X-chromosome and kidney function:evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.</p

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Association of occupational exposures with cardiovascular disease among US Hispanics/Latinos

ObjectiveCardiovascular disease (CVD) is a leading cause of mortality and morbidity in the USA. The role of occupational exposures to chemicals in the development of CVD has rarely been studied even though many agents possess cardiotoxic properties. We therefore evaluated associations of self-reported exposures to organic solvents, metals and pesticides in relation to CVD prevalence among diverse Hispanic/Latino workers.MethodsCross-sectional data from 7404 employed individuals, aged 18–74 years, enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analysed. Participants from four US cities provided questionnaire data and underwent clinical examinations, including ECGs. CVD was defined as the presence of at least one of the following: coronary heart disease, atrial fibrillation, heart failure or cerebrovascular disease. Prevalence ratios reflecting the relationship between each occupational exposure and CVD as well as CVD subtypes were calculated using Poisson regression models.ResultsHispanic/Latino workers reported exposures to organic solvents (6.5%), metals (8.5%) and pesticides (4.7%) at their current jobs. Overall, 6.1% of participants had some form of CVD, with coronary heart disease as the most common (4.3%) followed by cerebrovascular disease (1.0%), heart failure (0.8%) and atrial fibrillation (0.7%). For individuals who reported working with pesticides, the prevalence ratios for any CVD were 2.18 (95% CI 1.34 to 3.55), coronary heart disease 2.20 (95% CI 1.31 to 3.71), cerebrovascular disease 1.38 (95% CI 0.62 3.03), heart failure 0.91 (95% CI 0.23 to 3.54) and atrial fibrillation 5.92 (95% CI 1.89 to 18.61) after adjustment for sociodemographic, acculturation, lifestyle and occupational characteristics. Metal exposures were associated with an almost fourfold (3.78, 95% CI 1.24 to 11.46) greater prevalence of atrial fibrillation. Null associations were observed for organic solvent exposures.ConclusionsOur results suggest that working with metals and pesticides could be risk factors for CVD among Hispanic/Latino workers. Further work is needed to evaluate these relationships prospectively

Abstract P313: Association of Positive Emotion and Cardiovascular Health in Hispanics/Latinos With Chronic Kidney Disease: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Introduction: Mounting evidence exists, linking positive emotion (e.g., joy) to favorable health outcomes. Little is known of the relationship between positive emotion and the American Heart Association defined concept of cardiovascular health ( CVH ), particularly in Hispanics/Latinos with chronic kidney disease ( CKD ), a group at high risk of cardiovascular mortality. Hypothesis: In Hispanics/Latinos with CKD, those with greater positive emotion will display more favorable CVH profiles. Methods: We analyzed data from adults ages 18-74 with stage 1-5 non-dialysis dependent CKD enrolled in the Hispanic Community Health Study/Study of Latinos in 2008-11. Positively worded items of the Center for Epidemiologic Studies Depression Scale were used to create a composite positive emotion score (range, 0-6; higher scores indicative of greater positive emotion). A composite overall CVH score was calculated using metrics of diet, body mass index, physical activity, cholesterol, blood pressure, fasting glucose, and smoking status. Each metric was defined as ideal, intermediate, or poor to compute an additive score ranging from 0-14; ideal metrics were also enumerated to compute an ideal CVH score, ranging from 0-7. Linear and logistic regression analyses were used to examine associations of positive emotion with CVH, after adjusting for relevant covariates. Results: Overall, 1,716 participants screened positive for CKD † . In multivariable-adjusted models, a higher positive emotion score was associated with higher overall and ideal CVH scores when modeling CVH as a continuous outcome, (overall CVH: β=0.11, 95% CI=0.01, 0.20; ideal CVH: β=0.06, 95% CI=0.01, 0.11) ( Table 1 ). A 1-unit increase in positive emotion was associated with 1.14 times higher odds of having > 4 (vs. <4) ideal CVH indicators. Conclusions: These findings provide preliminary evidence for an association between positive emotion and CVH in Hispanics/Latinos with CKD. Future studies should explore the mechanism through which emotion influence heart health

Abstract P072: Association of Occupational Exposures with Cardiovascular Disease among Hispanics/Latinos: Results from the Hispanic Community Health Study/Study of Latinos

