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Obesity in pregnancy and gestational diabetes (GDM) increase cardiometabolic disease risk but are difficult to disentangle. This study aimed to test the hypothesis that 4-10 years after a pregnancy complicated by overweight/obesity and GDM (OB-GDM), women and children would have greater adiposity and poorer cardiometabolic health than those with overweight/obesity (OB) or normal weight (NW) and no GDM during the index pregnancy.In this cross-sectional study, mother-child dyads were stratified into three groups based on maternal health status during pregnancy (OB-GDM = 67; OB = 76; NW = 76). Weight, height, waist and hip circumferences, and blood pressure were measured, along with fasting glucose, insulin, HbA1c, lipids, adipokines, and cytokines.Women in the OB and OB-GDM groups had greater current adiposity and poorer cardiometabolic health outcomes than those in the NW group (Poor cardiometabolic health in women with prior GDM is independent of current adiposity. Although greater adiposity among children exposed to GDM is evident at 4-10 years, differences in cardiometabolic health may not emerge until later.

Introduction: The association of apolipoprotein L1 (APOL1) nephropathy risk variants (APOL1), unique to African-ancestry (African-American [AA]) populations, with systemic inflammation, a contributor to chronic kidney disease (CKD) and end-stage kidney disease (ESKD) is ill-defined. This study aimed to describe the role of inflammatory markers in the relationship between APOL1 and incident kidney outcomes using a prospective cohort study. Methods: APOL1 high-risk status under a recessive genetic model was studied in 10,605 AA adults aged ≥45 years from the Reasons for Geographic and Racial Differences in Stroke study. The primary variables of interest were inflammatory markers: C-reactive protein (mg/dL), white blood cell count (cells/mm3), and serum albumin (sALB) (mg/dL). High inflammation status was defined if at least one of these inflammatory markers exceeded clinical threshold. The association between APOL1 and biomarkers were assessed using regression models adjusting for age, sex, ancestry, hypertension, lipid medications, albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR). Models were stratified by diabetes status. We identified incident ESKD using USRDS linkage, and we defined incident CKD as an eGFR 2 and ≥25% decline in the eGFR and normal baseline eGFR and tested for mediation of APOL1 and outcomes by biomarkers using the causal inference approach. Results: Among 7,151 participants with data available on all inflammation markers, 4,479 participants had ≥1 marker meeting the clinical threshold. APOL1 high-risk status was associated with lower adjusted odds of reduced sALB {odds ratio (OR) (95% confidence interval [CI]): 0.59 [0.36, 0.96])}, and this association was significant in people with diabetes (OR [95% CI]: 0.40 [0.18, 0.89]) but not in those without diabetes. There was no association of APOL1 high-risk status with other markers or high inflammation status. APOL1 was independently associated with ESKD (OR [95% CI] = 1.78 [1.28, 2.48]) and CKD (OR [95% CI] = 1.38 [1.00, 1.91]). On mediation analysis, the direct effect between APOL1 and ESKD strengthened after accounting for sALB, but the estimated mediated effect was not statistically significant (OR [95% CI]: 0.98 [0.92, 1.05], p = 0.58). Conclusion: APOL1 high-risk variants were associated with sALB. However, sALB did not statistically mediate the association between APOL1 and incident ESKD.

As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN‐designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity‐focused investigators and next‐step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.

BackgroundSome but not all African-Americans (AA) who carry APOL1 nephropathy risk variants (APOL1) develop kidney failure (end-stage kidney disease, ESKD). To identify genetic modifiers, we assessed gene–gene interactions in a large prospective cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.MethodsGenotypes from 8,074 AA participants were obtained from Illumina Infinium Multi-Ethnic AMR/AFR Extended BeadChip. We compared 388 incident ESKD cases with 7,686 non-ESKD controls, using a two-locus interaction approach. Logistic regression was used to examine the effect of APOL1 risk status (using recessive and additive models), single nucleotide polymorphism (SNP), and APOL1*SNP interaction on incident ESKD, adjusting for age, sex, and ancestry. APOL1*SNP interactions that met the threshold of 1.0 × 10−5 were replicated in the Genetics of Hypertension Associated Treatment (GenHAT) study (626 ESKD cases and 6,165 controls). In a sensitivity analysis, models were additionally adjusted for diabetes status. We conducted additional replication in the BioVU study.ResultsTwo APOL1 risk alleles prevalence (recessive model) was similar in the REGARDS and GenHAT studies. Only one APOL1–SNP interaction, for rs7067944 on chromosome 10, ~10 KB from the PCAT5 gene met the genome-wide statistical threshold (Pinteraction = 3.4 × 10−8), but this interaction was not replicated in the GenHAT study. Among other relevant top findings (with Pinteraction < 1.0 × 10−5), a variant (rs2181251) near SMOC2 on chromosome six interacted with APOL1 risk status (additive) on ESKD outcomes (REGARDS study, Pinteraction =5.3 × 10−6) but the association was not replicated (GenHAT study, Pinteraction = 0.07, BioVU study, Pinteraction = 0.53). The association with the locus near SMOC2 persisted further in stratified analyses. Among those who inherited ≥1 alternate allele of rs2181251, APOL1 was associated with an increased risk of incident ESKD (OR [95%CI] = 2.27[1.53, 3.37]) but APOL1 was not associated with ESKD in the absence of the alternate allele (OR [95%CI] = 1.34[0.96, 1.85]) in the REGARDS study. The associations were consistent after adjusting for diabetes.ConclusionIn a large genome-wide association study of AAs, a locus SMOC2 exhibited a significant interaction with the APOL1 locus. SMOC2 contributes to the progression of fibrosis after kidney injury and the interaction with APOL1 variants may contribute to an explanation for why only some APOLI high-risk individuals develop ESKD.

