Publications by authors named "Barbara V Howard"

408 Publications

Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.

J Lipid Res 2021 Sep 20:100119. Epub 2021 Sep 20.

University of Washington Cardiovascular Health Research Unit, 1730 Minor Ave #1360 Seattle, WA 98101 USA; Medicine, 1410 NE Campus Parkway, Seattle WA, 98105 USA.

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here we investigated associations of 15 ceramide and sphingomyelin species (i.e., all sphingolipids, measured with coefficient of variation less than 20%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dL or non-fasting glucose ≥200 mg/dL; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each ceramide species were: 1.21 (95% CI 1.09-1.34) for Cer-16, 1.23 (95% CI 1.10-1.37) for Cer-18, 1.14 (95% CI 1.02-1.26) for Cer-20, and 1.18 (95% CI 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.
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http://dx.doi.org/10.1016/j.jlr.2021.100119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517199PMC
September 2021

Comparing Vascular Brain Injury and Stroke by Cranial Magnetic Resonance Imaging, Physician-Adjudication, and Self-Report: Data from the Strong Heart Study.

Neuroepidemiology 2021 24;55(5):398-406. Epub 2021 Aug 24.

Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington, USA.

Background: Epidemiologic studies often use self-report as proxy for clinical history. However, whether self-report correctly identifies prevalence in minority populations with health disparities and poor health-care access is unknown. Furthermore, overlap of clinical vascular events with covert vascular brain injury (VBI), detected by imaging, is largely unexamined.

Methods: The Strong Heart Study recruited American Indians from 3 regions, with surveillance and adjudication of stroke events from 1989 to 2013. In 2010-2013, all 817 survivors, aged 65-95 years, underwent brain imaging, neurological history interview, and cognitive testing. VBI was defined as imaged infarct or hemorrhage.

Results: Adjudicated stroke was prevalent in 4% of participants and separately collected, self-reported stroke in 8%. Imaging-defined VBI was detected in 51% and not associated with any stroke event in 47%. Compared with adjudication, self-report had 76% sensitivity and 95% specificity. Participants with adjudicated or self-reported stroke had the poorest performance on cognitive testing; those with imaging-only (covert) VBI had intermediate performance.

Conclusion: In this community-based cohort, self-report for prior stroke had good performance metrics. A majority of participants with VBI did not have overt, clinically recognized events but did have neurological or cognitive symptoms. Data collection methodology for studies in a resource-limited setting must balance practical limitations in costs, accuracy, feasibility, and research goals.
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http://dx.doi.org/10.1159/000517804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448943PMC
August 2021

Predicting Incident Heart Failure in Women With Machine Learning: The Women's Health Initiative Cohort.

Can J Cardiol 2021 Aug 13. Epub 2021 Aug 13.

Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.

Background: Heart failure (HF) is a leading cause of cardiac morbidity among women, whose risk factors differ from those in men. We used machine-learning approaches to develop risk- prediction models for incident HF in a cohort of postmenopausal women from the Women's Health Initiative (WHI).

Methods: We used 2 machine-learning methods-Least Absolute Shrinkage and Selection Operator (LASSO) and Classification and Regression Trees (CART)-to perform variable selection on 1227 baseline WHI variables for the primary outcome of incident HF. These variables were then used to construct separate Cox proportional hazard models, and we compared these results, using receiver-operating characteristic (ROC) curve analysis, against a comparator model built using variables from the Atherosclerosis Risk in Communities (ARIC) HF prediction model. We analyzed 43,709 women who had 2222 incident HF events; median follow-up was 14.3 years.

Results: LASSO selected 10 predictors, and CART selected 11 predictors. The highest correlation between selected variables was 0.46. In addition to selecting well-established predictors such as age, myocardial infarction, and smoking, novel predictors included physical function, number of pregnancies, number of previous live births and age at menopause. In ROC analysis, the CART-derived model had the highest C-statistic of 0.83 (95% confidence interval [CI], 0.81-0.85), followed by LASSO 0.82 (95% CI, 0.81-0.84) and ARIC 0.73 (95% CI, 0.70-0.76).

Conclusions: Machine-learning approaches can be used to develop HF risk-prediction models that can have better discrimination compared with an established HF risk model and may provide a basis for investigating novel HF predictors.
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http://dx.doi.org/10.1016/j.cjca.2021.08.006DOI Listing
August 2021

Temporal Associations and Outcomes of Breast Cancer and Heart Failure in Postmenopausal Women.

JACC CardioOncol 2020 Nov 17;2(4):567-577. Epub 2020 Nov 17.

Creighton University, Omaha, Nebraska, USA.

Background: Heart failure (HF) and breast cancer are 2 of the leading causes of death in postmenopausal women. The temporal association between HF and breast cancer in postmenopausal women has not been described.

Objectives: This study sought to examine the temporal association between HF and breast cancer.

Methods: Postmenopausal women within the WHI (Women's Health Initiative) cohort were studied. All prevalent HF and prevalent breast cancer at enrollment were self-reported. Incident hospitalized HF and breast cancer diagnoses were adjudicated through 2017.

Results: Among a cohort of 44,174 women (mean age 63 ± 7 years), 2,188 developed incident invasive breast cancer and 2,416 developed incident hospitalized HF over a median follow-up of 14 and 15 years, respectively. When compared with a breast cancer- and HF-free cohort, there was no association between prevalent HF and incident invasive breast cancer and similarly, there was no association between prevalent breast cancer and incident hospitalized HF. Across the entire cohort, the median survival after incident hospitalized HF was worse compared with an incident invasive breast cancer diagnosis (5 and 19 years, respectively). In women with incident invasive breast cancer, prevalent HF was associated with an increased risk of mortality (hazard ratio: 2.28; 95% confidence interval: 1.31 to 3.95). In women with incident hospitalized HF, prevalent breast cancer was associated with an increased risk of mortality (hazard ratio: 1.66; 95% confidence interval: 1.03 to 2.68). Cause of death after incident HF was different only in women with prevalent and interim breast cancer compared with those without prevalent and interim breast cancer.

