic acid (14:0): β: -0.22 (95% CI: -0.30, -0.14), palmitic acid (16:0): β: -0.02 (95% CI: -0.04, -0.01), cis-palmitoleic acid (16:1n7): β: -0.15 (95% CI: -0.24, -0.05), alpha-linolenic acid (18:3n3): β: -0.19 (95% CI: -0.31, -0.07], and dihomo-gamma-linoleic acid (20:3n6): β:-0.16; 95% CI: -0.21, -0.11)], whereas 3 showed increases [heptadecanoic acid (17:0): β: 0.17 (95% CI: 0.11, 0.22), cis-vaccenic acid (18:1n7): β: 0.06 (95% CI: 0.03, 0.10), and arachidonic acid (20:4n6): β: 0.10 (95% CI: 0.06, 0.13)].

Conclusions: Our study identified 8 FAs with unique patterns of change before and after GDM diagnosis that differed significantly between women with and without GDM. Our findings may shed light on the role of FA metabolism in the pathophysiology and disease management and progression of GDM.

Clinical Trial Registry: NCT00912132.
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http://dx.doi.org/10.1093/clinchem/hvab169DOI Listing
October 2021

Longitudinal Plasma Metabolomics Profile in Pregnancy-A Study in an Ethnically Diverse U.S. Pregnancy Cohort.

Nutrients 2021 Sep 1;13(9). Epub 2021 Sep 1.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20817, USA.

Amino acids, fatty acids, and acylcarnitine metabolites play a pivotal role in maternal and fetal health, but profiles of these metabolites over pregnancy are not completely established. We described longitudinal trajectories of targeted amino acids, fatty acids, and acylcarnitines in pregnancy. We quantified 102 metabolites and combinations (37 fatty acids, 37 amino acids, and 28 acylcarnitines) in plasma samples from pregnant women in the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort ( = 214 women at 10-14 and 15-26 weeks, 107 at 26-31 weeks, and 103 at 33-39 weeks). We used linear mixed models to estimate metabolite trajectories and examined variation by body mass index (BMI), race/ethnicity, and fetal sex. After excluding largely undetected metabolites, we analyzed 77 metabolites and combinations. Levels of 13 of 15 acylcarnitines, 7 of 25 amino acids, and 18 of 37 fatty acids significantly declined over gestation, while 8 of 25 amino acids and 10 of 37 fatty acids significantly increased. Several trajectories appeared to differ by BMI, race/ethnicity, and fetal sex although no tests for interactions remained significant after multiple testing correction. Future studies merit longitudinal measurements to capture metabolite changes in pregnancy, and larger samples to examine modifying effects of maternal and fetal characteristics.
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http://dx.doi.org/10.3390/nu13093080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471130PMC
September 2021

Adhesion pathway proteins and risk of atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis.

BMC Cardiovasc Disord 2021 09 14;21(1):436. Epub 2021 Sep 14.

Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA.

Background: The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population.

Methods: Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons.

Results: After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P < 0.05/15 = 0.0033), circulating levels of the following proteins were positively associated with a higher risk of AF: MMP-2 (HR per standard deviation increment, 1.27; 95% CI 1.11‒1.45), TIMP-2 (HR 1.28; 95% CI 1.12‒1.46), VCAM-1 (HR 1.32; 95% CI 1.16‒1.50), and SLPI (HR 1.22; 95% CI 1.07‒1.38). The association between proteins and AF did not differ by race/ethnicity.

Conclusions: Circulating levels of MMP-2, TIMP-2, VCAM-1, and SLPI were positively associated with an increased risk of incident AF in a diverse population. Our findings suggest that adhesion pathway proteins may be important risk predictors of AF.
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http://dx.doi.org/10.1186/s12872-021-02241-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442417PMC
September 2021

Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis.

Eur Heart J 2021 Sep 11. Epub 2021 Sep 11.

Division of Cardiology, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.

Aims: Traditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events.

Methods And Results: The association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2.

Conclusion: Two atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.
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http://dx.doi.org/10.1093/eurheartj/ehab600DOI Listing
September 2021

High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis.

J Am Coll Cardiol 2021 Sep;78(11):1083-1094

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA. Electronic address:

Background: Little is known about the relationship between lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) and their joint association with atherosclerotic cardiovascular disease (ASCVD).

Objectives: The purpose of this study was to assess whether Lp(a)-associated ASCVD risk is modified by hsCRP in the context of primary prevention.

Methods: The current study included 4,679 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) Apolipoprotein ancillary data set. Cox proportional hazards models and Kaplan-Meier curves were used to assess the association among Lp(a), hsCRP, and time to cardiovascular disease (CVD) events.

Results: During a mean follow-up of 13.6 years, 684 CVD events occurred. A significant interaction was observed between Lp(a) and hsCRP (P = 0.04). With hsCRP <2 mg/L, no significant CVD risk was observed at any level of Lp(a) from <50 mg/dL to >100 mg/dL. However, with hsCRP ≥2 mg/L, a significant CVD risk was observed with Lp(a) of 50-99.9 mg/dL (HR: 1.36; 95% CI: 1.02-1.81) and Lp(a) ≥100 mg/dL (HR: 2.09; 95% CI: 1.40-3.13). Isolated elevations of either Lp(a) or hsCRP were not associated with increased CVD risk. In contrast, the combination of elevated Lp(a) (≥50 mg/dL) and hsCRP (≥2 mg/L) was independently associated with significant CVD risk (HR: 1.62; 95% CI: 1.25-2.10) and all-cause mortality (HR: 1.39; 95% CI: 1.12-1.72).

