Showing papers by "Barbara V. Howard published in 2018"

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Circulating Sphingolipids, Insulin, HOMA-IR, and HOMA-B: The Strong Heart Family Study.

Abstract: Experimental studies suggest ceramides may play a role in insulin resistance. However, the relationships of circulating ceramides and related sphingolipids with plasma insulin have been underexplored in humans. We measured 15 ceramide and sphingomyelin species in fasting baseline samples from the Strong Heart Family Study (SHFS), a prospective cohort of American Indians. We examined sphingolipid associations with both baseline and follow-up measures of plasma insulin, HOMA of insulin resistance (HOMA-IR), and HOMA of β-cell function (HOMA-B) after adjustment for risk factors. Among the 2,086 participants without diabetes, higher levels of plasma ceramides carrying the fatty acids 16:0 (16 carbons, 0 double bond), 18:0, 20:0, or 22:0 were associated with higher plasma insulin and higher HOMA-IR at baseline and at follow-up an average of 5.4 years later. For example, a twofold higher baseline concentration of ceramide 16:0 was associated with 14% higher baseline insulin (P < 0.0001). Associations between sphingomyelin species carrying 18:0, 20:0, 22:0, or 24:0 and insulin were modified by BMI (P < 0.003): higher levels were associated with lower fasting insulin, HOMA-IR, and HOMA-B among those with normal BMI. Our study suggests lowering circulating ceramides might be a target in prediabetes and targeting circulating sphingomyelins should take into account BMI.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Abstract: Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals Stage 1 analysis examined ∼188 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries We identified 15 loci that were genome-wide significant (p < 5 × 10−8) in stage 1 and formally replicated in stage 2 A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively) A total of 56 known BP loci were also identified by our results (p < 5 × 10−8) Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2 Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2)

Menopausal Hormone Therapy and Long-Term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials

Abstract: (ed from JAMA 2017;318(10):927–938)This study was a further investigation of the data accumulated in the hormone trials of the Women's Health Initiative (WHI). While the general results derived from the WHI hormone trials have been reported previously, this study focused on the long-term fol

The Association of Arsenic Exposure and Arsenic Metabolism With the Metabolic Syndrome and Its Individual Components: Prospective Evidence From the Strong Heart Family Study.

Abstract: Inorganic arsenic exposure is ubiquitous, and both exposure and interindividual differences in its metabolism have been associated with cardiometabolic risk. However, the associations of arsenic exposure and arsenic metabolism with the metabolic syndrome (MetS) and its individual components are relatively unknown. We used Poisson regression with robust variance to evaluate the associations of baseline arsenic exposure (urinary arsenic levels) and metabolism (relative percentage of arsenic species over their sum) with incident MetS and its individual components (elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, hypertension, and elevated fasting plasma glucose) in 1,047 participants from the Strong Heart Family Study, a prospective family-based cohort study in American Indian communities (baseline visits were held in 1998-1999 and 2001-2003, follow-up visits in 2001-2003 and 2006-2009). Over the course of follow-up, 32% of participants developed MetS. An interquartile-range increase in arsenic exposure was associated with a 1.19-fold (95% confidence interval: 1.01, 1.41) greater risk of elevated fasting plasma glucose concentration but not with other individual components of the MetS or MetS overall. Arsenic metabolism, specifically lower percentage of monomethylarsonic acid and higher percentage of dimethylarsinic acid, was associated with higher risk of overall MetS and elevated waist circumference but not with any other MetS component. These findings support the hypothesis that there are contrasting and independent associations of arsenic exposure and arsenic metabolism with metabolic outcomes which may contribute to overall diabetes risk.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Abstract: Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Evaluation of the Pooled Cohort Risk Equations for Cardiovascular Risk Prediction in a Multiethnic Cohort From the Women's Health Initiative.

