Differential prediction performance between Caribbean- and Mainland-subgroups using state-of-the-art polygenic risk scores for coronary heart disease: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Background: Coronary heart disease (CHD) is a leading cause of death for Hispanic/Latino populations in the United States. We evaluated polygenic risk scores (PRS) with incident myocardial infarction (MI) in a Hispanic/Latino study sample. Methods: We leveraged data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to assess four CHD-PRS from the PGS catalog, derived using multiple methods (LDpred, AnnoPred, stacked clumping and thresholding, and LDPred2). We evaluated associations between each standardized PRS and time to adjudicated incident MI, adjusted for age, sex, first 5 principal components, and weighted for survey design. Concordance statistics (c-index) compared predictive accuracy of each PRS with, and in addition to, traditional risk factors (TRF) for CHD (obesity, hypercholesterolemia, hypertension, diabetes, and smoking). Analyses were stratified by self-reported Caribbean- (Puerto Rican, Dominican or Cuban) and Mainland-(those of Mexican, Central American, or South American) heritage subgroups. Results: After 11 years follow-up, for 9055 participants (mean age (SD) 47.6(13.1), 62.2% female), the incidence of MI was 1.0% (n = 95). Each PRS was more strongly associated with MI among Mainland participants. LDPred2 + TRF performed best among the Mainland subgroup; HR=2.69, 95% CI [1.71, 4.20], c-index = 0.897, 95% CI [0.848, 0.946]; a modest increase over TRF alone, c-index = 0.880, 95% CI [0.827, 0.933]. AnnoPred + TRF performed best among the Caribbean sample; c-index = 0.721, 95% CI [0.647, 0.795]; however, was not significantly associated with rate of MI (HR=1.14, 95% CI [0.82, 1.60]). Conclusion: PRS performance for CHD is lacking for Hispanics/Latinos of Caribbean origin who have substantial proportions of African genetic ancestry, risking increased health disparities. AnnoPred, using functional annotations, outperformed other PRS in the Caribbean subgroup, suggesting a potential strategy for PRS construction in diverse populations. These results underscore the need to optimize cumulative genetic risk prediction of CHD in diverse Hispanic/Latino populations.

Toxic Metals Impact Gut Microbiota and Metabolic Risk in Five African-Origin Populations.

Exposure to toxic metals impacts obesity and type 2 diabetes (T2DM) risk. Yet, the underlying mechanisms remain largely unknown. Gut microbiota has been strongly associated with progression of cardiometabolic risk. To determine whether high metal exposures and gut dysbiosis interact to promote metabolic dysregulation and cardiometabolic risk, we assessed relationships between these factors. We analyzed cross-sectional associations between arsenic, lead, mercury, cadmium, and cardiometabolic health markers in 178 randomly selected African-origin adults (52% female, 51% obese, mean age=43.0±6.4 years) from Ghana, South Africa, Seychelles, Jamaica, and USA. Metal levels were dichotomized to high or low at the median level of each metal. We analyzed associations between gut microbiome taxa, metal levels, clinical measures (BMI, fasting blood glucose, and blood pressure) and diagnoses (hypertension, obesity, and diabetes status). High vs. low lead and arsenic exposures had a significant effect on beta diversity (p <0.05). 71 taxa were associated with high lead levels: 30 with elevated BMI, 22 with T2DM, and 23 with elevated fasting blood glucose (p<0.05). 115 taxa were associated with high arsenic levels: 32 with elevated BMI, 33 with T2DM, and 26 with elevated blood glucose (p<0.05). Of the taxa associated with high lead and arsenic exposure and either elevated BMI or fasting blood glucose, porphyrin metabolism was the most enriched metabolic pathway. These data collectively provide the first findings in a human study that the gut microbiome may drive the association between lead and arsenic exposure and obesity and T2DM risk.

Prevalence and Risk Factors of Iron Deficiency and Anemia in Women of Reproductive Age in the Hispanic Community Health Study/Study of Latinos.