Conclusions: Lp(a)-associated ASCVD risk is observed only with concomitant elevation of hsCRP. Individuals with concomitant presence of elevated Lp(a) and systemic inflammation have greater ASCVD risk and all-cause mortality, and thus may merit closer surveillance and more aggressive ASCVD risk management.
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http://dx.doi.org/10.1016/j.jacc.2021.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444216PMC
September 2021

A longitudinal study of plasma acylcarnitines throughout pregnancy and associations with risk of gestational diabetes mellitus.

Clin Nutr 2021 08 10;40(8):4863-4870. Epub 2021 Jul 10.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background & Aims: Prospective and longitudinal data on the association between acylcarnitines and gestational diabetes (GDM) are lacking. This study aims to prospectively investigate 28 acylcarnitines in relation to subsequent GDM risk.

Methods: Within the NICHD Fetal Growth Studies-Singleton Cohort, plasma levels of acylcarnitines and cardiometabolic biomarkers were measured at gestational week (GW) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases and 214 controls.

Results: At GW 10-14, per standard deviation (SD) increased level of C14:1-OH was associated with a 55% increased risk of GDM after adjusting for major risk factors for GDM [OR (95% CI): 1.55 (1.05-2.29)]. At GW 15-26, C4, C8:1 and C16:1-OH were associated with an increased risk of GDM [OR (95% CI) for per SD increase: 1.42 (1.01-2.00), 1.41 (1.02-1.96), and 1.77 (1.10-2.84), respectively]. Whereas increased C10 and C18 were related to lower risk of GDM [OR (95% CI) for per SD increase: 0.74 (0.55-1.00), and 0.69 (0.49-0.97), respectively]. Moreover, we observed correlations of individual acylcarnitine with multiple clinical markers implicated in glucose homeostasis and cardiometabolic function among non-GDM women.

Conclusions: Our results demonstrate that several plasma acylcarnitine species are differentially associated with GDM risk by chain length. Future studies are warranted to investigate the distinct roles of individual acylcarnitine in glucose homeostasis in pregnancy.
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http://dx.doi.org/10.1016/j.clnu.2021.07.008DOI Listing
August 2021

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

Commun Biol 2021 07 28;4(1):918. Epub 2021 Jul 28.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of 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 ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind 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. 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.
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http://dx.doi.org/10.1038/s42003-021-02431-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319323PMC
July 2021

Assessment of Coronary Artery Calcium Scoring to Guide Statin Therapy Allocation According to Risk-Enhancing Factors: The Multi-Ethnic Study of Atherosclerosis.

JAMA Cardiol 2021 Oct;6(10):1161-1170

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, Maryland.

Importance: The 2018 American Heart Association/American College of Cardiology Guideline on the Management of Blood Cholesterol recommends the use of risk-enhancing factor assessment and the selective use of coronary artery calcium (CAC) scoring to guide the allocation of statin therapy among individuals with an intermediate risk of atherosclerotic cardiovascular disease (ASCVD).

Objective: To examine the association between risk-enhancing factors and incident ASCVD by CAC burden among those at intermediate risk of ASCVD.

Design, Setting, And Participants: The Multi-Ethnic Study of Atherosclerosis is a multicenter population-based prospective cross-sectional study conducted in the US. Baseline data for the present study were collected between July 15, 2000, and July 14, 2002, and follow-up for incident ASCVD events was ascertained through August 20, 2015. Participants were aged 45 to 75 years with no clinical ASCVD or diabetes at baseline, were at intermediate risk of ASCVD (≥7.5% to <20.0%), and had a low-density lipoprotein cholesterol level of 70 to 189 mg/dL.

Exposures: Family history of premature ASCVD, premature menopause, metabolic syndrome, chronic kidney disease, lipid and inflammatory biomarkers, and low ankle-brachial index.

Main Outcomes And Measures: Incident ASCVD over a median follow-up of 12.0 years.

Results: A total of 1688 participants (mean [SD] age, 65 [6] years; 976 men [57.8%]). Of those, 648 individuals (38.4%) were White, 562 (33.3%) were Black, 305 (18.1%) were Hispanic, and 173 (10.2%) were Chinese American. A total of 722 participants (42.8%) had a CAC score of 0. Among those with 1 to 2 risk-enhancing factors vs those with 3 or more risk-enhancing factors, the prevalence of a CAC score of 0 was 45.7% vs 40.3%, respectively. Over a median follow-up of 12.0 years (interquartile range [IQR], 11.5-12.6 years), the unadjusted incidence rate of ASCVD among those with a CAC score of 0 was less than 7.5 events per 1000 person-years for all individual risk-enhancing factors (with the exception of ankle-brachial index, for which the incidence rate was 10.4 events per 1000 person-years [95% CI, 1.5-73.5]) and combinations of risk-enhancing factors, including participants with 3 or more risk-enhancing factors. Although the individual and composite addition of risk-enhancing factors to the traditional risk factors was associated with improvement in the area under the receiver operating curve, the use of CAC scoring was associated with the greatest improvement in the C statistic (0.633 vs 0.678) for ASCVD events. For incident ASCVD, the net reclassification improvement for CAC was 0.067.