Conclusions: In postmenopausal women, prevalent HF was not associated with a higher incidence of breast cancer and vice versa. However, the presence of incident invasive breast cancer or incident HF in those with prevalent HF or prevalent breast cancer, respectively, was associated with increased mortality.
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http://dx.doi.org/10.1016/j.jaccao.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352239PMC
November 2020

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study.

JAMA Cardiol 2021 Aug 4. Epub 2021 Aug 4.

Population Health Program, Texas Biomedical Research Institute, San Antonio.

Importance: American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.

Objective: To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.

Design, Setting, And Participants: This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.

Exposure: Blood DNA methylation.

Main Outcome And Measure: Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.

Results: The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.

Conclusions And Relevance: In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.
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http://dx.doi.org/10.1001/jamacardio.2021.2704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340006PMC
August 2021

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer Epidemiol 2021 10 19;74:101978. Epub 2021 Jul 19.

MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD, 20782, USA; Georgetown, Howard Universities Center for Clinical and Translational Research, Washington, DC, 2000, USA. Electronic address:

Background: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

Methods: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

Results: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

Conclusions: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.
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http://dx.doi.org/10.1016/j.canep.2021.101978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455435PMC
October 2021

Change to a Higher Carbohydrate Diet and Energy Expenditure among Postmenopausal Women.

J Nutr 2021 Jun;151(6):1673-1674

Department of Medicine, Georgetown University Medical Center, and MedStar Health Research Institute, Hyattsville MD, USA.

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http://dx.doi.org/10.1093/jn/nxab095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169807PMC
June 2021

Biomarker-Calibrated Macronutrient Intake and Chronic Disease Risk among Postmenopausal Women.

J Nutr 2021 Aug;151(8):2330-2341

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Knowledge about macronutrient intake and chronic disease risk has been limited by the absence of objective macronutrient measures. Recently, we proposed novel biomarkers for protein, protein density, carbohydrate, and carbohydrate density, using established biomarkers and serum and urine metabolomics profiles in a human feeding study.

Objectives: We aimed to use these biomarkers to develop calibration equations for macronutrient variables using dietary self-reports and personal characteristics and to study the association between biomarker-calibrated intake estimates and cardiovascular disease, cancer, and diabetes risk in Women's Health Initiative (WHI) cohorts.

Methods: Prospective disease association analyses are based on WHI cohorts of postmenopausal US women aged 50-79 y when enrolled at 40 US clinical centers (n = 81,954). We used biomarker intake values in a WHI nutritional biomarker study (n = 436) to develop calibration equations for each macronutrient variable, leading to calibrated macronutrient intake estimates throughout WHI cohorts. We then examined the association of these intakes with chronic disease incidence over a 20-y (median) follow-up period using HR regression methods.

Results: In analyses that included doubly labeled water-calibrated total energy, HRs for cardiovascular diseases and cancers were mostly unrelated to calibrated protein density. However, many were inversely related to carbohydrate density, with HRs (95% CIs) for a 20% increment in carbohydrate density of 0.81 (0.69, 0.95) and 0.83 (0.74, 0.93), respectively, for primary outcomes of coronary heart disease and breast cancer, as well as 0.74 (0.60, 0.91) and 0.87 (0.81, 0.93) for secondary outcomes of heart failure and total invasive cancer. Corresponding HRs (95% CIs) for type 2 diabetes incidence in relation to protein density and carbohydrate density were 1.17 (1.09, 1.75) and 0.73 (0.66, 0.80), respectively.

Conclusions: At specific energy intake, a diet high in carbohydrate density is associated with substantially reduced risk of major chronic diseases in a population of US postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.
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http://dx.doi.org/10.1093/jn/nxab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349120PMC
August 2021

Nutritional epidemiology and the Women's Health Initiative: a review.

Am J Clin Nutr 2021 05;113(5):1083-1092

Lundquist Institute for Innovative Biomedical Research at Harbor-UCLA Medical Center, Torrance, CA, USA.

The dietary modification (DM) clinical trial, within the Women's Health Initiative (WHI), studied a low-fat dietary pattern intervention that included guidance to increase vegetables, fruit, and grains. This study was motivated in part from uncertainty about the reliability of observational studies examining the association between dietary fat and chronic disease risk by using self-reported dietary data. In addition to this large trial, which had breast and colorectal cancer as its primary outcomes, a substantial biomarker research effort was initiated midway in the WHI program to contribute to nutritional epidemiology research more broadly. Here we review and update findings from the DM trial and from the WHI nutritional biomarker studies and examine implications for future nutritional epidemiology research. The WHI included the randomized controlled DM trial (n = 48,835) and a prospective cohort observational (OS) study (n = 93,676), both among postmenopausal US women, aged 50-79 y when enrolled during 1993-1998. Also reviewed is a nutrition and physical activity assessment study in a subset of 450 OS participants (2007-2009) and a related controlled feeding study among 153 WHI participants (2010-2014). Long-term follow-up in the DM trial provides evidence for intervention-related reductions in breast cancer mortality, diabetes requiring insulin, and coronary artery disease in the subset of normotensive healthy women, without observed adverse effects or changes in all-cause mortality. Studies of intake biomarkers, and of biomarker-calibrated intake, suggest important associations of total energy intake and macronutrient dietary composition with the risk for major chronic diseases among postmenopausal women. Collectively these studies argue for a nutrition epidemiology research agenda that includes major efforts in nutritional biomarker development, and in the application of biomarkers combined with self-reported dietary data in disease association analyses. We expect such efforts to yield novel disease association findings and to inform disease prevention approaches for potential testing in dietary intervention trials. This trial was registered at clinicaltrials.gov as NCT00000611.
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http://dx.doi.org/10.1093/ajcn/nqab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120331PMC
May 2021

Plasma epoxyeicosatrienoic acids and dihydroxyeicosatrieonic acids, insulin, glucose and risk of diabetes: The strong heart study.

