Publications by authors named "Lisa W Martin"

101 Publications

Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

HGG Adv 2021 Jan 31;2(1). Epub 2020 Oct 31.

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
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http://dx.doi.org/10.1016/j.xhgg.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562625PMC
January 2021

Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.

Circ Genom Precis Med 2021 08 16;14(4):e003288. Epub 2021 Jul 16.

Department of Clinical Epidemiology (R.L.G., D.O.M.-K., F.R.R., R.dM.), Leiden University Medical Center, the Netherlands.

Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.

Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.

Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

Conclusions: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.
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http://dx.doi.org/10.1161/CIRCGEN.120.003288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373451PMC
August 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517040PMC
April 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Diet quality indices and risk of metabolic syndrome among postmenopausal women of Mexican ethnic descent in the Women's Health Initiative Observational Study.

Nutr Healthy Aging 2020 Nov 3;5(4):261-272. Epub 2020 Nov 3.

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

Background: The prevalence of metabolic syndrome is higher among minority populations, including individuals of Mexican ethnic descent. Whether alignment to healthy dietary patterns is associated with lower risk of metabolic syndrome in this population is largely unknown.

Objective: To prospectively evaluate the associations between diet quality scores and risk of metabolic syndrome and its components among postmenopausal women of Mexican ethnic descent.

Methods: A total of 334 women of Mexican ethnic descent who participated in the Women's Health Initiative (WHI) observational study without metabolic syndrome or diabetes at baseline (1993-1998) were included. Baseline diets were scored with the Alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), the Healthy Eating Index (HEI-2010), the Mediterranean Diet Score (MDS), and the traditional Mexican Diet (MexD) score. Multivariable linear and logistic regression models were used to test the associations between baseline diet quality and risk of metabolic syndrome and its individual components at follow-up (2012-2013).

Results: Approximately 16% of women met the criteria for metabolic syndrome at follow-up. None of the diet quality indices were associated with risk of metabolic syndrome. However, higher vs lower DASH scores were associated with lower waist circumference (85.2 vs 88.0 cm) and glucose concentrations (90.0 vs 95.1 mg/dL), and higher HDL cholesterol (62.6 vs 59.0 mg/dL), while higher vs lower HEI-2010 scores were associated with lower waist circumference (83.9 vs 88.1 cm), triglycerides (103 vs 117 mg/dL) and glucose concentrations (89.5 vs 94.4 mg/dL), and higher HDL cholesterol levels (63.9 vs 58.5 mg/dL).

Conclusions: Diet quality was not associated with risk of metabolic syndrome in this population. However, the results suggest that alignment to DASH and HEI-2010 recommendations may be beneficial for reducing some individual components of metabolic syndrome among postmenopausal women of Mexican descent.
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http://dx.doi.org/10.3233/NHA-190076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745721PMC
November 2020

When the At-Risk Do Not Develop Heart Failure: Understanding Positive Deviance Among Postmenopausal African American and Hispanic Women.

J Card Fail 2021 Feb 22;27(2):217-223. Epub 2020 Nov 22.

Division of General Medicine and Clinical Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: African American and Hispanic postmenopausal women have the highest risk for heart failure compared with other races, but heart failure prevalence is lower than expected in some national cohorts. It is unknown whether psychosocial factors are associated with lower risk of incident heart failure hospitalization among high-risk postmenopausal minority women.

Methods And Results: Using the Women's Health Initiative Study, African American and US Hispanic women were classified as high-risk for incident heart failure hospitalization with 1 or more traditional heart failure risk factors and the highest tertile heart failure genetic risk scores. Positive psychosocial factors (optimism, social support, religion) and negative psychosocial factors (living alone, social strain, depressive symptoms) were measured using validated survey instruments at baseline. Adjusted subdistribution hazard ratios of developing heart failure hospitalization were determined with death as a competing risk. Positive deviance indicated not developing incident heart failure hospitalization with 1 or more risk factors and the highest tertile for genetic risk. Among 7986 African American women (mean follow-up of 16 years), 27.0% demonstrated positive deviance. Among high-risk African American women, optimism was associated with modestly reduced risk of heart failure hospitalization (subdistribution hazard ratio 0.94, 95% confidence interval 0.91-0.99), and social strain was associated with modestly increased risk of heart failure hospitalization (subdistribution hazard ratio 1.07, 95% confidence interval 1.02-1.12) in the initial models; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses. Among 3341 Hispanic women, 25.1% demonstrated positive deviance. Among high-risk Hispanic women, living alone was associated with increased risk of heart failure hospitalization (subdistribution hazard ratio 1.97, 95% confidence interval 1.06-3.63) in unadjusted analyses; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses.