Conclusions And Relevance: In this cross-sectional study, among participants with CAC scores of 0, the presence of risk-enhancing factors was generally not associated with an overall ASCVD risk that was higher than the recommended treatment threshold for the initiation of statin therapy. The use of CAC scoring was associated with significant improvements in the reclassification and discrimination of incident ASCVD. The results of this study support the utility of CAC scoring as an adjunct to risk-enhancing factor assessment to more accurately classify individuals with an intermediate risk of ASCVD who might benefit from statin therapy.
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http://dx.doi.org/10.1001/jamacardio.2021.2321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281019PMC
October 2021

Free fatty acids and heart failure in the Multi-Ethnic Study of Atherosclerosis (MESA).

J Clin Lipidol 2021 Jul-Aug;15(4):608-617. Epub 2021 May 31.

Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware St SE, Minneapolis 55455 MN, USA. Electronic address:

Background: Free fatty acids (FFAs) may be associated with heart failure (HF) risk, but prospective research is lacking.

Objective: This study investigated associations between fasting FFAs and HF incidence overall and by ejection fraction (EF) subtypes [HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF)] to evaluate FFAs as a potential biomarker for HF risk prediction.

Methods: This study was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort among 6,667 participants with complete baseline (2000-2002) FFAs and HF follow-up (through 2015). Associations between FFAs and HF incidence were evaluated with Cox proportional hazards regression. Cross-sectional associations between FFAs and HF risk markers were also evaluated using linear regression [N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular (LV) mass index] and logistic regression [LV hypertrophy (LVH)]. Stratification and cross-product terms were utilized to evaluate differences by age, sex, race/ethnicity and diabetes.

Results: FFAs were not associated with HF overall or with HFrEF. FFAs were not associated with HFpEF in the overall population or among males, but were borderline positively associated with risk among females (fully-adjusted tertile 3 vs. 1 HR=2.17, 95% CI: 1.06, 4.42) (sex P-interaction=0.05). FFAs were not associated with NT-proBNP, but were inversely associated with LV mass index and LVH with stronger associations among females (P-interaction≥0.10). Associations did not differ by age, race/ethnicity or diabetes status.

Conclusions: FFAs generally do not appear to be an independent predictor for HF risk. Additional research is needed to confirm findings particularly studies evaluating associations by sex and EF subtypes.
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http://dx.doi.org/10.1016/j.jacl.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616771PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Association Between Omega-3 Fatty Acid Levels and Risk for Incident Major Bleeding Events and Atrial Fibrillation: MESA.

J Am Heart Assoc 2021 06 27;10(11):e021431. Epub 2021 May 27.

Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology Johns Hopkins University School of Medicine Baltimore MD.

Background Randomized trials of pharmacologic strength omega-3 fatty acid (n3-FA)-based therapies suggest a dose-dependent cardiovascular benefit. Whether blood n3-FA levels also mediate safety signals observed in these trials, such as increased bleeding and atrial fibrillation (AF), remains uncertain. We hypothesized that higher baseline n3-FA levels would be associated with incident bleeding and AF events in MESA (Multi-Ethnic Study of Atherosclerosis), which included a population free of clinical cardiovascular disease at baseline. Methods and Results We examined the association between baseline plasma n3-FA levels (expressed as percent mass of total fatty acid) with incident bleeding and AF in MESA, an ongoing prospective cohort study. Bleeding events were identified from review of hospitalization (), and (), codes, and AF from participant report, discharge diagnoses, Medicare claims data, and study ECGs performed at MESA visit 5. Separate multivariable Cox proportional hazard modeling was used to estimate hazard ratios of the association of continuous n3-FA (log eicosapentaenoic acid [EPA], log docosahexaenoic acid [DHA], log [EPA+DHA]) and incident hospitalized bleeding events and AF. Among 6546 participants, the mean age was 62.1 years and 53% were women. For incident bleeding, consistent statistically significant associations with lower rates were seen with increasing levels of EPA and EPA+DHA in unadjusted and adjusted models including medications that modulate bleeding risk (aspirin, NSAIDS, corticosteroids, and proton pump inhibitors). For incident AF, a significant association with lower rates was seen with increasing levels of DHA, but not for EPA or EPA+DHA. Conclusions In MESA, higher plasma levels of n3-FA (EPA and EPA+DHA, but not DHA) were associated with significantly fewer hospitalized bleeding events, and higher DHA levels (but not EPA or EPA+DHA) with fewer incident AF events.
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http://dx.doi.org/10.1161/JAHA.121.021431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483537PMC
June 2021

Performance of novel low-density lipoprotein-cholesterol calculation methods in predicting clinical and subclinical atherosclerotic cardiovascular disease risk: The Multi-Ethnic Study of Atherosclerosis.

Atherosclerosis 2021 06 8;327:1-4. Epub 2021 May 8.