Abstract: Importance Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear. Objective We evaluated the predictive accuracy of the PCE in the Women’s Health Initiative (WHI), a multiethnic cohort of contemporary US postmenopausal women. We evaluated the effects of time-varying treatments such as aspirin and statins, and ascertainment of additional ASCVD events by linkage with the Centers for Medicare and Medicaid Services (CMS) claims. Design, Setting, and Participants The WHI recruited the largest number of US women (n = 161 808) with the racial/ethnic, geographic, and age diversity of the general population (1993-1998). For this study, we included women aged 50 to 79 (n = 19 995) participating in the WHI with data on the risk equation variables at baseline and who met the guideline inclusion and exclusion criteria. Median follow-up was 10 years. Main Outcomes and Measures For this study, ASCVD was defined as myocardial infarction, stroke, or cardiovascular death. Results Among the 19 995 women (mean [SD] age, 64 [7.3] years; 8305 [41.5%] white, 7688 [38.5%] black, 3491 [17.5%] Hispanic, 103 [0.5%] American Indian, 321 [1.6%] Asian/Pacific Islander, and 87 [0.4%] other/unknown), a total of 1236 ASCVD events occurred in 10 years and were adjudicated through medical record review by WHI investigators. The WHI-adjudicated observed risks were lower than predicted. The observed (predicted) risks for baseline 10-year risk categories less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more were 1.7 (2.8), 4.4 (6.2), 5.3 (8.7), and 12.4 (18.2), respectively. Small changes were noted after adjusting for time-dependent changes in statin and aspirin use. Among women 65 years or older enrolled in Medicare, WHI-adjudicated risks were also lower than predicted, but observed (predicted) risks became aligned after including events ascertained by linkage with CMS for additional surveillance for events: 3.8 (4.3), 7.1 (6.4), 8.3 (8.7), and 18.9 (18.7), respectively. Similar results were seen across ethnic/racial groups. Overall, the equations discriminated risk well (C statistic, 0.726; 95% CI, 0.714-0.738). Conclusions and Relevance Without including surveillance for ASCVD events using CMS, observed risks in the WHI were lower than predicted by PCE as noted in several other US cohorts, but risks were better aligned after including CMS events. Trial Registration ClinicalTrials.gov identifier:NCT00000611

Cadmium body burden, hypertension, and changes in blood pressure over time: results from a prospective cohort study in American Indians.

Abstract: American Indian communities are at greater risk of hypertension and cardiovascular disease than the general US population and are exposed to greater cadmium levels. However, cadmium's effect on blood pressure is unclear. This study assesses the association between baseline urinary cadmium and longitudinal changes in blood pressure in American Indian communities. Cadmium was measured in 3047 baseline urine samples from Strong Heart Study participants from three geographic areas. Longitudinal changes in blood pressure across three study visits (1989–1999) were modeled using linear mixed models by baseline log urinary cadmium to creatinine ratio. Hypertension risk was evaluated using interval-censored survival analysis. Higher levels of urinary cadmium at baseline were associated with faster rates of increase in diastolic and systolic blood pressure (P [trend] = .001 and .02, respectively). The estimated change in diastolic and systolic blood pressures per year was 0.18 mm Hg (0.05–0.31) and 0.62 mm Hg (0.37–0.87) in the upper quintile of cadmium level compared with −0.11 mm Hg (−0.24 to 0.02) and 0.21 mm Hg (−0.04 to 0.46) in the lowest, respectively. A one-unit increase in log-transformed urinary cadmium was associated with 10% greater hypertension risk (95% confidence interval: 1.01–1.20). In conclusion, blood pressure of individuals with greater baseline levels of urinary cadmium increased at a faster rate relative to those with lower levels.