EBioMedicine 2021 Apr 19;66:103279. Epub 2021 Mar 19.

Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.

Background: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians.

Methods: We measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts.

Findings: We observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose.

Interpretation: In this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2021.103279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010619PMC
April 2021

Association of Major Dietary Protein Sources With All-Cause and Cause-Specific Mortality: Prospective Cohort Study.

J Am Heart Assoc 2021 02 24;10(5):e015553. Epub 2021 Feb 24.

Department of Epidemiology College of Public Health University of Iowa Iowa City IA.

Background Dietary recommendations regarding protein intake have been focused on the amount of protein. However, such recommendations without considering specific protein sources may be simplistic and insufficient. Methods and Results We included 102 521 postmenopausal women enrolled in the Women's Health Initiative between 1993 and 1998, and followed them through February 2017. During 1 876 205 person-years of follow-up, 25 976 deaths occurred. Comparing the highest with the lowest quintile, plant protein intake was inversely associated with all-cause mortality (hazard ratio [HR], 0.91 [0.86, 0.96]), cardiovascular disease mortality (HR, 0.88 [0.79, 0.97]), and dementia mortality (HR, 0.79 [0.67, 0.94]). Among major protein sources, comparing the highest with the lowest quintile of consumption, processed red meat (HR, 1.06 [1.01, 1.10]) or eggs (HR, 1.14 [1.10, 1.19]) was associated with higher risk of all-cause mortality. Unprocessed red meat (HR, 1.12 [1.02, 1.23]), eggs (HR, 1.24 [1.14, 1.34]), or dairy products (HR, 1.11 [1.02, 1.22]) was associated with higher risk of cardiovascular disease mortality. Egg consumption was associated with higher risk of cancer mortality (HR, 1.10 [1.02, 1.19]). Processed red meat consumption was associated with higher risk of dementia mortality (HR, 1.20 [1.05, 1.32]), while consumption of poultry (HR, 0.85 [0.75, 0.97]) or eggs (HR, 0.86 [0.75, 0.98]) was associated with lower risk of dementia mortality. In substitution analysis, substituting of animal protein with plant protein was associated with a lower risk of all-cause mortality, cardiovascular disease mortality, and dementia mortality, and substitution of total red meat, eggs, or dairy products with nuts was associated with a lower risk of all-cause mortality. Conclusions Different dietary protein sources have varying associations with all-cause mortality, cardiovascular disease mortality, and dementia mortality. Our findings support the need for consideration of protein sources in future dietary guidelines.
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http://dx.doi.org/10.1161/JAHA.119.015553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174240PMC
February 2021

Cooking for Health: a healthy food budgeting, purchasing, and cooking skills randomized controlled trial to improve diet among American Indians with type 2 diabetes.

BMC Public Health 2021 02 15;21(1):356. Epub 2021 Feb 15.

Department of Epidemiology, University of Washington, 1410 NE Campus Parkway, Seattle, WA, 98195, USA.

Background: The prevalence of poor diet quality and type 2 diabetes are exceedingly high in many rural American Indian (AI) communities. Because of limited resources and infrastructure in some communities, implementation of interventions to promote a healthy diet is challenging-which may exacerbate health disparities by region (urban/rural) and ethnicity (AIs/other populations). It is critical to adapt existing evidence-based healthy food budgeting, purchasing, and cooking programs to be relevant to underserved populations with a high burden of diabetes and related complications. The Cooking for Health Study will work in partnership with an AI community in South Dakota to develop a culturally-adapted 12-month distance-learning-based healthy food budgeting, purchasing, and cooking intervention to improve diet among AI adults with type 2 diabetes.

Methods: The study will enroll 165 AIs with physician-diagnosed type 2 diabetes who reside on the reservation. Participants will be randomized to an intervention or control arm. The intervention arm will receive a 12-month distance-learning curriculum adapted from Cooking Matters® that focuses on healthy food budgeting, purchasing, and cooking skills. In-person assessments at baseline, month 6 and month 12 will include completion of the Nutrition Assessment Shared Resources Food Frequency Questionnaire and a survey to assess frequency of healthy and unhealthy food purchases. Primary outcomes of interest are: (1) change in self-reported intake of sugar-sweetened beverages (SSBs); and (2) change in the frequency of healthy and unhealthy food purchases. Secondary outcomes include: (1) change in self-reported food budgeting skills; (2) change in self-reported cooking skills; and (3) a mixed-methods process evaluation to assess intervention reach, fidelity, satisfaction, and dose delivered/received.

Discussion: Targeted and sustainable interventions are needed to promote optimal health in rural AI communities. If effective, this intervention will reduce intake of SSBs and the purchase of unhealthy foods; increase the purchase of healthy foods; and improve healthy food budgeting and cooking skills among AIs with type 2 diabetes - a population at high risk of poor health outcomes. This work will help inform future health promotion efforts in resource-limited settings.