Background: Women of reproductive age are at elevated risk of iron deficiency (ID) and anemia; in the United States, those of Hispanic/Latino background are at especially high risk. Causes of ID and anemia and variations in risk within Hispanic/Latino women of reproductive age are not well described. Objectives: To characterize ID and anemia and their risk factors/markers in Hispanic/Latina women. Methods: Data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were used. HCHS/SOL enrolled participants in 2008-2011 at 4 sites: Bronx, Chicago, Miami, and San Diego; 5386 were non-pregnant women ages 18-49 y. Primary outcomes were ID (ferritin <30 µg/L) and anemia (hemoglobin <12 g/dL). Predictors were background/heritage, Short Acculturation Scale for Hispanics scores, years lived in the United States, and interview language, diet summarized in the Alternate Healthy Eating Index 2010, sociodemographic covariates, and study site. Main analyses used survey log binomial regressions adjusted for age, site, and smoking. Results: Almost half (42%) of participants were of Mexican background, 15% of Cuban background, and <15% each were of Puerto Rican, Dominican, Central American, or South American background. ID prevalence was 34.4% overall but differed by site-background pairings. The lowest and highest prevalence were 26% and 42% among women of Cuban background in Miami and women of Mexican background in Chicago, respectively. Anemia prevalence was 16% and ranged from 8.9% (Central American background/Miami) to 22% (Dominican background/Bronx). Acculturation, sociodemographic, and diet variables examined did not explain observed prevalence differences by site/background. Conclusions: Prevalence of ID and anemia were high among HCHS/SOL women and differed by field center and background. These differences highlight the importance of characterizing nutritional risk by background within Hispanic/Latino women.

Accelerated Longitudinal Glycemic Changes in Relation to Urinary Toxic/Essential Metals and Metal Mixtures Among Mexican Americans Living in Starr County, Texas.

OBJECTIVE: Metal and metalloid exposures (hereafter "metals") are associated with adverse health outcomes, including type 2 diabetes; however, previous studies were largely cross-sectional or underpowered. Furthermore, underserved racial and ethnic groups are underrepresented in environmental health research despite having higher rates of type 2 diabetes and a greater risk of metal exposures. Consequently, we evaluated continuous glycemic traits in relation to baseline urinary toxic metal, essential metal, and metal mixtures in a cohort of Mexican American adults. RESEARCH DESIGN AND METHODS: A total of 510 participants were selected based upon self-reported diabetes status and followed over 3 years. Urinary metals were assessed at baseline. Linear mixed-effects models were used to estimate per-month changes in hemoglobin A1c, fasting plasma glucose, and postload glucose in relation to urinary metal levels. Multiple statistical approaches were used to assess the associations between glycemic traits and metal mixtures. RESULTS: After adjustment, higher urinary levels of arsenic, selenium, copper, molybdenum, nickel, and tin were associated with faster increases in measures of glycemia. The toxic metal mixture composed of arsenic, lead, cadmium, nickel, and tin was associated with faster increases in postload glucose. Using postload glucose criteria, highest versus lowest arsenic was predicted to accelerate conversion of normoglycemia to prediabetes and diabetes by 23 and 65 months, respectively. CONCLUSIONS: In this underrepresented, high-risk Mexican American population, exposure to toxic metals and alterations in essential metal homeostasis were associated with faster increases in glycemia over time that may accelerate type 2 diabetes development.

Associations of Epigenetic Age Acceleration With CVD Risks Across the Lifespan: The Bogalusa Heart Study.

Although epigenetic age acceleration (EAA) might serve as a molecular signature of childhood cardiovascular disease (CVD) risk factors and further promote midlife subclinical CVD, few studies have comprehensively examined these life course associations. This study sought to test whether childhood CVD risk factors predict EAA in adulthood and whether EAA mediates the association between childhood CVD risks and midlife subclinical disease. Among 1,580 Bogalusa Heart Study participants, we estimated extrinsic EAA, intrinsic EAA, PhenoAge acceleration (PhenoAgeAccel), and GrimAge acceleration (GrimAgeAccel) during adulthood. We tested prospective associations of longitudinal childhood body mass index (BMI), blood pressure, lipids, and glucose with EAAs using linear mixed effects models. After confirming EAAs with midlife carotid intima-media thickness and carotid plaque, structural equation models examined mediating effects of EAAs on associations of childhood CVD risk factors with subclinical CVD measures. After stringent multiple testing corrections, each SD increase in childhood BMI was significantly associated with 0.6-, 0.9-, and 0.5-year increases in extrinsic EAA, PhenoAgeAccel, and GrimAgeAccel, respectively (P < 0.001 for all 3 associations). Likewise, each SD increase in childhood log-triglycerides was associated with 0.5- and 0.4-year increases in PhenoAgeAccel and GrimAgeAccel (P < 0.001 for both), respectively, whereas each SD increase in childhood high-density lipoprotein cholesterol was associated with a 0.3-year decrease in GrimAgeAccel (P = 0.002). Our findings indicate that PhenoAgeAccel mediates an estimated 27.4% of the association between childhood log-triglycerides and midlife carotid intima-media thickness (P = 0.022). Our data demonstrate that early life CVD risk factors may accelerate biological aging and promote subclinical atherosclerosis.