Background: Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the US. Acute, high-dose exposures to some solvents, metals, and pesticides can be cardiotoxic, but little is known about the cardiovascular effects of chronic, low-level exposures. Thus, we evaluated cross-sectional associations of self-reported occupational exposures to solvents, metals, and pesticides with CVD prevalence among diverse Hispanics/Latinos in the US. Methods: The analyses included baseline data from 7,404 currently employed participants, ages 18-74 years, from the HCHS/SOL. CVD was defined as the presence of one or more of the following: coronary heart disease (self-reported angina, myocardial infarction, coronary bypass surgery, balloon angioplasty, or stent placement in coronary arteries, or electrocardiogram [ECG] evidence of major Q wave abnormalities or minor Q, QS waves with ST, T abnormalities); atrial fibrillation (self-reported or ECG evidence of atrial fibrillation or flutter); heart failure (self-reported); or cerebrovascular disease (self-reported stroke or transient ischemic attack). Survey-weighted Poisson regression models were used to estimate prevalence ratios (PR) and 95% confidence intervals (CIs) for each occupational exposure, adjusted for sociodemographic (age, gender, field center, Hispanic/Latino background, health insurance), acculturation (language, years of duration in the US), lifestyle (smoking, alcohol, physical activity, diet), and occupational (full- or part-time employment) characteristics. Results: Overall, 6.1% of participants had any prevalent CVD; coronary heart disease (4.3%) was most common, followed by cerebrovascular disease (1.0%), heart failure (0.8%), and atrial fibrillation (0.7%). Current occupational exposures to solvents, metals, and pesticides were reported by 6.5%, 8.5%, and 4.7% of participants, respectively. The prevalence of any CVD (PR: 2.18, 95% CI: 1.34-3.55), coronary heart disease (PR: 2.20, 95% CI: 1.31-3.71), and atrial fibrillation (PR: 5.92, 95% CI: 1.89-18.61) were significantly elevated for participants who reported current occupational pesticide exposure compared to no exposure. Current occupational metal exposure was associated with a greater prevalence of atrial fibrillation (PR: 3.78, 95% CI: 1.24-11.46). Further adjustment for hypertension, hypercholesterolemia, diabetes, or body mass index did not appreciably change the results. Current occupational solvent exposure was not associated with CVD prevalence. Conclusions: Occupational exposure to pesticides and metals is associated with higher CVD prevalence at baseline. These cross-sectional associations do not appear to be attenuated by hypertension, hypercholesterolemia, diabetes, or obesity. Further research is needed to examine other biologic mechanisms that may underlie these associations

Prevalence, Awareness, and Treatment of Hypertension in Hispanics/Latinos With CKD in the Hispanic Community Health Study/Study of Latinos

Lower rates of hypertension awareness, treatment, and control have been observed in Hispanics/Latinos compared with non-Hispanic whites. These factors have not been studied in Hispanics/Latinos with chronic kidney disease (CKD). We sought to describe the prevalence, awareness, treatment, and control of hypertension in Hispanic/Latino adults with CKD. Cross-sectional cohort. US.Hispanics/Latinos aged 18 to 74 years enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) with CKD. Comparisons were made with the National Health and Nutrition Examination Survey (NHANES) 2007 to 2010. CKD was defined as estimated glomerular filtration rate < 60mL/min/1.73m2 or urinry albumin-creatinine ratio ≥ 30mg/g creatinine. Hypertension was defined as systolic blood pressure (BP) ≥ 140 or diastolic BP ≥ 90mm Hg or use of antihypertensives. For hypertension control, 2 thresholds were examined: <140/90 and <130/80mm Hg. The prevalence of hypertension was 51.5%; among those with hypertension, hypertension awareness and treatment were present in 78.1% and 70.4%, respectively. A low prevalence of BP control was observed (32.6% with BP < 140/90mm Hg; 17.9% with BP < 130/80mm Hg). Health insurance coverage was associated with higher odds of BP < 140/90mm Hg (OR, 1.98; 95% CI, 1.15-3.43). Compared with non-Hispanic whites with CKD in NHANES, HCHS/SOL participants with CKD had a lower prevalence of hypertension but a lower rate of BP control (32.6% vs 48.6% for BP < 140/90mm Hg). Use of a single measurement of creatinine, cystatin C, and urinary albumin excretion to define CKD. Single-visit measurement of BP. Hispanics/Latinos with CKD residing in the United States have very low rates of BP control. The association of health insurance coverage with hypertension control suggests that improved access to health care may improve outcomes for this growing population. [Display omitted