Trial Registration: This study was registered on ClinicalTrials.gov on October 9, 2018 with Identifier NCT03699709 .
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http://dx.doi.org/10.1186/s12889-021-10308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883757PMC
February 2021

Ten-year weight gain is not associated with multiple cardiometabolic measures in Alaska EARTH study participants.

Nutr Metab Cardiovasc Dis 2021 02 24;31(2):403-410. Epub 2020 Sep 24.

Clinical and Research Services, Community Health Services, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.

Background And Aims: Alaska Native (AN) traditional lifestyle may be protective against chronic disease risk. Weight gain in adulthood has been linked to increases in chronic disease risk among other populations; yet, its impact among Alaska Native people has never been evaluated. We aimed to evaluate changes in obesity-related metrics over time, and determine associations of changes with cardiometabolic markers of chronic disease risk among AN people.

Methods And Results: Study participants enrolled in the southcentral Alaska Education and Research Towards Health Study in 2004-2006 were invited to participate in a follow-up study conducted 2015-2017. Of the original 1320 participants, 388 completed follow-up health assessments consisting of multiple health surveys, anthropometric measurements, and cardiometabolic measures including blood sugars, blood lipids, and blood pressure. Differences in measurements between visits were determined and associations of weight change with cardiometabolic measures evaluated. Body mass index increased by 3.7 kg/m among men and 4.8 kg/m among women. Hip circumference (1.1 cm, p < 0.01) and waist circumference (0.7 cm, p < 0.01) increased among women; only waist circumference increased among men (1.6 cm, p < 0.01). Among men, there were no associations of weight change with cardiometabolic measures. Among women, there was an inverse association between weight gain and high-density lipoprotein cholesterol only (0.17 mg/dL (CI: -3.1, -0.03), p = 0.02).

Conclusions: While weight increase over a 10-year period was not associated with substantive changes in cardiometabolic measures among AN men, there was a decrease in high density lipid cholesterol associated with weight gain among AN women.
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http://dx.doi.org/10.1016/j.numecd.2020.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887000PMC
February 2021

Genetics of Smoking Behaviors in American Indians.

Cancer Epidemiol Biomarkers Prev 2020 11 27;29(11):2180-2186. Epub 2020 Aug 27.

Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, Texas.

Background: The smoking behavior of American Indians (AI) differs from that of non-Hispanic whites (NHW). Typically light smokers, cessation interventions in AIs are generally less effective. To develop more effective cessation programs for AIs, clinicians, researchers, and public health workers need a better understanding of the genetic factors involved in their smoking behavior. Our aim was to assess whether SNPs associated with smoking behavior in NHWs are also associated with smoking in AIs.

Methods: We collected questionnaire data on smoking behaviors and analyzed blood and saliva samples from two Tribal populations with dramatically different cultures and smoking prevalence, one in the Northern Plains ( = 323) and the other in the Southwest ( = 176). A total of 384 SNPs were genotyped using an Illumina custom GoldenGate platform. Samples were also assessed for cotinine and 3-hydroxycotinine as markers of nicotine intake and nicotine metabolite ratio.

Results: Among 499 participants, we identified, in the Northern Plains sample only, a variant of the gamma-aminobutyric acid receptor subunit alpha-2 () (rs2119767) on chromosome 4p that was associated with many of the intake biomarkers of smoking we examined, suggesting a role for this gene in modifying smoking behavior in this population. We also identified three SNPs, in the Southwest sample only, as significant correlates of only cigarettes per day: rs4274224, rs4245147 (both dopamine receptor D2 gene), and rs1386493 (tryptophan hydroxylase 2 gene).

Conclusions: The contribution of many genes known to underlie smoking behaviors in NHWs may differ in AIs.

Impact: Once validated, these variants could be useful in developing more effective cessation strategies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0026DOI Listing
November 2020

Increase in diabetes among urban Alaska Native people in the Alaska EARTH follow-up study: A call for prediabetes screening, diagnosis, and referral for intervention.

Diabetes Res Clin Pract 2020 Sep 31;167:108357. Epub 2020 Jul 31.

Medstar Health Research Institute, Hyattsville, MD, United States; Georgetown/Howard Universities, Center for Clinical and Translational Research, Washington, DC, United States.

Aims: This study estimates incidence of diabetes (DM) and pre-DM relative to DM risk factors among relatively healthy Alaska Native and American Indian (henceforth AN) adults living in urban south central Alaska.

Methods: Baseline (2004-2006) and follow-up (2014-2017) surveys, blood samples, and medical chart review data were collected from AN adults living in south central Alaska. We analyzed associations between prevalent risk factors and incident DM and pre-DM using Cox proportional hazards and used multivariable models to identify independent predictors for both DM and pre-DM.

Results: Among 379 participants with follow-up data, overall DM incidence was 16.5/1,000 PY; overall pre-DM incidence was 77.6/1,000 PY, with marked differences between men and women. Prevalent cardiometabolic risk factors also varied with greater amounts of overweight in men and greater amounts of obesity in women. Controlling for age and sex, obesity, abdominal adiposity, pre-DM, and metabolic syndrome independently increased DM risk.

Conclusion: Health care providers of AN populations must seize the opportunity to screen, refer, and treat individuals with pre-DM and other modifiable DM risk factors prior to DM diagnosis if we are to alter the epidemiologic course of disease progression in this urban AN population.
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http://dx.doi.org/10.1016/j.diabres.2020.108357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530054PMC
September 2020

Cardiovascular Health in American Indians and Alaska Natives: A Scientific Statement From the American Heart Association.

Circulation 2020 06 28;141(25):e948-e959. Epub 2020 May 28.