Diabetes in America

Abstract: Diabetes in America, 3rd Edition, is a compilation and assessment of epidemiologic, public health, clinical, and clinical trial data on diabetes and its complications in the United States. It was published by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, during 2016–2018. The intended audience is the wide range of individuals in the research community, clinicians, health policy makers, and individuals with diabetes, as well as their caregivers and family members.Diabetes in America, 3rd Edition, contains 42 chapters organized into three areas: Section I: Spectrum of Diabetes: Descriptive epidemiology of diabetes in the United States based on national surveys and community-based studies, including prevalence and incidence; sociodemographic, metabolic, and lifestyle characteristics; genetics and risk factors for developing diabetes; and unique aspects of diabetes in younger and older populations, and in pregnant women (chapters 1–16) Section II: Complications of Diabetes and Related Conditions: The myriad complications that affect patients with diabetes, including mortality (chapters 17–36) Section III: Prevention and Medical Care for Diabetes: Clinical trials and studies to prevent diabetes; medication use and self-care practices, health care utilization, and quality of care; and economic aspects including health insurance and health care costs (chapters 37–42)

Associations of Biomarker-Calibrated Intake of Total Sugars With the Risk of Type 2 Diabetes and Cardiovascular Disease in the Women's Health Initiative Observational Study.

Abstract: The inconsistent findings from epidemiologic studies relating total sugars (TS) consumption to cardiovascular disease (CVD) or type 2 diabetes (T2D) risk may be partly due to measurement error in self-reported intake. Using regression calibration equations developed based on the predictive biomarker for TS and recovery biomarker for energy, we examined the association of TS with T2D and CVD risk, before and after dietary calibration, in 82,254 postmenopausal women participating in the Women's Health Initiative Observational Study. After up to 16 years of follow-up (1993-2010), 6,621 T2D and 5,802 CVD incident cases were identified. The hazard ratio for T2D per 20% increase in calibrated TS was 0.94 (95% confidence interval (CI): 0.77, 1.15) in multivariable energy substitution, and 1.00 (95% CI: 0.85, 1.18) in energy partition models. Multivariable hazard ratios for total CVD were 0.97 (95% CI: 0.87, 1.09) from energy substitution, and 0.91 (95% CI: 0.80, 1.04) from energy partition models. Uncalibrated TS generated a statistically significant inverse association with T2D and total CVD risk in multivariable energy substitution and energy partition models. The lack of conclusive findings from our calibrated analyses may be due to the low explanatory power of the calibration equations for TS, which could have led to incomplete deattenuation of the risk estimates.

Risk Factor Burden, Heart Failure, and Survival in Women of Different Ethnic Groups: Insights From the Women's Health Initiative.

Abstract: Background: The higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups. Methods and Results: In the WHI (Women’s Health Initiative; 1993–2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased ( P P =0.18)—African-Americans 1 RF: 1.80 (1.01–3.20), 2 RFs: 3.19 (1.84–5.54), 3+ RFs: 7.31 (4.26–12.56); Whites 1 RF: 1.27 (1.04–1.54), 2 RFs: 1.95 (1.60–2.36), 3+ RFs: 4.07 (3.36–4.93); Hispanics 1 RF: 1.72 (0.68–4.34), 2 RFs: 3.87 (1.60–9.37), 3+ RFs: 8.80 (3.62–21.42). Risk of death before developing HF increased with subsequent RFs ( P P =0.001). The number of RFs was not associated with the risk of death after developing HF in any group ( P =0.25; interaction P =0.48). Conclusions: Among diverse racial/ethnic groups, an increase in the number of baseline RFs was associated with higher risk of HF and death before HF but was not associated with death after HF. Early RF prevention may reduce the burden of HF across multiple racial/ethnic groups.

Physical activity and telomere length in American Indians: the Strong Heart Study.