Abstract P083: Relationship Between Prevalent Cardiovascular Disease and 6-Year Incidence of Diabetes: Findings From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Introduction: Cardiovascular disease (CVD) may prevent the adoption of healthy lifestyle habits such as physical activity, and thus may lead to weight gain and increased risk for lifestyle-related conditions such as diabetes mellitus (DM). Evidence suggests that medications commonly used in the management of CVD such as diuretics, β blockers, and statins are also associated with increased risk of diabetes. We examined the association of CVD with incident DM and investigated whether this association is mediated by change in BMI or medication use. Methods: Data from the HCHS/SOL Visit 1 (2008-2011) and Visit 2 (2014-2017) examinations were used to compare incidence of DM among persons with and without CVD at Visit 1. DM was defined using the American Diabetes Association criteria, and prevalent CVD using the Framingham Heart Study definition (i.e., self-reported history of coronary heart disease, cerebrovascular events, peripheral artery disease, or heart failure). Of the 8672 participants free of DM at Visit 1 and with complete data on DM at Visit 2 and on key covariates of interest, 2191 (25.3%) had prevalent CVD at baseline. A total of 2050 participants with CVD were matched to controls free of CVD at Visit 1 using 1:1 propensity matching. Covariates included in the propensity model were age, gender, educational attainment, marital status, Hispanic background, history of hypertension, family history of diabetes, health insurance coverage, chronic kidney disease at baseline, gestational diabetes, high cholesterol, metabolic syndrome, alcohol use, cigarette pack years, physical activity level, diet quality based on alternative healthy eating index, baseline BMI, baseline prediabetes. Matched pairs were analyzed. McNemar’s test was used to compare incidence of DM among cases and controls. The mediating effects of change in BMI and medication use were examined. Results: Covariate distributions were similar among participants with and without CVD. The incidence of DM among persons with CVD was 15.7% vs. 13.6% among those without CVD (p=0.06). No natural direct effect of CVD on DM was found. The association between CVD and incidence of DM was not mediated by change in BMI. On average, BMI increased by 0.38 (SE=2.56) and 0.33 (SE=2.50) among persons with and without CVD, respectively (p=0.55). The association between CVD and DM was indirectly mediated by the use of beta-blockers (percent mediated=24.8%), statins (percent mediated=9.8%), and diuretics (percent mediated=8.9%). Conclusion: There is slight evidence that medications used to treat CVD increase risk for new onset diabetes

The association of positive affect and cardiovascular health in Hispanics/Latinos with chronic kidney disease: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

The beneficial influence of positive affect (e.g., joy) remains unexplored in relation to heart health in adults with chronic kidney disease (CKD)—a population at increased risk for poor cardiovascular health (CVH). Therefore, we evaluated the association of positive affect and CVH in a diverse U.S. population of Hispanics/Latinos with CKD. We analyzed cross-sectional data of adults ages 18–74 enrolled between 2008 and 2011 in the Hispanic Community Health Study/Study of Latinos with prevalent CKD (N = 1712). Positively worded items from the Center for Epidemiologic Studies Depression Scale were used to create a composite positive affect score (0–6; higher scores indicate greater positive affect). Prevalent CKD was defined as estimated glomerular filtration 4 (vs. <4) ideal CVH indicators. Positive affect is associated with favorable CVH profiles in Hispanics/Latinos with CKD. Replication and prospective studies are needed to elucidate whether emotional well-being is a potential therapeutic target for intervention. •Positive affect is unexplored in relation to heart health in adults with chronic kidney disease.•Positive affect is associated with favorable cardiovascular health profiles in Hispanics/Latinos with chronic kidney disease.•No effect modification by age, sex, or heritage background in the relationship of positive affect and cardiovascular health.•Replication studies are needed to elucidate whether emotional wellbeing is a potential therapeutic target for intervention

Association of elevated serum aminotransferase levels with chronic kidney disease measures: hispanic community health study/study of latinos

Abstract Background Previous studies have shown an association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), but it is unclear whether the association is independent of metabolic syndrome. Methods Data from 13,006 participants aged 18 to 74 years in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) without viral hepatitis, excessive alcohol consumption, or high transferrin saturation levels were analyzed. Suspected NAFLD was defined as presence of sex-specific elevations in serum aminotransferase levels (aspartate aminotransferase (AST) > 37 U/L or alanine aminotransferase (ALT) > 40 U/L for men and AST or ALT > 31 U/L for women). Logistic regression was used to examine cross-sectional associations of elevated serum aminotransferase levels with low estimated glomerular filtration rate (eGFR  17 mg/g in men and > 25 mg/ g in women) in separate models adjusting for demographic characteristics and metabolic syndrome. Results Mean (SD) age was 41 (0.27) years, and 45 % were male. Elevated serum aminotransferase levels were noted in 18.8 % of the population and were associated with greater odds of high UACR (OR = 1.31; 95 % CI = 1.10, 1.56) after adjusting for demographic characteristics; this association became non-significant after adjustment for metabolic syndrome (OR = 1.11, 95 % CI = 0.92, 1.33). In contrast, elevated serum aminotransferase levels were not associated with low eGFR (odds ratio (OR) = 0.73; 95 % confidence interval (CI) = 0.45, 1.18) after adjusting for covariates. Conclusions In this sample of diverse U.S. Hispanic Latino adults, elevated serum aminotransferase levels were not independently associated with measures of CKD