Background: Cardiovascular disease (CVD) is the leading cause of death among American Indians and Alaska Natives. Over the past 50 years, the prevalence of CVD has been rising among American Indians and Alaska Natives. The objective of this statement is to summarize population-level risk factors and management techniques tailored for the American Indian and Alaska Native populations.

Methods: PubMed/MEDLINE, the Centers for Disease Control and Prevention, and the annual Heart Disease and Stroke Statistics report from the American Heart Association were used to identify risk factors and interventions specific to American Indians and Alaska Natives.

Results: Diabetes mellitus is a major contributor to disproportionately higher rates of coronary heart disease among American Indians and Alaska Natives compared with other racial and ethnic groups. Additional risk factors for CVD include low-density lipoprotein cholesterol levels, hypertension, renal disease, age, and sex. Smoking and exposure to toxic metals are risk factors for some subpopulations. A quarter of American Indians live below the federal poverty line, and thus, low socioeconomic status is an important social determinant of cardiovascular health. Community-based interventions have reduced CVD risk in American Indians and Alaska Natives. Underreporting of American Indian and Alaska Native race could underestimate the extent of CVD in this population.

Conclusions: Prevention and treatment of CVD in American Indians and Alaska Natives should focus on control of risk factors and community-based interventions that address social determinants of health, particularly among individuals with diabetes mellitus. Accurate reporting of race/ethnicity is encouraged to address race-specific risk factors.
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http://dx.doi.org/10.1161/CIR.0000000000000773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351358PMC
June 2020

Lifestyle and Psychosocial Patterns and Diabetes Incidence Among Women with and Without Obesity: a Prospective Latent Class Analysis.

Prev Sci 2020 08;21(6):850-860

Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA.

We conducted latent class analyses to identify women with homogeneous combinations of lifestyle and behavioral variables and tested whether latent classes were prospectively associated with diabetes incidence for women with or without baseline obesity. A total of 64,710 postmenopausal women aged 50-79 years without prevalent diabetes at baseline (years 1993-1998) were followed until 2018 with a mean follow-up of 14.6 years (sd = 6.4). Lifestyle variables included smoking, diet quality, physical activity, and sleep quality. Psychosocial variables included social support, depression, and optimism. Multivariable Cox proportional hazards regression models tested associations between latent classes and diabetes incidence controlling for age, race/ethnicity, and education. During follow-up, 8076 (12.4%) women developed diabetes. For women without baseline obesity, five latent classes were identified. Compared with a lower risk referent, diabetes incidence was higher in classes characterized by high probability of multiple lifestyle and psychosocial risks (HR = 1.45; 95% CI 1.28, 1.64), poor diet and exercise (HR = 1.23; 95% CI 1.13, 1.33), and psychosocial risks alone (HR = 1.20; 95% CI 1.12, 1.29). For women with baseline obesity, four latent classes were identified. Compared with a lower risk referent, diabetes incidence was higher for women with obesity in classes characterized by high probability of multiple lifestyle and psychosocial risks (HR = 1.48; 95% CI 1.32, 1.66), poor diet and exercise (HR = 1.32; 95% CI 1.19, 1.47), and intermediate probabilities of multiple risks (HR = 1.17; 95% CI 1.05, 1.30). Diabetes prevention efforts that focus on diet and exercise may benefit from attention to how lifestyle behaviors interact with psychosocial variables to increase diabetes risks, and conversely, how psychological or social resources may be leveraged with lifestyle changes to reduce the risk for women with and without obesity.
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http://dx.doi.org/10.1007/s11121-020-01130-6DOI Listing
August 2020

Eating Pattern Response to a Low-Fat Diet Intervention and Cardiovascular Outcomes in Normotensive Women: The Women's Health Initiative.

Curr Dev Nutr 2020 Mar 12;4(3):nzaa021. Epub 2020 Feb 12.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Women without cardiovascular disease (CVD) or hypertension at baseline assigned to intervention in the Women's Health Initiative Dietary Modification (DM) trial experienced 30% lower risk of coronary heart disease (CHD), whereas results in women with hypertension or prior CVD could have been confounded by postrandomization use of statins.

Objectives: Intervention participants reported various self-selected changes to achieve the 20% total fat goals. Reviewed are intervention compared with comparison group HRs for CHD, stroke, and total CVD in relation to specific dietary changes in normotensive participants.

Methods: Dietary change was assessed by comparing baseline with year 1 FFQ data in women ( = 10,371) without hypertension or CVD at baseline with intake of total fat above the median to minimize biases due to use of the FFQ in trial eligibility screening.

Results: Intervention participants self-reported compensating reduced energy intake from total fat by increasing carbohydrate and protein. Specifically they increased plant protein, with those in the upper quartile (increased total protein by ≥3.3% of energy) having a CHD HR of 0.39 (95% CI: 0.22, 0.71), compared with 0.92 (95% CI: 0.57, 1.48) for those in the lower quartile of change (decreased total protein ≥0.6% of energy), with -trend of 0.04. CHD HR did not vary significantly with change in percentage energy from carbohydrate, and stroke HR did not vary significantly with any macronutrient changes. Scores reflecting adherence to recommended dietary patterns including the Dietary Approaches to Stop Hypertension Trial and the Healthy Eating Index showed favorable changes in the intervention group.

Conclusions: Intervention group total fat reduction replaced with increased carbohydrate and some protein, especially plant-based protein, was related to lower CHD risk in normotensive women without CVD who reported high baseline total fat intake. This trial was registered at clinicaltrials.gov as NCT00000611. Link to the WHI trial protocol: https://www.whi.org/about/SitePages/Dietary%20Trial.aspx.
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http://dx.doi.org/10.1093/cdn/nzaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056819PMC
March 2020

Associations of maternal arsenic exposure with adult fasting glucose and insulin resistance in the Strong Heart Study and Strong Heart Family Study.