Abstract: Telomere length, a marker of biological aging, has been associated with many chronic diseases, but its relations with physical activity remains unclear. The purpose of this study was to examine the association of objectively measured ambulatory activity with leukocyte telomere length (LTL), a marker of biological aging, among American Indians. This cross-sectional study included 2312 AI participants from the Strong Heart Family Study. Steps per day were measured using Accusplit AE120 pedometers. Quantitative PCR was used to measure LTL. Generalized estimating equations were used to examine the associations of steps per day with LTL. The median steps per day over a 1 week period was 5118 steps (interquartile range = 3163–7576 steps). Compared to participants in the lowest quartile of steps per day, participants in the upper three quartiles of steps per day had longer LTL: beta ± SE = 0.0195 ± 0.0144, 0.0273 ± 0.0139, and 0.0375 ± 0.0143 T/S ratio units longer (p trend = 0.010) after adjustment for potential confounders. These data suggest that ambulatory activity is associated with LTL. Further studies are needed to determine the mechanism by which ambulatory activity influences LTL.

Relationships Between Smoking Behaviors and Cotinine Levels Among Two American Indian Populations With Distinct Smoking Patterns

Abstract: Introduction Smoking prevalence, cigarettes per day (CPD), and lung cancer incidence differ between Northern Plains (NP) and Southwest (SW) American Indian populations We used cotinine as a biomarker of tobacco smoke exposure to biochemically characterize NP and SW smokers and nonsmokers and to investigate factors associated with variation in tobacco exposure Methods American Indians (N = 636) were recruited from two different tribal populations (NP and SW) as part of a study conducted as part of the Collaborative to Improve Native Cancer Outcomes P50 project For each participant, a questionnaire assessed smoking status, CPD, second-hand smoke exposure, and traditional ceremonial tobacco use; plasma and/or salivary cotinine was measured Results Cotinine levels were (mean ± 95% confidence interval [CI]) 816 ± 141 and 213 ± 73 ng/ml among NP smokers and non-mokers, respectively, and 448 ± 144 and 98 ± 58 ng/ml among SW smokers and nonsmokers, respectively Cotinine levels correlated with CPD in both populations (p < 0001) Cotinine ≥15 ng/ml was measured in 734% of NP smokers and 478% of SW smokers and in 190% of NP nonsmokers and 109% of SW nonsmokers Ceremonial traditional tobacco use was associated with higher cotinine among NP smokers only (p = 0004) Second-hand smoke exposure was associated with higher cotinine among NP non-smokers (P < 002) More secondhand smoke exposure was associated with smoking more CPD in both populations (p = 003-029) Linear regression modeling mirrored these findings Conclusions High prevalence of smoking in the Northern Plains and high cotinine levels among nonsmokers in both regions highlights the tribal populations' risk for tobacco-related disease Implications There is a high prevalence of smoking in Northern Plains American Indians Among Northern Plains and Southwest nonsmokers, relatively high cotinine levels, representative of high tobacco exposure, suggest considerable exposure to second-hand smoke It is critical to highlight the extent of second-hand smoke exposure among the Northern Plains and Southwest American Indians and to enhance efforts to initiate smoke-free policies in tribal communities, which are not subject to state-level polices

Parental longevity predicts healthy ageing among women

Abstract: Author(s): Shadyab, Aladdin H; Manson, JoAnn E; Li, Wenjun; Gass, Margery; Brunner, Robert L; Naughton, Michelle J; Cannell, Brad; Howard, Barbara V; LaCroix, Andrea Z | Abstract: Objective:to examine the association of parental longevity with healthy survival to age 90 years. Methods:this was a prospective study among a racially and ethnically diverse cohort of 22,735 postmenopausal women from the Women's Health Initiative recruited from 1993 to 1998 and followed through 2017. Women reported maternal and paternal ages at death and current age of alive parents. Parental survival categories were l70, 70-79 (reference), 80-89 and ≥90 years (longevity). Healthy ageing was defined as reaching age 90 without major chronic conditions (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or physical limitations. Results:women whose mothers survived to ≥90 years were more likely to attain healthy ageing (OR, 1.25; 95% CI, 1.11-1.42) and less likely to die before age 90 (OR, 0.75; 95% CI, 0.68-0.83). Women whose fathers survived to ≥90 years did not have significantly increased odds of healthy ageing but showed 21% (OR, 0.79; 95% CI, 0.70-0.90) decreased odds of death before age 90. Women whose mother and father both lived to 90 had the strongest odds of healthy ageing (OR, 1.38; 95% CI, 1.09-1.75) and decreased odds of death (OR, 0.68; 95% CI, 0.54-0.85). The proportion of healthy survivors was highest among women whose mother and father lived to 90 (28.6%), followed by those whose mother only lived to 90 (23.2%). Conclusions:parental longevity predicted healthy ageing in a national cohort of postmenopausal women, supporting the view that genetic, environmental, and behavioral factors transmitted across generations may influence ageing outcomes among offspring.