Predictors of Toxic Metal/Metalloid Exposures Among Mexican Americans in Starr County, Texas.

BACKGROUND: Arsenic, cadmium, and lead are toxic elements that widely contaminate our environment. These toxicants are associated with acute and chronic health problems, and evidence suggests that minority communities, including Hispanic/Latino Americans, are disproportionately exposed. Few studies have assessed culturally specific predictors of exposure to understand the potential drivers of racial/ethnic exposure disparities. OBJECTIVE: We sought to evaluate acculturation measures as predictors of metal/metalloid (hereafter "metal") concentrations among Mexican American adults to illuminate potential exposure sources that may be targeted for interventions. METHODS: As part of a longitudinal cohort, 510 adults, aged 35 to 69 years, underwent baseline interview, physical examination, and urine sample collection. Self-reported acculturation was assessed across various domains using the Short Acculturation Scale for Hispanics (SASH). Multivariable linear regression was used to assess associations between acculturation and urinary concentrations of arsenic, cadmium, and lead. Ordinal logistic regression was utilized to assess associations between acculturation and a metal mixture score. Lastly, best subset selection was used to build a prediction model for each toxic metal with a combination of the acculturation predictors. RESULTS: After adjustment, immigration factors were positively associated with arsenic and lead concentrations. For lead alone, English language and American media and food preferences were associated with lower levels. Immigration and parental heritage from Mexico were positively associated with the metal mixture, while preferences for English language, media, and food were negatively associated. CONCLUSION: Acculturation-related predictors of exposure provide information about potential sources of toxic metals, including international travel, foods, and consumer products. The findings in this research study provide information to empower future efforts to identify and address specific acculturation-associated toxicant exposures in order to promote health equity through clinical guidance, patient education, and public policy.

Exposure to metal mixtures and telomere length in Bangladeshi children.

Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (µg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.

Molecular Profiling and the Interaction of Somatic Mutations with Transcriptomic Profiles in Non-Melanoma Skin Cancer (NMSC) in a Population Exposed to Arsenic.

Exposure to inorganic arsenic (As) is recognized as a risk factor for non-melanoma skin cancer (NMSC). We followed up with 7000 adults for 6 years who were exposed to As. During follow-up, 2.2% of the males and 1.3% of the females developed basal cell carcinoma (BCC), while 0.4% of the male and 0.2% of the female participants developed squamous cell carcinoma (SCC). Using a panel of more than 400 cancer-related genes, we detected somatic mutations (SMs) in the first 32 NMSC samples (BCC = 26 and SCC = 6) by comparing paired (tissue-blood) samples from the same individual and then comparing them to the SM in healthy skin tissue from 16 participants. We identified (a) a list of NMSC-associated SMs, (b) SMs present in both NMSC and healthy skin, and (c) SMs found only in healthy skin. We also demonstrate that the presence of non-synonymous SMs in the top mutated genes (like PTCH1, NOTCH1, SYNE1, PKHD1 in BCC and TP53 in SCC) significantly affects the magnitude of differential expressions of major genes and gene pathways (basal cell carcinoma pathways, NOTCH signaling, IL-17 signaling, p53 signaling, Wnt signaling pathway). These findings may help select groups of patients for targeted therapy, like hedgehog signaling inhibitors, IL17 inhibitors, etc., in the future.

Thyroid-related Hormones and Hypertension Incidence in Middle-Aged and Older Hispanic/Latino Adults: The HCHS/SOL Study.