Environ Int 2020 04 18;137:105531. Epub 2020 Feb 18.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA. Electronic address:

Experimental and prospective epidemiologic evidence suggest that arsenic exposure has diabetogenic effects. However, little is known about how family exposure to arsenic may affect risk for type 2 diabetes (T2D)-related outcomes in adulthood. We evaluated the association of both maternal and offspring arsenic exposure with fasting glucose and incident T2D in 466 participants of the Strong Heart Family Study. Total arsenic (ΣAs) exposure was calculated as the sum of inorganic arsenic (iAs) and methylated (MMA, DMA) arsenic species in maternal and offspring baseline urine. Median maternal ΣAs at baseline (1989-91) was 7.6 µg/g creatinine, while median offspring ΣAs at baseline (2001-03) was 4.5 µg/g creatinine. Median offspring glucose in 2006-2009 was 94 mg/dL, and 79 participants developed T2D. The fully adjusted mean difference (95% CI) for offspring glucose was 4.40 (-3.46, 12.26) mg/dL per IQR increase in maternal ΣAs vs. 2.72 (-4.91 to 10.34) mg/dL per IQR increase in offspring ΣAs. The fully adjusted odds ratio (95%CI) of incident T2D was 1.35 (1.07, 1.69) for an IQR increase in maternal ΣAs and 1.15 (0.92, 1.43) for offspring ΣAs. The association of maternal ΣAs with T2D outcomes were attenuated with adjustment for offspring adiposity markers. Familial exposure to arsenic, as measured in mothers 15-20 years before offspring follow-up, is associated with increased odds of offspring T2D. More research is needed to confirm findings and better understand the importance of family exposure to arsenic in adult-onset diabetes.
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http://dx.doi.org/10.1016/j.envint.2020.105531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521956PMC
April 2020

Should the Haptoglobin Genotype Be Considered in Setting Glycemic Goals for Diabetes Patients?

J Am Coll Cardiol 2020 02;75(5):522-524

MedStar Health Research Institute and Georgetown/Howard University Center for Clinical and Translational Sciences, Hyattsville, Maryland.

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http://dx.doi.org/10.1016/j.jacc.2019.11.052DOI Listing
February 2020

Associations of diet quality and blood serum lipoprotein levels in a population at high risk for diabetes: the Strong Heart Family Study.

Eur J Clin Nutr 2020 07 5;74(7):1084-1090. Epub 2019 Dec 5.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Background/objectives: Previous studies consistently report that diet quality is inversely associated with risk of cardiovascular disease (CVD) and type 2 diabetes. However, few studies have assessed the association of diet quality with serum lipoproteins, an intermediate marker of cardio-metabolic health, or assessed whether type 2 diabetes modifies these associations. This study assessed associations of diet quality (evaluated using the Alternative Healthy Eating Index (AHEI)), and the interaction of diet quality with diabetes, on total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), apolipoprotein A (apoA1), and apolipoprotein B (apoB) among American Indians (AIs).

Subjects/methods: Participants comprised AIs who participated in the Strong Heart Family Study (SHFS)-a study of CVD and its risk factors in 12 AI communities. Generalized estimated equations (GEEs) were used to examine the following associations: (1) the cross-sectional associations of diet quality (as determined by AHEI) with serum lipoproteins (n = 2200); and (2) the prospective associations of the AHEI measured at baseline with serum lipoproteins (n = 1899).

Results: In cross-sectional analyses, associations of AHEI with TC (p < 0.0001) LDL-C (p = 0.005), and ApoB (p = 0.002) differed according to diabetes status. In prospective analysis, AHEI was associated with more favorable levels of TC (p = 0.029) and LDL-C (p = 0.008) among participants with diabetes independent of other demographic, behavioral, and health factors; associations of diet quality with TC, LDL-C, and ApoB were much weaker among participants without diabetes. There was no association of diet quality with TG, HDL-C, or ApoA.

Conclusions: The associations of diet quality with TC, LDL-C, and ApoB differ according to diabetes status.
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http://dx.doi.org/10.1038/s41430-019-0539-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272258PMC
July 2020

Intentional Weight Loss and Obesity-Related Cancer Risk.

JNCI Cancer Spectr 2019 Dec 9;3(4):pkz054. Epub 2019 Aug 9.

Los Angeles Biomedical Research Institute, Torrance, CA.

Background: Epidemiologic studies regarding weight loss and subsequent cancer risk are sparse. The study aim was to evaluate the association between weight change by intentionality and obesity-related cancer incidence in the Women's Health Initiative Observational Study. Eleven cancers were considered obesity related: breast, ovary, endometrium, colon and rectum, esophagus, kidney, liver, multiple myeloma, pancreas, stomach, and thyroid.

Methods: Postmenopausal women (n = 58 667) aged 50-79 years had body weight and waist circumference (WC) measured at baseline and year 3. Weight or WC change was categorized as stable (change < ±5%), loss (≥5%), and gain (≥5%). Self-report at year 3 characterized weight loss as intentional or unintentional. During the subsequent 12 years (mean) of follow-up, 6033 incident obesity-related cancers were identified. Relationships were evaluated using multivariable Cox proportional hazards regression models.

Results: Compared to women with stable weight, women with intentional weight loss had lower obesity-related cancer risk (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.80 to 0.98). A similar result was observed for intentional WC reduction (HR = 0.88, 95% CI = 0.80 to 0.96). Among all cancers, intentional weight loss was most strongly associated with endometrial cancer (HR = 0.61, 95% CI = 0.42 to 0.88). Intentional WC loss was also associated with lower colorectal cancer risk (HR = 0.79, 95% CI = 0.63 to 0.99). Unintentional weight loss or weight gain was not associated with overall obesity-related cancer risk.