Availability and Cost of Healthy Foods in a Large American Indian Community in the North-Central United States.

Abstract: To understand the local food environment in a rural American Indian community, we assessed the availability and price of healthy foods offered at all stores (n = 27) within a 90-mile radius of the town center of a large American Indian reservation. Stores were classified by type, and availability and cost of foods were measured using the Nutrition Environment Measures Survey in Stores (January-February 2016). Healthy foods were available at most grocery stores (>97%), although the price of foods varied considerably among stores. Having quantified the availability and cost of food, efforts must focus on understanding other structural and contextual factors that influence diet in this community.

Effects of reproductive period duration and number of pregnancies on midlife ECG indices: a secondary analysis from the Women's Health Initiative Clinical Trial.

Abstract: Objectives Pregnancy, menses and menopause are related to fluctuations in endogenous sex hormones in women, which cumulatively may alter cardiac electrical conduction. Therefore, we sought to study the association between number of pregnancies and reproductive period duration (RD, time from menarche to menopause) with ECG intervals in the Women’s Health Initiative Clinical Trials. Design Secondary analysis of multicentre clinical trial. Setting USA. Primary outcome measures ECGintervals: PR interval, P-wave duration, P-wave dispersion, QTc interval. Participants n=40 687 women (mean age=62 years) participating in the Women’s Health Initiative Clinical Trials. 82.5% were white, 9.3% black, 4% Hispanic and 2.7% Asian. Methods In primary analysis, we employed multivariable linear regression models relating number of pregnancies and RD with millisecond changes in intervals from enrolment ECG. We studied effect modification by hormone therapy use. Results Among participants, 5+ live births versus 0 prior pregnancies was associated with a 1.32 ms increase in PR interval (95% CI 0.25 to 2.38), with a graded association with longer QTc interval (ms) (none (prior pregnancy, no live births)=0.66 (–0.56 to 1.88), 1=0.15 (–0.71 to 1.02), 2–4=0.25 (–0.43 to 0.94) and 5+ live births=1.15 (0.33 to 1.98), p=0.008). RD was associated with longer PR interval and maximum P-wave duration (but not P-wave dispersion) among never users of hormone therapy: (PR (ms) per additional RD year: 0.10 (0.04 to 0.16); higher P-wave duration (ms): 0.09 (0.06 to 0.12)). For every year increase in reproductive period, QTc decreased by 0.04 ms (−0.07 to –0.01). Conclusions An increasing number of live births is related to increased and RD to decreased ventricular repolarisation time. Both grand multiparity and longer RD are related to increased atrial conduction time. Reproductive factors that alter midlife cardiac electrical conduction system remodelling in women may modestly influence cardiovascular disease risk in later life. Trial registration number NCT00000611; Post-results.

The effect of genetic variants on the relationship between statins and breast cancer in postmenopausal women in the Women’s Health Initiative observational study

Abstract: Statins have been postulated to have chemopreventive activity against breast cancer. We evaluated whether germline genetic polymorphisms modified the relationship between statins and breast cancer risk using data from the Women’s Health Initiative. We evaluated these interactions using both candidate gene and agnostic genome-wide approaches. To identify candidate gene–statin interactions, we tested interactions between 22 SNPS in nine candidate genes implicated in the effect of statins on lipid metabolism in 1687 cases and 1687 controls. We then evaluated statin use interaction with the remaining 30,380 SNPs available in this sample from the CGEMS GWAS study. After adjusting for multiple comparisons, no SNP interactions with statin usage and risk of breast cancer were statistically significant in either the candidate genes or genome-wide approaches. We found no evidence of SNP interactions with statin usage for breast cancer risk in a population of 3374 individuals. These results suggest that genome-wide common genetic variants do not moderate the association between statin usage and breast cancer in the population of women in the Women’s Health Initiative.