Conclusions: Among postmenopausal African American and Hispanic women, a significant proportion remained free from heart failure hospitalization despite having the highest genetic risk profile and 1 or more traditional risk factors. No observed psychosocial factors were associated with incident heart failure hospitalization in high-risk African Americans and Hispanics. Additional investigation is needed to understand protective factors among high-risk African American and Hispanic women.
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http://dx.doi.org/10.1016/j.cardfail.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880886PMC
February 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Walking Volume and Speed Are Inversely Associated With Incidence of Treated Hypertension in Postmenopausal Women.

Hypertension 2020 11 28;76(5):1435-1443. Epub 2020 Sep 28.

From the Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo-SUNY, NY (C.R.M., J.W.-W., K.M.H., M.J.L.).

Few studies have evaluated hypertension incidence in relation to walking, which is a common physical activity among adults. We examined the association between walking and hypertension incidence in 83 435 postmenopausal women who at baseline were aged 50 to 79 years, without known hypertension, heart failure, coronary heart disease, or stroke, and reported the ability to walk at least one block without assistance. Walking volume (metabolic equivalent hours per week) and speed (miles per hour) were assessed by questionnaire. Incident physician-diagnosed hypertension treated with medication was ascertained through annual questionnaires. During a mean 11-year follow-up, 38 230 hypertension cases were identified. After adjustment for covariates including nonwalking activities, a significant inverse association with hypertension was observed across categories of baseline walking volume (0 [referent], >0-3.5, 3.6-7.5, and >7.5 metabolic equivalent hours per week), hazard ratio: 1.00 (referent), 0.98, 0.95, 0.89; trend <0.001. Faster walking speeds (<2, 2-3, 3-4, and >4 miles per hour) also were associated with lower hypertension risk, hazard ratio: 1.00 (referent), 1.07, 0.95, 0.86, 0.79; trend <0.001. Further adjustment for walking duration (h/wk) had little impact on the association for walking speed (hazard ratio: 1.00 [referent], 1.08, 0.96, 0.86, 0.77; trend <0.001). Significant inverse associations for walking volume and speed persisted after additional control for baseline blood pressure. Results for time-varying walking were comparable to those for baseline exposures. This study showed that walking at guideline-recommended volumes (>7.5 metabolic equivalent hours per week) and at faster speeds (≥2 miles per hour) is associated with lower hypertension risk in postmenopausal women. Walking should be encouraged as part of hypertension prevention in older adults.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544673PMC
November 2020

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Nat Genet 2020 09 24;52(9):969-983. Epub 2020 Aug 24.

Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1038/s41588-020-0676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483769PMC
September 2020

Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.

Circ Genom Precis Med 2020 08 8;13(4):e002772. Epub 2020 Jun 8.

Department of Epidemiology, School of Public Health (L.F.B., J.A.S., W.Z., S.L.R.K.), University of Michigan, Ann Arbor, MI.

Background: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

Methods: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

Results: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

Conclusions: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
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http://dx.doi.org/10.1161/CIRCGEN.119.002772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442680PMC
August 2020

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

PLoS Genet 2020 03 30;16(3):e1008684. Epub 2020 Mar 30.

Department of Medicine, University of Washington Medical Center, Seattle, Washington, United States of America.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.
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http://dx.doi.org/10.1371/journal.pgen.1008684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145272PMC
March 2020

Relationship Between Dietary Magnesium Intake and Incident Heart Failure Among Older Women: The WHI.

J Am Heart Assoc 2020 04 20;9(7):e013570. Epub 2020 Mar 20.

Center for Primary Care and Prevention and the Department of Family Medicine Memorial Hospital of Rhode Island Pawtucket RI.