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population.

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value

Introduction: Life’s Simple 7 (LS7) comprises seven health factors and behaviors promoted by the American Heart Association to reduce cardiovascular morbidity and mortality. Despite compelling evidence of inverse association between LS7 adherence and a variety of adverse health outcomes, the epigenetic sequelae of healthy lifestyle have not been comprehensively characterized and may offer valuable insights into the underlying biological mechanisms. Hypothesis: We hypothesized that LS7 adherence is associated with an epigenetic signature that is consistent with the deceleration of the aging process. Methods: Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=853), we have estimated cross-sectional associations between epigenome-wide DNA methylation at 487,432 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells and the number of achieved LS7 goals as measured by study staff (blood pressure, body mass index, total cholesterol, and fasting glucose) or reported by the participant (diet, smoking, physical activity). The associations were tested using linear mixed models adjusted for age, sex, study site, technical artifacts (fixed effects), and family relatedness (random effect). Additionally, we tested associations between LS7 compliance and age acceleration, estimated from DNA methylation data and chronological age using two complementary validated algorithms (1: Horvath and 2: Hannum). These linear mixed models adjusted for chronological age, sex, study site, CD4+ T-cell subtype estimates (fixed effects), and family relatedness (random effect). Epigenome-wide association results were considered statistically significant if they fell under the Bonferroni corrected threshold (alpha=0.05/487,432= 1.03x10 -7 ). Results: Methylation of an intronic CpG site in CPT1A , cg00574958, was positively associated with the number of achieved LS7 goals at the epigenome-wide significance level (beta= 0.008, SE= 0.001, P= 4.7x10 -8 ). CPT1A encodes a key enzyme in the beta-oxidation process and has previously been linked to fasting triglycerides, body mass index, and adiponectin levels. Age acceleration was associated with LS7 adherence under the Hannum algorithm (beta=-0.01, SE= 0.006, P= 0.02) but not the Horvath algorithm (beta=-0.005, SE= 0.004, P= 0.18). Conclusions: Achievement of LS7 goals was significantly associated with methylation variation in CPT1A , a critical lipid metabolism gene, and was associated with age deceleration in the Hannum but not the Horvath models. Following independent replication, future studies should consider interrogating CPT1A methylation in relation to cardiovascular morbidity and mortality in a prospective setting.

Background: Animal model studies reported robust associations between fructose intake, a known determinant of metabolic health across species, and DNA methylation/ gene expression patterns. To date, these associations have not been comprehensively investigated in humans. Methods: Using DNA methylation data on ~470,000 cytosine-phosphate-guanine (CpG) sites in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=991) quantified in CD4+ T-cells, we have interrogated the cross-sectional relationships between fructose intake (ascertained using a validated food frequency questionnaire) and epigenome-wide methylation. We fit linear mixed models adjusted for age, sex, study site, technical covariates (fixed effects) and family relatedness (random effect). We have supplemented the methylation analyses with a transcriptome-wide scan on 98 unrelated GOLDN participants with available RNASeq data in whole blood. For the RNASeq data analysis, we used negative binomial models of read counts as a function of fructose intake, adjusted for age, sex, study site, technical covariates (including differential white blood cell counts). Results and Conclusions: The top loci differentially methylated with respect to fructose intake mapped to SNED1 (regression coefficient +/- SE= 0.002 +/- 0.0005, P=5x10-6) and FARSB (regression coefficient +/- SE= 0.002 +/- 0.0004, P=5x10-6) on chromosome 2. SNED1 is an insulin responsive transcription factor that has previously been shown to be downregulated in the setting of metabolic syndrome. FARSB encodes an aminoacyl-tRNA synethetase implicated in cell growth. Additionally, two genes reached transcriptome-wide significance in the RNASeq analysis: MTATP8P1 (P=1x10-7) and PDXDC1 (P=6x10-7). Sequence variation in PDXDC1 (pyridoxal-dependent decarboxylase isoform) has previously been linked to lipid metabolism, while MTATP8P1 is a pseudogene for a mitochondrially encoded ATP synthase. Upon future replication and functional validation, our preliminary findings offer promising insights into the link between fructose intake and metabolic health.