Depression, Metabolic Syndrome, and Locus of Control in Arab Americans Living in the DC Metropolitan Area: A Structural Equation Model.

Abstract: Arab Americans have high prevalences of metabolic syndrome (MetS) and depression. Depression and external locus of control (LOC) may worsen MetS. We examined the relationship between depression and MetS with a convenience sample of 136 Arab Americans living in the Washington, DC, metropolitan area. Participants were surveyed with the Multidimensional Health Locus of Control questionnaire and the Center of Epidemiological Studies-Depression scale. Laboratory measurements were collected based on the components of MetS. A structural equation model was used to explore the relationship between MetS and depression through analysis of LOC. MetS was significantly correlated with external LOC (powerful others and chance), and depression was correlated with a weak internal LOC. Future study of the effect of LOC on health outcomes in Arab Americans may be used to mitigate MetS and depression in this population.

An analysis of the effect of statins on the risk of Non-Hodgkin's Lymphoma in the Women's Health Initiative cohort.

Abstract: Statins have been shown to induce a phosphoprotein signature that modifies MYC (myelocytomatosis viral oncogene) activation and to have anti-inflammatory activity that may impact the risk of Non-Hodgkin's lymphoma (NHL). We analyzed the relationship between statins and risk of NHL using data from the Women's Health Initiative (WHI). The study population included 161,563 postmenopausal women ages 50-79 years from which 712 cases of NHL were diagnosed after 10.8 years of follow-up. Information on statin use and other risk factors was collected by self- and interviewer-administered questionnaires. Multivariable-adjusted HR and 95% CI evaluating the relationship between statin use at baseline, as well as in a time-dependent manner and risk of NHL, were computed from Cox proportional hazards analyses. A separate analysis was performed for individual NHL subtypes: diffuse large B-Cell lymphoma (DLBCL) (n = 228), follicular lymphoma (n = 169), and small lymphocytic lymphoma (n = 74). All statistical tests were two-sided. There was no significant association between use of statins at baseline and risk of NHL (HR 0.85, 95% C.I. 0.67-1.08). However, in the multivariable-adjusted time-dependent models, statin use was associated with a borderline lower risk of NHL (HR 0.81, 95% C.I. 0.66-1.00). Considering subtypes of NHL, statin use was associated with a lower risk of DLBCL (HR 0.62, 95% C.I. 0.42-0.91). This effect was driven by lipophilic statins (HR 0.62, 95% C.I. 0.40-0.96). In the WHI, statins were associated with a lower overall risk of DLBCL, particularly attributable to lipophilic statins. These results may have impact on primary or secondary prevention of NHL, particularly DLBCL.

Transitions from Ideal to Intermediate Cholesterol Levels may vary by Cholesterol Metric.

Abstract: To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (≥20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007–2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008–2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C.

An additive Cox model for coronary heart disease study

Abstract: Existing models for coronary heart disease study use a set of common risk factors to predict the survival time of the disease, via the standard Cox regression model. For complex relationships betwe...

Lower body functioning and correlates among older American Indians: The Cerebrovascular Disease and Its Consequences in American Indians Study.