Department of Pathology and Laboratory Medicine, University of Minnesota, Twin Cities, USA. Electronic address:

Background And Aims: This study examined the performance of two novel low-density lipoprotein-cholesterol (LDL-C) calculations, LDL and LDL, on predicting atherosclerotic cardiovascular diseases (ASCVD) risk compared to traditional LDL according to the 2018 American Heart Association/American College of Cardiology (AHA/ACC) primary prevention guidelines.

Methods: A total of 6701 randomly recruited Multi-Ethnic Study of Atherosclerosis (MESA) participants free of ASCVD at baseline were followed for ASCVD during a median of 13.9 years and for subclinical ASCVD-coronary artery calcium (CAC) during a median of 12.5 years. Prevalence of borderline high triglyceride (≥1.7 mmol/L) was 15.2% and was at 13.5% for high triglyceride (≥2.3 mmol/L).

Results: Applying the criteria of LDL-C<1.8 mmol/L in 40-75 year olds without diabetes mellitus to be exempt from risk discussion, LDL and LDL classified less individuals in this category than LDL (p < 0.001), both had 20 individuals with ASCVD, versus 22 by LDL. Positive CAC in the discussion-exempt group were over 38% higher (p < 0.001) when classified by LDL than by LDL or LDL. Individuals with LDL-C≥4.9 mmol/L are recommended to high-intensity statin therapy by the AHA/ACC guidelines. The LDL≥4.9 mmol/L group had 20 ASCVD events, versus 21 in LDL and 22 in LDL group.

Conclusions: In a multi-ethnic USA population, LDL and LDL did not over- or under-estimate ASCVD risk compared to LDL in primary prevention according to AHA/ACC guidelines, while LDL under-estimated subclinical ASCVD risk in the low-risk population. These findings support the replacement of LDL by LDL or LDL for lipid screen in the general population.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.018DOI Listing
June 2021

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

Nat Commun 2021 04 22;12(1):2329. Epub 2021 Apr 22.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
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http://dx.doi.org/10.1038/s41467-021-22370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062567PMC
April 2021

Associations of D-Dimer with Computed Tomographic Lung Abnormalities, Serum Biomarkers of Lung Injury, and Forced Vital Capacity: MESA Lung Study.

Ann Am Thorac Soc 2021 11;18(11):1839-1848

Department of Medicine.

The coagulation cascade may play a role in the pathogenesis of interstitial lung disease through increased production of thrombin and fibrin deposition. Whether circulating coagulation cascade factors are linked to lung inflammation and scarring among community-dwelling adults is unknown. To test the hypothesis that higher baseline D-dimer concentrations are associated with markers of early lung injury and scarring. Using the MESA (Multi-Ethnic Study of Atherosclerosis) cohort ( = 6,814), we examined associations of baseline D-dimer concentrations with high attenuation areas from examination 1 (2000-2002; = 6,184) and interstitial lung abnormalities from examination 5 computed tomographic (CT) scans (2010-2012; = 2,227), and serum MMP-7 (matrix metalloproteinase-7) and SP-A (surfactant protein-A) from examination 1 ( = 1,098). We examined longitudinal change in forced vital capacity (FVC) from examinations 3-6 (2004-2018, = 3,562). We used linear logistic regression and linear mixed models to examine associations and adjust for potential confounders. The mean (standard deviation) age of the cohort was 62 (10) years, and the D-dimer concentration was 0.35 (0.69) ug/ml. For every 10% increase in D-dimer concentration, there was an increase in high attenuation area percentage of 0.27 (95% confidence interval (CI), 0.08-0.47) after adjustment for covariates. Associations were stronger among those older than 65 years ( values for interaction < 0.001). A 10% increase in D-dimer concentration was associated with an odds ratio of 1.05 for interstitial lung abnormalities (95% CI, 0.99-1.11). Higher D-dimer concentrations were associated with higher serum MMP-7 and a faster decline in FVC. D-dimer was not associated with SP-A. Higher D-dimer concentrations were associated with a greater burden of lung parenchymal abnormalities detected on CT scan, MMP-7, and FVC decline among community-dwelling adults.
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http://dx.doi.org/10.1513/AnnalsATS.202012-1557OCDOI Listing
November 2021

Conception by fertility treatment and offspring deoxyribonucleic acid methylation.

Fertil Steril 2021 08 3;116(2):493-504. Epub 2021 Apr 3.

Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York.

Objective: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment.

Design: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.

Setting: New York State (excluding New York City).

Patient(s): This analysis included 855 newborns and 152 children at approximately 9 years of age.

Intervention(s): None.

Main Outcome Measure(s): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.

Result(s): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction.

Conclusion(s): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.
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http://dx.doi.org/10.1016/j.fertnstert.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349775PMC
August 2021

Plasma ω-3 and ω-6 PUFA Concentrations and Risk of Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis.

J Nutr 2021 06;151(6):1479-1486

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.

Background: Current literature examining the prospective relation of circulating omega-3 (n-3) and omega-6 (n-6) PUFAs and atrial fibrillation (AF) is limited to predominantly white populations.

Objectives: We investigated the association of circulating n-3 and n-6 PUFAs with incident AF in participants from the Multi-Ethnic Study of Atherosclerosis.