Background: Thyroid-related hormones act to regulate metabolic pathways and blood pressure (BP). However, the relationship of TSH and peripheral thyroid hormones and the role of the hypothalamic-pituitary-thyroid axis on hypertension development is not fully understood. We assessed sex-specific associations of thyroid-related hormones with BP and hypertension in Hispanic/Latino adults followed for 6 years. Methods: We studied 1789 adults, ages 45 to 74, free of diabetes at baseline from a subcohort of the Hispanic Community Health Study/Study of Latinos. We assessed TSH, free T4 (FT4), T3, and various indicators of thyroid axis. Using multivariable linear and Poisson regression adjusted for survey design and confounding variables, we estimated a priori sex-specific associations of thyroid-related hormones with changes in BP and hypertension development. Results: In men and women, TSH and TSH/FT4 ratios were associated with changes in diastolic BP and T3 with changes in pulse pressure and the development of hypertension from prehypertension. In men, a 1-SD increase in TSH [incident rate ratio (IRR) = 1.42; 95% confidence interval (CI): 1.15, 1.75] and TSH/FT4 ratio (IRR = 1.20; 95% CI: 1.07, 1.35) were positively associated with the development of hypertension from prehypertension while the TSH/FT4 ratio (IRR = 0.85; 95% CI: .72, 1.00) was protective in women. We observed sex-specific differences in associations of the T3/FT4 ratio and indices of pituitary sensitivity to thyroid hormones with changes in pulse pressure and hypertension development. Conclusion: Thyroid-related hormones are associated with sex-specific changes in BP and hypertension among Hispanic/Latino adults consistent with selected studies conducted in other populations. Mechanisms underlying associations of pituitary sensitivity to thyroid hormones with BP and hypertension development warrant further study.

Untargeted Metabolome Atlas for Sleep Phenotypes in the Hispanic Community Health Study/Study of Latinos.

Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep phenotypes and blood metabolites. Utilizing data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep phenotypes, grouped in several domains (i.e., sleep disordered breathing (SDB), sleep duration, timing, insomnia symptoms, and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualize and interpret the associations between sleep phenotypes and metabolites. The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, some xenobiotic metabolites were associated with sleep duration and heart rate phenotypes (e.g. 1H-indole-7-acetic acid, 4-allylphenol sulfate), while ketone bodies and fatty acid metabolism metabolites were associated with sleep timing measures (e.g. 3-hydroxybutyrate (BHBA), 3-hydroxyhexanoylcarnitine (1)). Heart rate phenotypes had the overall largest number of detected metabolite associations. Many of these associations were shared with both SDB and with sleep timing phenotypes, while SDB phenotypes shared relatively few metabolite associations with sleep duration measures. A number of metabolites were associated with multiple sleep phenotypes, from a few domains. The amino acids vanillylmandelate (VMA) and 1-carboxyethylisoleucine were associated with the greatest number of sleep phenotypes, from all domains other than insomnia. This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.

Air quality and cancer risk in the All of Us Research Program.

INTRODUCTION: The NIH All of Us Research Program has enrolled over 544,000 participants across the US with unprecedented racial/ethnic diversity, offering opportunities to investigate myriad exposures and diseases. This paper aims to investigate the association between PM2.5 exposure and cancer risks. MATERIALS AND METHODS: This work was performed on data from 409,876 All of Us Research Program participants using the All of Us Researcher Workbench. Cancer case ascertainment was performed using data from electronic health records and the self-reported Personal Medical History questionnaire. PM2.5 exposure was retrieved from NASA's Earth Observing System Data and Information Center and assigned using participants' 3-digit zip code prefixes. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Generalized additive models (GAMs) were used to investigate non-linear relationships. RESULTS: A total of 33,387 participants and 46,176 prevalent cancer cases were ascertained from participant EHR data, while 20,297 cases were ascertained from self-reported survey data from 18,133 participants; 9,502 cancer cases were captured in both the EHR and survey data. Average PM2.5 level from 2007 to 2016 was 8.90 µg/m3 (min 2.56, max 15.05). In analysis of cancer cases from EHR, an increased odds for breast cancer (OR 1.17, 95% CI 1.09-1.25), endometrial cancer (OR 1.33, 95% CI 1.09-1.62) and ovarian cancer (OR 1.20, 95% CI 1.01-1.42) in the 4th quartile of exposure compared to the 1st. In GAM, higher PM2.5 concentration was associated with increased odds for blood cancer, bone cancer, brain cancer, breast cancer, colon and rectum cancer, endocrine system cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. CONCLUSIONS: We found evidence of an association of PM2.5 with breast, ovarian, and endometrial cancers. There is little to no prior evidence in the literature on the impact of PM2.5 on risk of these cancers, warranting further investigation.