Abstract: More than six million American Indians live in the United States, and an estimated 1.6 million will be aged ≥65 years old by 2050 tripling in numbers since 2012. Physical functioning and related factors in this population are poorly understood. Our study aimed to assess lower body functioning and identify the prevalence and correlates of “good” functioning in a multi-tribe, community-based sample of older American Indians. Assessments used the Short Physical Performance Battery (SPPB). “Good” lower body functioning was defined as a total SPPB score of ≥10. Potential correlates included demographic characteristics, study site, anthropometrics, cognitive functioning, depressive symptomatology, grip strength, hypertension, diabetes mellitus, heart disease, prior stroke, smoking, alcohol use, and over-the-counter medication use for arthritis or pain. Data were collected between 2010 and 2013 by the Cerebrovascular Disease and Its Consequences in American Indians Study from community-dwelling adults aged ≥60 years (n = 818). The sample’s mean age was 73 ± 5.9 years. After adjustment for age and study site, average SPPB scores were 7.0 (95% CI, 6.8, 7.3) in women and 7.8 (95% CI, 7.5, 8.2) in men. Only 25% of the sample were classified with “good” lower body functioning. When treating lower body functioning as a continuous measure and adjusting for age, gender, and study site, the correlates of better functioning that we identified were younger age, male gender, married status, higher levels of education, higher annual household income, Southern Plains study site, lower waist-hip ratio, better cognitive functioning, stronger grip strength, lower levels of depressive symptomatology, alcohol consumption, and the absence of hypertension, diabetes mellitus, and heart disease. In our fully adjusted models, correlates of “good” lower body functioning were younger age, higher annual household income, better cognitive functioning, stronger grip, and the absence of diabetes mellitus and heart disease. These results suggest that “good” lower body functioning is uncommon in this population, whereas its correlates are similar to those found in studies of other older adult populations. Future efforts should include the development or cultural tailoring of interventions to improve lower body functioning in older American Indians.

Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study

Abstract: Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10-7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10-9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B. Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.

Stroke and Diabetes

Abstract: In the total population, stroke is the fifth most common cause of death and the leading neurological cause of long-term disability in the United States, accounting in 2011 for $34 billion in health care costs. With the advent of sensitive brain imaging techniques, it is common to observe magnetic resonance imaging evidence of subclinical vascular brain injury, such as covert brain infarcts (CBI) and white matter hyperintensities (WMH). In an unselected sample of persons age >65 years without a history of clinical events, 10%–15% had CBI and 95% had WMH. The subclinical findings do not cause abrupt clinical symptoms but are often associated with cognitive decline and with an increased risk of subsequent stroke. Therefore, the clinical and public health burden of cerebrovascular disease is far greater than that of overt clinical disease. This burden is higher in persons with diabetes. Diabetes, a risk equivalent for cardiovascular disease, has been recognized as one of the major risk factors for stroke and subclinical vascular brain injury, such as CBI, WMH, and vascular cognitive impairment.Stroke is clinically defined as an acute-onset focal neurological deficit persisting for more than 24 hours. About 85% of all strokes are ischemic, and the other 15% are hemorrhagic. Ischemic stroke is caused by an abrupt blockage of the artery, either by an embolus from the heart or from a more proximal artery, or from an in situ thrombus growing to occlude a cerebral artery affected by an atherosclerotic plaque, leading to an acute blockage of blood supply to the brain. Hemorrhagic stroke can result in accumulation of blood in the substrate of the brain, which is called intracerebral hemorrhage, in the cerebrospinal fluid around the brain, or in the cerebrospinal fluid spaces within the brain.The etiology of stroke in persons with diabetes is comparable to the etiologies in other populations. However, multiple underlying pathophysiological processes in diabetes lead to a high prevalence of small vessel and/or large vessel atherosclerosis in persons with diabetes. Persons with diabetes have about twice the risk for stroke, particularly of ischemic stroke. Diabetic individuals after stroke have about a 25% reduction in a favorable outcome, such as being able to function independently in activities of daily living, and are more likely to die from the stroke. Those who survive are more likely to have recurrent strokes and to develop vascular cognitive impairment than persons without diabetes.Diabetes is more common in nonwhite populations, and stroke risk has been assessed in various racial/ethnic subgroups. Diabetes is at least as important a risk factor for stroke in blacks, Japanese Americans, and Native Americans as it is in whites, with a 40%–100% higher risk in racial/ethnic minorities.Coexistence of various risk factors, such as hypertension and hyperlipidemia, and concomitant coronary or peripheral vascular disease are common problems in persons with type 2 diabetes and are also independent risk factors for stroke and its serious complications. Impaired glucose tolerance and the metabolic syndrome, as well as microalbuminuria, are other stroke risk factors in persons with diabetes, with the metabolic syndrome increasing risk by 20%–40% and microalbuminuria increasing risk by approximately 80%.Strict control of hyperglycemia has not been shown to reduce stroke incidence in persons with diabetes. Vigorous management of primary disease (diabetes) and careful identification and treatment of the concomitant vascular risk factors, especially hypertension, along with lifestyle modifications remain the fundamental approach for stroke prevention in this vulnerable population. Statins and low-dose aspirin may also be beneficial in preventing stroke or attenuating its adverse impact. Studies of oral hypoglycemic drugs and peroxisome proliferator-activated receptor-gamma (PPAR-γ) inhibitors have not, so far, shown a convincing effect on altering stroke risk among persons with diabetes.