Methods: A total of 6229 participants (mean age = 62 y; 53% female; 39% white, 27% black, 22% Hispanic, and 12% Chinese) who were free of baseline AF and with plasma phospholipid PUFAs measured at baseline using GC were prospectively followed for the development of AF. Incident AF was ascertained using International Classification of Diseases-9 codes from hospital discharge records and Medicare claims data with follow-up through 2014. Multivariable Cox proportional hazards regression analysis was performed to determine the risk of incident AF.

Results: During a median follow-up of 12.9 y, 813 (13%) participants developed AF. Each higher SD increment in arachidonic acid (AA; 20:4n-6) concentrations was associated with an 11% decreased risk of incident AF (HR: 0.89; 95% CI: 0.82, 0.96). Similarly, higher overall n-6 PUFA concentrations were also associated with a reduced AF risk (HR per SD increment: 0.93; 95% CI: 0.87, 1.00). Although no significant overall associations were observed for any individual n-3 PUFAs, higher circulating concentrations of DHA (22:6n-3) and EPA (20:5n-3) were associated with a decreased AF risk in blacks and Hispanics (DHA only) but not whites or Chinese Americans.

Conclusions: In a multiethnic cohort of individuals free of baseline cardiovascular disease, higher plasma concentrations of n-6 PUFAs, particularly AA, were associated with a reduced risk of incident AF. Important differences in AF risk were also noted across race/ethnicity for the n-3 PUFAs DHA and EPA.
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http://dx.doi.org/10.1093/jn/nxab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243886PMC
June 2021

Plasma lipidomics profile in pregnancy and gestational diabetes risk: a prospective study in a multiracial/ethnic cohort.

BMJ Open Diabetes Res Care 2021 03;9(1)

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA

Introduction: Disruption of lipid metabolism is implicated in gestational diabetes (GDM). However, prospective studies on lipidomics and GDM risk in race/ethnically diverse populations are sparse. Here, we aimed to (1) identify lipid networks in early pregnancy to mid-pregnancy that are associated with subsequent GDM risk and (2) examine the associations of lipid networks with glycemic biomarkers to understand the underlying mechanisms.

Research Design And Methods: This study included 107 GDM cases confirmed using the Carpenter and Coustan criteria and 214 non-GDM matched controls from the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, untargeted lipidomics data of 420 metabolites (328 annotated and 92 unannotated), and information on glycemic biomarkers in maternal plasma at visit 0 (10-14 weeks) and visit 1 (15-26 weeks). We constructed lipid networks using weighted correlation network analysis technique. We examined prospective associations of lipid networks and individual lipids with GDM risk using linear mixed effect models. Furthermore, we calculated Pearson's partial correlation for GDM-related lipid networks and individual lipids with plasma glucose, insulin, C-peptide and glycated hemoglobin at both study visits.

Results: Lipid networks primarily characterized by elevated plasma diglycerides and short, saturated/low unsaturated triglycerides and lower plasma cholesteryl esters, sphingomyelins and phosphatidylcholines were associated with higher risk of developing GDM (false discovery rate (FDR) <0.05). Among individual lipids, 58 metabolites at visit 0 and 96 metabolites at visit 1 (40 metabolites at both time points) significantly differed between women who developed GDM and who did not (FDR <0.05). Furthermore, GDM-related lipid networks and individual lipids showed consistent correlations with maternal glycemic markers particularly in early pregnancy at visit 0.

Conclusions: Plasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk in race/ethnically diverse US women. Future research is warranted to assess lipid metabolites as etiologic markers of GDM.
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http://dx.doi.org/10.1136/bmjdrc-2020-001551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939004PMC
March 2021

Lipoprotein (a) and coronary artery calcification: prospective study assessing interactions with other risk factors.

Metabolism 2021 03 7;116:154706. Epub 2021 Jan 7.

Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. Electronic address:

Background: Elevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular risk factors could affect their relationship.

Methods: We tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline.

Results: Elevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm/year higher for Lp(a) ≥30 versus <30 mg/dL, and Lp(a) ≥50 versus <50 mg/dL, respectively), but not relative change in CAC volume. No association was found with change in CAC density when assessing continuous ln-transformed Lp(a). The association between elevated Lp(a) (≥30 mg/dL) and absolute change in CAC volume was greater in participants with higher circulating levels of interleukin-2 soluble receptor α, soluble tumor necrosis factor alpha receptor 1 and fibrinogen (15.33, 11.81 and 7.02 mm/year in quartile 4, compared to -3.44, -0.59 and 1.91 mm/year in quartile 1, respectively). No significant interaction was found for other study variables. Similar interactions were seen when assessing Lp(a) levels ≥50 mg/dL.

Conclusions: Elevated Lp(a) was associated with an absolute increase in CAC volume, especially in participants with higher levels of selected markers of inflammation and coagulation. These results suggest Lp(a) as a potential biomarker for CAC volume progression.
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http://dx.doi.org/10.1016/j.metabol.2021.154706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853621PMC
March 2021

Plasma omega-3 and saturated fatty acids are differentially related to pericardial adipose tissue volume across race/ethnicity: the Multi-ethnic Study of Atherosclerosis.

Eur J Clin Nutr 2021 08 4;75(8):1237-1244. Epub 2021 Jan 4.

Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA.

Background: Pericardial adipose tissue (PAT) is a cardiometabolic risk factor influenced by race/ethnicity, inflammation, and metabolic dysfunction. Omega-3 fatty acids (FAs) and saturated FAs (SFAs) are known to affect these latter phenomena and may influence PAT accumulation. We aimed to determine whether plasma levels of these FAs are related to PAT volume and its rate of change over a median 3-year follow-up.

Methods: Cardiac computed tomography assessed PAT in 6785 Multi-Ethnic Study of Atherosclerosis participants. Gas chromatography flame-ionization estimated plasma phospholipid FAs. Regression analyses estimated associations of FAs with PAT volume and its rate of change with adjustments for other risk factors. Race-interactions were tested.

Results: In cross-section, top tertiles of omega-3 FAs and odd-chained SFAs were associated with 2.8 and 4.93 cm lower PAT volumes, respectively; race/ethnicity was a significant modifying variable (p < 0.002). Even-chained SFAs were associated with 3.5 cm greater PAT volume. With stratification by race/ethnicity, Chinese Americans in the top tertile of omega-3 FAs showed 10.5 cm greater PAT volume than those in the referent tertile. Black individuals in the top tertile of odd-chained SFAs showed 5.0 cm lower PAT compared to referents. Black and Chinese Americans in top tertiles of even-chained SFAs showed respective 3.7 and 5.9 cm greater PAT volumes compared to referents. Two associations were observed in prospective analyses among Caucasians; race interactions were non-significant.

Conclusions: Cross-sectional and prospective findings provide inconclusive evidence as to whether plasma FAs are related to PAT in healthy individuals. Cohort studies with longer follow-up periods are warranted.
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http://dx.doi.org/10.1038/s41430-020-00833-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254815PMC
August 2021

Lipoprotein (a) and the risk of elevated depressive symptoms: The Multi-Ethnic Study of Atherosclerosis.

J Psychiatr Res 2021 01 13;133:119-124. Epub 2020 Dec 13.

Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. Electronic address:

Previous studies suggested a potential relationship between plasma lipoprotein (a) [Lp(a)] and elevated depressive symptoms. We aimed to investigate any such relationship in the Multi-Ethnic Study of Atherosclerosis participants who were free of cardiovascular events. Analysis included 4938 participants without elevated depressive symptoms and with Lp(a) levels measured at baseline. Participants were examined at four clinic visits over a 10-year period. Elevated depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D) and were defined as a CES-D score ≥16 or use of anti-depressants. Lp(a) level was measured with a latex-enhanced turbidimetric immunoassay. After adjusting for demographics, socioeconomic factors and other confounding factors in Cox regression analyses, a higher ln-transformed Lp(a) level was associated with new elevated depressive symptoms since baseline (hazard ratio [95% CI] = 1.09 [1.02-1.16] per SD increment in ln-transformed level, P = 0.01). However, no association was found when elevated Lp(a) levels were assessed using clinical cut-off point (≥30 or 50 mg/dL), nor in sensitivity analyses using alternative definitions of elevated depressive symptoms. No significant interaction with race/ethnicity was found for all the above analyses. Also, no significant association was found between baseline Lp(a) levels and absolute or relative changes in CES-D score between baseline and last follow-up visits. Our study suggests a potential association between Lp(a) level and new elevated depressive symptoms, but such association was not robust in the sensitivity analyses. Future studies are warranted to investigate the role of Lp(a) in depressive symptoms in other cohorts.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.022DOI Listing
January 2021

Plasma Phospholipid -3/-6 Polyunsaturated Fatty Acids and Desaturase Activities in Relation to Moderate-to-Vigorous Physical Activity through Pregnancy: A Longitudinal Study within the NICHD Fetal Growth Studies.

Nutrients 2020 Nov 19;12(11). Epub 2020 Nov 19.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Maternal plasma phospholipid polyunsaturated fatty acids (PUFAs) play critical roles in maternal health and fetal development. Beyond dietary factors, maternal moderate-to-vigorous physical activity (MVPA) has been linked to multiple health benefits for both the mother and offspring, but studies investigating the influence of maternal MVPA on maternal PUFA profile are scarce. The objective of present study was to examine the time-specific and prospective associations of MVPA with plasma PUFA profile among pregnant women. This study included 321 participants from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort. Maternal plasma phospholipid PUFAs and MPVA were measured at four visits during pregnancy (10-14, 15-26, 23-31, and 33-39 gestational weeks (GW)). Associations of maternal MVPA with individual plasma PUFAs and desaturase activity were examined using generalized linear models. Maternal MVPA was associated inversely with plasma phospholipid linoleic acid, gamma-linolenic acid, and Δ6-desaturase in late pregnancy (23-31 or 33-39 GW), independent of maternal age, race, education, parity, pre-pregnancy body mass index, and dietary factors. Findings from this longitudinal study indicate that maternal habitual MVPA may play a role on PUFAs metabolism, particular by alerting plasma -6 subclass and desaturase activity in late pregnancy. These associations are novel and merit confirmation in future studies.
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http://dx.doi.org/10.3390/nu12113544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699189PMC
November 2020

Lifetime duration of lactation and chronic inflammation among middle-aged women with a history of gestational diabetes.