Association of Acculturation and Hispanic/Latino Background with Endogenous Sex and Thyroid-Related Hormones Among Middle-Aged and Older Hispanic/Latino Adults: the HCHS/SOL Study.

BACKGROUND: Hormones are linked to cardiometabolic diseases and may be impacted by acculturation though multiple mechanisms. We evaluated associations of Hispanic/Latino background and acculturation with levels of sex- and thyroid-related hormones and the potential mediating effect of adiposity, lifestyle factors, and sleep apnea syndrome on these associations. METHODS: We studied 1789 adults, aged 45-74, from a sub-cohort of the Hispanic Community Health Survey/Study of Latinos. Peri/pre-menopausal women and individuals on medications related to hormones were excluded. Our study assessed eleven sex- and thyroid-related hormones, Hispanic/Latino background, and five acculturation measures. Associations were assessed using multivariable linear and logistic regression adjusted for survey design and confounding variables. We explored potential mediation using a path analysis. RESULTS: In postmenopausal women, acculturation score-MESA was associated with decreased thyroid-stimulating hormone (ß = - 0.13;95%CI = - 0.22, - 0.03) while age at immigration greater than the median (vs US-born) was associated with decreased (ß = - 14.6; 95%CI = - 28.2, - 0.99) triiodothyronine (T3). In men, language acculturation and acculturation score-MESA were associated with increased estradiol and sex hormone-binding globulin (SHBG) while age at immigration greater and lesser than the median (vs US-born) was associated with decreased SHBG. Hispanic/Latino background (Mexicans as reference) were selectively associated with sex- and thyroid-related hormone levels in both sexes. Current smoking and sleep apnea syndrome partially mediated the association of Cuban and Puerto Rican heritage (vs Mexican) with T3 levels in men and postmenopausal women, respectively. CONCLUSION: Selected acculturation measures were associated with thyroid-related hormones in postmenopausal women and sex-related hormones in men. Understanding the mechanisms involved in the relationship of acculturation and Hispanic/Latino background with hormones warrants additional investigation.

Association between adverse childhood experiences and later-life allostatic load in UK Biobank female participants.

BACKGROUND: Adverse childhood experiences during key developmental periods have been shown to impact long-term health outcomes. Adverse childhood experiences may include psychological, physical, or sexual abuse; neglect; or socioeconomic factors. Adverse childhood experiences are linked with an increase in poor health behavior such as smoking and alcohol consumption, and may also influence epigenetic changes, inflammatory response, metabolic changes, and allostatic load. OBJECTIVE: We sought to explore associations between adverse childhood experiences and allostatic load in adult female participants in the UK Biobank. DESIGN: The UK Biobank is a multisite cohort study established to capture lifestyle, environment, exposure, health history, and genotype data on individuals in the United Kingdom. METHODS: Adverse childhood experiences were assessed from the Childhood Trauma Screener, which measures abuse and neglect across five items. Biological measures at enrollment were used to construct allostatic load, including measures of metabolic, inflammatory, and cardiovascular function. Females with a cancer diagnosis prior to enrollment were removed as it may influence allostatic load. Poisson regression models were used to assess the association between adverse childhood experiences and allostatic load, accounting for a priori confounders. RESULTS: A total of 33,466 females with complete data were analyzed, with a median age at enrollment of 54 (range = 40-70) years. Among the study sample, the mean allostatic load ranged from 1.85 in those who reported no adverse childhood experiences to 2.45 in those with all adverse childhood experiences reported. In multivariable analysis, there was a 4% increase in average allostatic load among females for every additional adverse childhood experience reported (incidence rate ratio = 1.04, 95% confidence interval = 1.03-1.05). Similar results were observed when assessing individual adverse childhood experience components. CONCLUSION: This analysis supports a growing body of evidence suggesting that increased exposure to early life abuse or neglect is associated with increased allostatic load in females.