Conclusion: Intentional weight or WC loss in postmenopausal women was associated with lower risk of obesity-related cancer. These findings suggest that postmenopausal women who intentionally lose weight can reduce their obesity-related cancer risk.
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http://dx.doi.org/10.1093/jncics/pkz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795232PMC
December 2019

Alaska Native Traditional Food and Harvesting Activity Patterns over 10 Years of Follow-Up.

Curr Dev Nutr 2019 Nov 9;3(11):nzz114. Epub 2019 Oct 9.

Alaska Native Tribal Health Consortium, Anchorage, AK, USA.

Background: Alaska Native (AN) traditional foods and associated harvesting activities are beneficial to human health.

Objective: This study assessed longitudinal self-reported traditional food use and harvesting activities among Alaska Native and American Indian (AN/AI) participants in the Alaska Education and Research Towards Health (EARTH) study.

Methods: In 2004-2006, southcentral Alaska EARTH study participants ( = 1320) completed diet and activity questionnaires which were repeated in 2015-2017; results were compared between participants who completed both questionnaires ( = 388).

Results: In the follow-up questionnaire, >93% of participants reported eating ≥1 traditional food in the past year. The top 3 traditional foods were fish (75%), moose (42%), and shellfish (41%). Women were more likely than men to consume traditional foods, especially fish, gathered berries, shellfish, and seal oil ( < 0.05). Participants aged ≥60 y in the original cohort were significantly more likely to consume fish and shellfish at follow-up, whereas those aged 40-59 y were the most likely of the 3 age groups to consume seal oil ( < 0.05). Between the original cohort and follow-up, there was a significant decline in the mean number of traditional foods eaten from 6.3 to 5.5, as well as reduced consumption of multiple traditional foods ( < 0.001). Over 59% of participants reported ≥1 traditional harvesting activity in the past year; this proportion did not significantly change between baseline and follow-up. Picking berries/greens (44%), cutting/smoking fish or meat (33%), and fishing (30%) were the most common activities. Participation in traditional harvesting activities was greater among women than men ( < 0.05), but did not differ by age.

Conclusions: Longitudinal follow-up demonstrated that AN/AI people maintained participation in traditional harvesting activities, but the variety of traditional foods declined significantly among both men and women. Promotion of traditional foods and harvesting activities that serve as protective factors against chronic diseases may benefit this population.
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http://dx.doi.org/10.1093/cdn/nzz114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834783PMC
November 2019

Plasma Ceramide Species Are Associated with Diabetes Risk in Participants of the Strong Heart Study.

J Nutr 2020 05;150(5):1214-1222

Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.

Background: Few studies have assessed the associations of ceramides and sphingomyelins (SMs) with diabetes in humans.

Objective: We assessed associations of 15 circulating ceramides and SM species with incident diabetes in 2 studies.

Methods: The analysis included 435 American-Indian participants from the Strong Heart Study (nested case-control design for analyses; mean age: 57 y; 34% male; median time until diabetes 4.3 y for cases) and 1902 participants from the Strong Heart Family Study (prospective design for analyses; mean age: 37 y; 39% male; median 12.5 y of follow-up). Sphingolipid species were measured using stored plasma samples by sequential LC and MS. Using logistic regression and parametric survival models within studies, and an inverse-variance-weighted meta-analysis across studies, we examined associations of 15 ceramides and SM species with incident diabetes.

Results: There were 446 cases of incident diabetes across the studies. Higher circulating concentrations of ceramides containing stearic acid (Cer-18), arachidic acid (Cer-20), and behenic acid (Cer-22) were each associated with a higher risk of diabetes. The RRs for incident diabetes per 1 SD of each log ceramide species (μM) were 1.22 (95% CI: 1.09, 1.37) for Cer-18, 1.18 (95% CI: 1.06, 1.31) for Cer-20, and 1.20 (95% CI: 1.08, 1.32) for Cer-22. Although the magnitude of the risk estimates for the association of ceramides containing lignoceric acid (Cer-24) with diabetes was similar to those for Cer-18, Cer-20, and Cer-22 (RR = 1.13; 95% CI: 1.01, 1.26), the association was not statistically significant after correction for multiple testing (P = 0.007). Ceramides carrying palmitic acid (Cer-16), SMs, glucosyl-ceramides, or a lactosyl-ceramide were not associated with diabetes risk.

Conclusions: Higher concentrations of circulating Cer-18, Cer-20, and Cer-22 were associated with a higher risk of developing diabetes in 2 studies of American-Indian adults. This trial was registered at clinicaltrials.gov as NCT00005134.
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http://dx.doi.org/10.1093/jn/nxz259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198314PMC
May 2020

Trends in Cardiovascular Disease Morbidity and Mortality in American Indians Over 25 Years: The Strong Heart Study.

J Am Heart Assoc 2019 11 25;8(21):e012289. Epub 2019 Oct 25.

MedStar Health Research Institute Georgetown/Howard University Center for Clinical and Translational Sciences Hyattsville MD.