BMJ Open Diabetes Res Care 2020 10;8(2)

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Introduction: Longer duration of lactation is associated with lower cardiometabolic disease risk, but pathogenic pathways involved in the disease progression are unclear, especially among high-risk women. We aimed to examine the associations of lifetime lactation duration with cardiometabolic biomarkers among middle-aged women with a history of gestational diabetes (GDM).

Research Design And Methods: Women with a history of GDM participating in the Nurses' Health Study II, a prospective cohort study, were identified and followed through biennial questionnaires beginning in 1991. Lactation history was asked in three follow-up questionnaires to calculate lifetime duration. In 2012-2014, fasting blood samples were collected through the Diabetes & Women's Health Study to measure inflammatory (C-reactive protein (CRP), interleukin (IL) 6), liver enzyme (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase), and lipid biomarkers (total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol).

Results: At follow-up blood collection, women were at median age 58.2 (95% CI 51 to 65) years and 26.3 (95% CI 15.7 to 34.1) years since GDM index pregnancy. After multiple adjustment including prepregnancy body mass index (BMI), longer duration of lactation was significantly associated with lower CRP (least squares (LS) mean 1.90 mg/L (95% CI 1.47 to 2.45) for 0-month lactation, 1.98 mg/L (95% CI 1.68 to 2.32) for up to 12-month lactation, 1.67 mg/L (95% CI 1.42 to 1.97) for 12-24 month lactation, and 1.39 mg/L (95% CI 1.19 to 1.62) for >24-month lactation; p trend=0.003) and IL-6 (1.25 pg/L (95% CI 0.94 to 1.68), 1.19 pg/L (95% CI 0.99 to 1.42), 1.04 pg/L (95% CI 0.87 to 1.25), and 0.93 pg/L (95% CI 0.78 to 1.11); p trend=0.04). Longer duration of lactation was associated with lower risk for chronic inflammation using CRP 3 mg/L cut-off in middle-aged women (OR 0.81 (95% CI 0.69 to 0.940 per 1-year increase) with multiple adjustment.

Conclusions: Longer lifetime duration of lactation was associated with favorable inflammatory biomarker concentrations in middle-aged women with a history of GDM. Chronic inflammatory pathways may be responsible for previously reported associations between lactation and long-term risk for cardiometabolic diseases.
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http://dx.doi.org/10.1136/bmjdrc-2020-001229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594200PMC
October 2020

Genome-Wide Association Study Highlights as a Novel Locus for Lipoprotein(a) Levels-Brief Report.

Arterioscler Thromb Vasc Biol 2021 01 29;41(1):458-464. Epub 2020 Oct 29.

Division of Experimental Medicine (M.H., H.Y.C., G.T., J.C.E.), McGill University, Montreal, Quebec.

Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance ≤5×10). In addition to validating previous associations at , , and , we identified a novel variant at the locus, encoding β2GPI (beta2-glycoprotein I). The variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; =2.8×10) and demonstrated a stronger effect after adjustment for variation at the locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; =3.8×10). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; =0.0071).

Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.
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http://dx.doi.org/10.1161/ATVBAHA.120.314965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769958PMC
January 2021

Lipoprotein (a) and aortic valve calcium in South Asians compared to other race/ethnic groups.

Atherosclerosis 2020 11 18;313:14-19. Epub 2020 Sep 18.

Johns Hopkins University, School of Medicine, 733 N Broadway, Baltimore, MD, 21205, USA; Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins University, 600 N Wolfe Street, Baltimore, MD, 21287, USA.

Background And Aims: South Asians are at increased risk for cardiovascular disease (CVD). Aortic valve calcium (AVC) is associated with CVD risk and aortic stenosis. Elevated Lp(a) is a heritable risk factor for CVD and AVC. AVC prevalence and its association with Lp(a) have not been studied in South Asians.

Methods: Among participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study (n = 695), AVC prevalence and extent were compared to four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA) (n = 4671). Multivariable regression was performed to evaluate associations between Lp(a) and AVC stratified by race/ethnic groups, adjusting for cardiovascular risk factors.

Results: After age and sex adjustment, South Asians had higher median Lp(a) (17.0 mg/dL) compared to Whites (12.9 mg/dL), Hispanics (13.1 mg/dL) and Chinese Americans (12.9 mg/dL), and Blacks had highest Lp(a) levels (35.1 mg/dL). There were no differences in the odds of AVC in South Asians compared with Whites or Hispanics, after age and sex adjustment (p = 0.64 and 0.63, respectively). Odds of AVC was lower in Chinese (OR 0.35; 95%CI 0.23-0.54) and somewhat lower in Blacks compared with South Asians (OR 0.76; 0.56-1.04). There were no associations between Lp(a) and AVC presence or extent in South Asians. Lp(a) was associated with AVC only among Blacks and Whites.

Conclusions: Although present in Whites and Blacks, there were no associations between Lp(a) and AVC in South Asians. These differences may be due to statistic power or race specific modifying factors that influences the effect of Lp(a) particles on AVC pathogenesis.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247632PMC
November 2020

Longitudinal Decline on the Dichotic Digits Test.