Arsenic metabolism, diabetes prevalence, and insulin resistance among Mexican Americans: A mendelian randomization approach.

Background: Differences in arsenic metabolism capacity may influence risk for type 2 diabetes, but the mechanistic drivers are unclear. We evaluated the associations between arsenic metabolism with overall diabetes prevalence and with static and dynamic measures of insulin resistance among Mexican Americans living in Starr County, Texas. Methods: We utilized data from cross-sectional studies conducted in Starr County, Texas, from 2010-2014. A Mendelian randomization approach was utilized to evaluate the associations between arsenic metabolism and type 2 diabetes prevalence using the intronic variant in the arsenic methylating gene, rs9527, as the instrumental variable for arsenic metabolism. To further assess mechanisms for diabetes pathogenesis, proportions of the urinary arsenic metabolites were employed to assess the association between arsenic metabolism and insulin resistance among participants without diabetes. Urinary biomarkers of arsenic metabolites were modeled as individual proportions of the total. Arsenic metabolism was evaluated both with a static outcome of insulin resistance, homeostatic measure of assessment (HOMA-IR), and a dynamic measure of insulin sensitivity, Matsuda Index. Results: Among 475 Mexican American participants from Starr County, higher metabolism capacity for arsenic is associated with higher diabetes prevalence driven by worse insulin resistance. Presence of the minor T allele of rs9527 is independently associated with an increase in the proportion of monomethylated arsenic (MMA%) and is associated with an odds ratio of 0.50 (95% CI: 0.24, 0.90) for type 2 diabetes. This association was conserved after potential covariate adjustment. Furthermore, among participants without type 2 diabetes, the highest quartile of MMA% was associated with 22% (95% CI: -33.5%, -9.07%) lower HOMA-IR and 56% (95% CI: 28.3%, 91.3%) higher Matsuda Index for insulin sensitivity. Conclusions: Arsenic metabolism capacity, indicated by a lower proportion of monomethylated arsenic, is associated with increased diabetes prevalence driven by an insulin resistant phenotype among Mexican Americans living in Starr County, Texas.

Interaction analysis of ancestry-enriched variants with APOE-ɛ4 on MCI in the Study of Latinos-Investigation of Neurocognitive Aging.

APOE-ɛ4 risk on Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) differs between race/ethnic groups, presumably due to ancestral genomic background surrounding the APOE locus. We studied whether African and Amerindian ancestry-enriched genetic variants in the APOE region modify the effect of the APOE-ɛ4 alleles on Mild Cognitive Impairment (MCI) in Hispanics/Latinos. We defined African and Amerindian ancestry-enriched variants as those common in one Hispanic/Latino parental ancestry and rare in the other two. We identified such variants in the APOE region with a predicted moderate impact based on the SnpEff tool. We tested their interaction with APOE-ɛ4 on MCI in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) population and African Americans from the Atherosclerosis Risk In Communities (ARIC) study. We identified 5 Amerindian and 14 African enriched variants with an expected moderate effect. A suggestive significant interaction (p-value = 0.01) was found for one African-enriched variant, rs8112679, located in the ZNF222 gene fourth exon. Our results suggest there are no ancestry-enriched variants with large effect sizes of interaction effects with APOE-ɛ4 on MCI in the APOE region in the Hispanic/Latino population. Further studies are needed in larger datasets to identify potential interactions with smaller effect sizes.

Awareness and utilization of genetic testing among Hispanic and Latino adults living in the US: The Hispanic Community Health Study/Study of Latinos.

We investigated the awareness, perceived usefulness, and use of genetic testing among Hispanic and Latino individuals. Annual follow-up surveys for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) from 2019 to April 2020 assessed participants' level of awareness and use of genetic tests to determine disease risks, likelihood of passing disease to children, disease treatment, or drug selection. They also were asked to rate the usefulness of the tests for managing a person's health on a 1 (not at all useful) to 10 (extremely useful) scale. There were 5,769 HCHS/SOL participants who completed at least one survey question. Of the target population, 55.2% was aware of at least one type of genetic test. Awareness varied between HCHS/SOL enrollment sites and was higher among individuals who had higher educational attainment and had higher incomes. Only 3.3% of the target population reported receiving one or more of the tests described. HCHS/SOL individuals rated the usefulness as 8.4, on average, with lower scores observed among U.S.-born individuals compared to individuals born outside the United States, with differences by HCHS/SOL enrollment sites. In conclusion, while awareness of genetic testing among Hispanic and Latino individuals varies by location, education, and income, perceptions about its usefulness are high while experiences with testing are rare. Results identify groups and locations that may benefit from greater outreach about the capabilities of genetic testing and precision medicine.