Large Cohort Data Based Group or Community Disease Prevention Design Strategy: Strong Heart Study

Abstract: Background and Objective: A multitude of large cohort studies have data on incidence rates and predictors of various chronic diseases. However, approaches for utilization of these costly collected data and translation of these valuable results to inform and guide clinical disease prevention practice are not well developed. In this paper we proposed a novel conceptual group/community disease prevention design strategy based on large cohort study data. Methods and Results: The data from participants (n = 3516; 2056 women) aged 45 to 74 years and the diabetes risk prediction model from Strong Heart Study were used. The Strong Heart Study is a population-based cohort study of cardiovascular disease and its risk factors in American Indians. A conceptual group/community disease prevention design strategy based on large cohort data was initiated. The application of the proposed strategy for group diabetes prevention was illustrated. Discussion: The strategy may provide reasonable solutions to the prevention design issues. These issues include complex associations of a disease with its combined and correlated risk factors, individual differences, choosing intervention risk factors and setting their appropriate, attainable, gradual and adaptive goal levels for different subgroups, and assessing effectiveness of the prevention program. Conclusions: The strategy and methods shown in the illustration example can be analogously adopted and applied for other diseases preventions. The proposed strategy for a target group/community in a population provides a way to translate and apply epidemiological study results to clinical disease prevention practice.

Large Cohort Data Based Cost-Effective Disease Prevention Design Strategy: Strong Heart Study.

Abstract: Background and Objective: A multitude of large cohort studies have collected data on incidence and covariates/risk factors of various chronic diseases. However, approaches for utilization of these large data and translation of the valuable results to inform and guide clinical disease prevention practice are not well developed. In this paper, we proposed, based on large cohort study data, a novel conceptual cost-effective disease prevention design strategy for a target group when it is not affordable to include everyone in the target group for intervention. Methods and Results: Data from American Indian participants (n = 3516; 2056 women) aged 45 - 74 years in the Strong Heart Study, the diabetes risk prediction model from the study, a utility function, and regression models were used. A conceptual cost-effective disease prevention design strategy based on large cohort data was initiated. The application of the proposed strategy for diabetes prevention was illustrated. Discussion: The strategy may provide reasonable solutions to address cost-effective prevention design issues. These issues include complex associations of a disease with its significant risk factors, cost-effectively selecting individuals at high risk of developing disease to undergo intervention, individual differences in health conditions, choosing intervention risk factors and setting their appropriate, attainable, gradual and adaptive goal levels for different subgroups, and assessing effectiveness of the prevention program. Conclusions: The strategy and methods shown in the illustrative example can also be analogously adopted and applied to other diseases preventions. The proposed strategy provides a way to translate and apply epidemiological study results to clinical disease prevention practice.