Am J Audiol 2020 Dec 25;29(4):862-872. Epub 2020 Sep 25.

Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison.

Purpose The dichotic digits test (DDT) is commonly administered in clinical and research settings, but it is not well understood how performance changes in aging. The purpose of this study is to determine the 5-year change on the free recall task and right ear advantage (REA) in a population-based cohort and factors associated with change. Method Participants in the population-based Epidemiology of Hearing Loss Study, who completed the DDT during the fourth (2009-2010) and fifth (2013-2016) examination periods were included ( = 865, = 72.8 years at baseline). Free recall DDT was administered using 25 sets of triple-digit pairs presented at 70 dB HL. The REA was calculated by subtracting the score in the left ear from the score in the right ear. Results In 5 years, most participants (62.4%) declined on free recall performance (mean decline = 3.0% [4.5 digits], < .01). In age-sex-adjusted models, higher baseline scores, hearing impairment, and lower education were significantly associated with increased risk of decline. An REA at baseline (76.8%) and follow-up (77.9%) was common. Half of participants (50.6%) had a 5-year REA widening ( = 1.9% [1.4 digits], = .01). Older age, but not hearing impairment, was associated with increased risk of REA widening. Conclusions The 5-year decline on free recall recognition performance was not associated with age but was associated with hearing impairment, whereas the 5-year widening of REA was associated with age but not hearing impairment. These results indicate that the REA may be a more sensitive measure of aging of the central auditory system than free recall performance.
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http://dx.doi.org/10.1044/2020_AJA-20-00098DOI Listing
December 2020

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Nat Genet 2020 09 24;52(9):969-983. Epub 2020 Aug 24.

Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1038/s41588-020-0676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483769PMC
September 2020

Associations of ω-3 Fatty Acids With Interstitial Lung Disease and Lung Imaging Abnormalities Among Adults.

Am J Epidemiol 2021 01;190(1):95-108

Docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models, but human studies are lacking. We examined associations of circulating levels of DHA and other polyunsaturated fatty acids with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000-2012; n = 6,541), the Framingham Heart Study (2005-2011; n = 3,917), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) (2002-2006; n = 1,106). Polyunsaturated fatty acid levels were determined from fasting blood samples and extracted from plasma phospholipids (MESA and AGES-Reykjavik) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalization due to ILD (per standard-deviation increment, adjusted rate ratio = 0.69, 95% confidence interval (CI): 0.48, 0.99) and a lower rate of death due to ILD (per standard-deviation increment, adjusted hazard ratio = 0.68, 95% CI: 0.47, 0.98). Higher DHA was associated with fewer interstitial lung abnormalities on computed tomography (per natural log increment, pooled adjusted odds ratio = 0.65, 95% CI: 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and fewer lung abnormalities on computed tomography in a meta-analysis of data from population-based cohort studies.
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http://dx.doi.org/10.1093/aje/kwaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784523PMC
January 2021

Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis.

Matern Fetal Med 2020 Jan 24;2(1):2-9. Epub 2020 Jan 24.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda MD 20817, USA.

Objective: This study investigated the prospective associations of circulating levels of sex hormone-binding globulin (SHBG) levels with cardiometabolic biomarkers and risk of gestational diabetes (GDM) during pregnancy. It also examines the longitudinal trajectory of SHBG in women with and without GDM.

Methods: We conducted a nested case-control study of 107 incident GDM cases and 214 matched controls within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort. The cohort enrolled non-obese and obese women aged 18-40 years with a singleton pregnancy between 8 and 13 weeks of gestation from 2009 to 2013. GDM was ascertained via medical records review. Blood samples were drawn four times at gestational weeks 10-14, 15-26, 23-31, and 33-39. The prospective associations between SHBG levels and cardiometabolic biomarkers were examined using the Spearman partial correlation among the controls. The longitudinal trajectories of SHBG levels were examined among the cases and the controls. Meta-analysis of prospective studies were performed to examine the association between SHBG levels and GDM risk.

Results: SHBG levels at gestational weeks 10-14 were significantly inversely associated with fasting insulin ( = -0.17, = 0.01) and insulin resistance as measured by HOMA-IR (= -0.17, = 0.01) at gestational week 15-26. SHBG at gestational weeks 10-14 and 15-26 was lower in cases than controls (mean ± standard deviation: (204.0 ± 97.6) . (220.9 ± 102.5) nmol/L, = 0.16 and (305.6 ± 124.3) . (322.7 ± 105.1) nmol/L, = 0.14, respectively), yet the differences were not significant. In the meta-analysis, SHBG was 41.5 nmol/L (95% confidence interval: 23.9, 59.1,  < 0.01) significantly lower among women with GDM than without, and each 50 nmol/L increase in SHBG was significantly associated with an odds ratio of 0.85 (95% confidence interval: 0.76-0.95,  = 0.01) for GDM.

Conclusion: Lower SHBG levels in early pregnancy were prospectively associated with higher high insulin levels and insulin resistance in mid-pregnancy and subsequent risk of GDM, independent of adiposity. SHBG may serve as a marker for the identification of high-risk pregnancies during early pregnancy.
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http://dx.doi.org/10.1097/FM9.0000000000000037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357819PMC
January 2020
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