Relationships Between Urinary Metals and Diabetes Traits Among Mexican Americans in Starr County, Texas, USA.

Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of diabetes and diabetes-associated mortality. We used multivariable linear regression to quantify the differences in homeostatic model assessments for pancreatic ß-cell function, insulin resistance, and insulin sensitivity (HOMA-ß, HOMA-IR, HOMA-S, respectively), plasma insulin, plasma glucose, and hemoglobin A1c (HbA1c) associated with increasing urinary metal concentrations. Quantile-based g-computation was utilized to assess mixture effects. After multivariable adjustment, urinary arsenic and molybdenum were associated with lower HOMA-ß, HOMA-IR, and plasma insulin levels and higher HOMA-S. Additionally, higher urinary copper levels were associated with a reduced HOMA-ß. Lastly, a higher concentration of the 8 metal mixtures was associated with lower HOMA-ß, HOMA-IR, and plasma insulin levels as well as higher HOMA-S. Our data indicate that arsenic, molybdenum, copper, and this metal mixture are associated with alterations in measures of glucose homeostasis among non-diabetics in Starr County. This study is one of the first to comprehensively evaluate associations of urinary metals with glycemic measures in a high-risk Mexican American population.

Interaction of Arsenic Exposure and Transcriptomic Profile in Basal Cell Carcinoma.

Exposure to inorganic arsenic (As) is recognized as risk factor for basal cell carcinoma (BCC). We have followed-up 7000 adults for 6 years who were exposed to As and had manifest As skin toxicity. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%). In this study, we compared transcriptome-wide RNA sequencing data from the very first 26 BCC cases and healthy skin tissue from independent 16 individuals. Genes in " cell carcinoma pathway", "Hedgehog signaling pathway", and "Notch signaling pathway" were overexpressed in BCC, confirming the findings from earlier studies in BCC in other populations known to be exposed to As. However, we found that the overexpression of these known pathways was less pronounced in patients with high As exposure (urinary As creatinine ratio (UACR) > 192 µg/gm creatinine) than patients with low UACR. We also found that high UACR was associated with impaired DNA replication pathway, cellular response to different DNA damage repair mechanisms, and immune response. Transcriptomic data were not strongly suggestive of great potential for immune checkpoint inhibitors; however, it suggested lower chance of platinum drug resistance in BCC patients with high UACR compared high platinum drug resistance potential in patients with lower UACR.

An Overview of Cancer in the First 315,000 All of Us Participants.

INTRODUCTION: The NIH All of Us Research Program will have the scale and scope to enable research for a wide range of diseases, including cancer. The program's focus on diversity and inclusion promises a better understanding of the unequal burden of cancer. Preliminary cancer ascertainment in the All of Us cohort from two data sources (self-reported versus electronic health records (EHR)) is considered. MATERIALS AND METHODS: This work was performed on data collected from the All of Us Research Program's 315,297 enrolled participants to date using the Researcher Workbench, where approved researchers can access and analyze All of Us data on cancer and other diseases. Cancer case ascertainment was performed using data from EHR and self-reported surveys across key factors. Distribution of cancer types and concordance of data sources by cancer site and demographics is analyzed. RESULTS AND DISCUSSION: Data collected from 315,297 participants resulted in 13,298 cancer cases detected in the survey (in 89,261 participants), 23,520 cancer cases detected in the EHR (in 203,813 participants), and 7,123 cancer cases detected across both sources (in 62,497 participants). Key differences in survey completion by race/ethnicity impacted the makeup of cohorts when compared to cancer in the EHR and national NCI SEER data. CONCLUSIONS: This study provides key insight into cancer detection in the All of Us Research Program and points to the existing strengths and limitations of All of Us as a platform for cancer research now and in the future.