Background American Indians experience high rates of cardiovascular disease. We evaluated whether cardiovascular disease incidence, mortality, and prevalence changed over 25 years among American Indians aged 30 to 85. Methods and Results The SHS (Strong Heart Study) and SHFS (Strong Heart Family Study) are prospective studies of cardiovascular disease in American Indians. Participants enrolled in 1989 to 1990 or 2000 to 2003 with birth years from 1915 to 1984 were followed for cardiovascular disease events through 2013. We used Poisson regression to analyze data for 5627 individuals aged 30 to 85 years during follow-up. Outcomes reflect change in age-specific cardiovascular disease incidence, mortality, and prevalence, stratified by sex. To illustrate generational change, 5-year relative risk compared most recent birth years for ages 45, 55, 65, and 75 to same-aged counterparts born 1 generation (23-25 years) earlier. At all ages, cardiovascular disease incidence was lower for people with more recent birth years. Cardiovascular disease mortality declined consistently among men, while prevalence declined among women. Generational comparisons were similar for women aged 45 to 75 (relative risk, 0.39-0.46), but among men magnitudes strengthened from age 45 to 75 (relative risk, 0.91-0.39). For cardiovascular disease mortality, risk was lower in the most recent versus the earliest birth years for women (relative risk, 0.56-0.83) and men (relative risk, 0.40-0.54), but results for women were inconclusive. Conclusions Cardiovascular disease incidence declined over a generation in an American Indian cohort. Mortality declined more for men, while prevalence declined more for women. These trends might reflect more improvement in case survival among men compared with women.
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http://dx.doi.org/10.1161/JAHA.119.012289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898852PMC
November 2019

Genetic analysis of hsCRP in American Indians: The Strong Heart Family Study.

PLoS One 2019 17;14(10):e0223574. Epub 2019 Oct 17.

Department of Nutrition and Nutrition Research Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Background: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations.

Methods: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses.

Results: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4.

Conclusion: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223574PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797125PMC
March 2020

Associations of parental ages at childbirth with healthy aging among women.

Maturitas 2019 Nov 10;129:6-11. Epub 2019 Aug 10.

Division of Epidemiology, Department of Family Medicine and Public Health, University of California San Diego School of Medicine, 9500 Gilman Drive #0725, La Jolla, CA 92093, USA.

Objective: To examine associations of parental ages at childbirth with healthy survival to age 90 years among older women.

Study Design: This study included a racially and ethnically diverse sub-cohort of 8,983 postmenopausal women from the larger Women's Health Initiative population, recruited during 1993-1998 and followed for up to 25 years through 2018.

Main Outcome Measures: The outcome was categorized as: 1) healthy survival, defined as survival to age 90 without major morbidities (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or mobility disability; 2) usual survival, defined as survival to age 90 without healthy aging (reference category); or 3) death before age 90. Women reported their own and their parents' birth years, and parental ages at childbirth were calculated and categorized as <25, 25-29, 30-34, or ≥35 years.

Results: Women were aged on average 71.3 (standard deviation 2.7; range 65-79) years at baseline. There was no significant association of maternal age at childbirth with healthy survival to age 90 or death before age 90. Women born to fathers aged ≥35 compared with 30-34 years at their births were more likely to achieve healthy than usual survival (OR, 1.15; 95% CI, 1.00-1.32). There was no association of paternal age at childbirth with death before age 90.

Conclusions: Findings suggest that being born to older fathers was associated with healthy survival to age 90 among women who had survived to ages 65-79 years at study baseline. There was no association of maternal age at childbirth with healthy survival to age 90 among these older women.
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http://dx.doi.org/10.1016/j.maturitas.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761991PMC
November 2019

Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial.

Ann Intern Med 2019 09 10;171(6):406-414. Epub 2019 Sep 10.

Fred Hutchinson Cancer Research Center, Seattle, Washington (A.K.A., G.L.A., R.L.P.).

Background: Whether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown.

Objective: To examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups.

Design: Subgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611).

Setting: 40 U.S. clinical centers.

Participants: 9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status.

Intervention: Conjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years.

Measurements: Incidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a "global index" (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up.

Results: The effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age.

Limitations: The timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing.

Conclusion: The effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term.

Primary Funding Source: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.
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http://dx.doi.org/10.7326/M19-0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120507PMC
September 2019

Plasma Phospholipid Fatty Acids and Coronary Heart Disease Risk: A Matched Case-Control Study within the Women's Health Initiative Observational Study.

Nutrients 2019 Jul 21;11(7). Epub 2019 Jul 21.

Department of Epidemiology, School of Public Health, Brown University, Providence, RI 02912, USA.

Background And Aims: The association of fatty acids with coronary heart disease (CHD) has been examined, mainly through dietary measurements, and has generated inconsistent results due to measurement error. Large observational studies and randomized controlled trials have shown that plasma phospholipid fatty acids (PL-FA), especially those less likely to be endogenously synthesized, are good biomarkers of dietary fatty acids. Thus, PL-FA profiles may better predict CHD risk with less measurement error.

Methods: We performed a matched case-control study of 2428 postmenopausal women nested in the Women's Health Initiative Observational Study. Plasma PL-FA were measured using gas chromatography and expressed as molar percentage (moL %). Multivariable conditional logistic regression was used to calculate odds ratios (95% CIs) for CHD associated with 1 moL % change in PL-FA.

Results: Higher plasma PL long-chain saturated fatty acids (SFA) were associated with increased CHD risk, while higher n-3 polyunsaturated fatty acids (PUFA) were associated with decreased risk. No significant associations were observed for very-long-chain SFA, monounsaturated fatty acids (MUFA), PUFA n-6 or fatty acids (TFA). Substituting 1 moL % PUFA n-6 or TFA with an equivalent proportion of PUFA n-3 were associated with lower CHD risk.

Conclusions: Higher plasma PL long-chain SFA and lower PUFA n-3 were associated with increased CHD risk. A change in diet by limiting foods that are associated with plasma PL long-chain SFA and TFA while enhancing foods high in PUFA n-3 may be beneficial in CHD among postmenopausal women.
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http://dx.doi.org/10.3390/nu11071672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682955PMC
July 2019
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