Background Women represent a large proportion of the growing heart failure (HF) epidemic, yet data are lacking regarding optimal dietary and lifestyle prevention strategies for them. Specifically, the association between magnesium intake and HF in a multiracial cohort of women is uncertain. Methods and Results We included 97 725 postmenopausal women from the WHI (Women's Health Initiative) observational studies and placebo arms of the hormone trial. Magnesium intake was measured at baseline by a 122-item validated food-frequency questionnaire and stratified into quartiles based on diet only, total intake (diet with supplements), and residual intake (calibration by total energy). Incident hospitalized HF (2153 events, median follow-up 8.1 years) was adjudicated by medical record abstraction. In Cox proportional hazards models, we evaluated the association between magnesium intake and HF adjusting for potential confounders. Analyses were repeated on a subcohort (n=18 745; median-follow-up, 13.2 years) for whom HF cases were subclassified into preserved ejection fraction (526 events), reduced ejection fraction (291 events) or unknown (168 events). Most women were white (85%) with a mean age of 63. Compared with the highest quartile of magnesium intake, women in the lowest quartile had an increased risk of incident HF, with adjusted hazard ratios of 1.32 (95% CI, 1.02-1.71) for diet only ( trend=0.03), 1.26 (95% CI, 1.03-1.56) for total intake, and 1.31 (95% CI, 1.02-1.67) for residual intake. Results did not significantly vary by race. Subcohort analyses showed low residual magnesium intake was associated with HF with reduced ejection fraction (hazard ratio, 1.81, lowest versus highest quartile; 95% CI, 1.08-3.05) but not HF with preserved ejection fraction. Conclusions Low magnesium intake in a multiracial cohort of postmenopausal women was associated with a higher risk of incident HF, especially HF with reduced ejection fraction.
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http://dx.doi.org/10.1161/JAHA.119.013570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428611PMC
April 2020

Association of Dietary Magnesium Intake with Fatal Coronary Heart Disease and Sudden Cardiac Death.

J Womens Health (Larchmt) 2020 01 12;29(1):7-12. Epub 2019 Dec 12.

Department of Family Medicine, Alpert Medical School of Brown University, Pawtucket, Rhode Island.

Postmenopausal women represent the highest population-based burden of cardiovascular disease, including sudden cardiac death (SCD). Our understanding of the etiology and risk factors contributing to fatal coronary heart disease (CHD) and SCD, particularly among women, is limited. This study examines the association between dietary magnesium intake and fatal CHD and SCD. We examined 153,569 postmenopausal women who participated in the Women's Health Initiative recruited between 1993 and 1998. Magnesium intake at baseline was assessed using a validated food frequency questionnaire, adjusting for energy via the residual method. Fatal CHD and SCD were identified over an average follow-up of 10.5 years. For every standard deviation increase in magnesium intake, there was statistically significant risk reduction, after adjustment for confounders, of 7% for fatal CHD (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.89-0.97), and 18% risk reduction for SCD (HR 0.82, 95% CI 0.58-1.15) the latter of which did not reach statistical significance. In age-adjusted quartile analysis, women with the lowest magnesium intake (189 mg/day) had the greatest risk for fatal CHD (HR 1.54, 95% CI 1.40-1.69) and SCD (HR 1.70, 95% CI 0.94-3.07). This association was attenuated in the fully adjusted model, with HRs of 1.19 (95% CI 1.06-1.34) for CHD and 1.24 (95% CI 0.58-2.65) for SCD for the lowest quartile of magnesium intake. This study provides evidence of a potential inverse association between dietary magnesium and fatal CHD and a trend of magnesium with SCD in postmenopausal women. Future studies should confirm this association and consider clinical trials to test whether magnesium supplementation could reduce fatal CHD in high-risk individuals.
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http://dx.doi.org/10.1089/jwh.2019.7775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983733PMC
January 2020

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 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

Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease.

Menopause 2019 08;26(8):841-849

Department of ObGyn, Reading Hospital, Reading, PA.

Objective: Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation.

Methods: A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model.

Results: In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation.

Conclusions: CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.
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http://dx.doi.org/10.1097/GME.0000000000001360DOI Listing
August 2019

Racial/Ethnic Differences in 25-Hydroxy Vitamin D and Parathyroid Hormone Levels and Cardiovascular Disease Risk Among Postmenopausal Women.

J Am Heart Assoc 2019 02;8(4):e011021

1 Department of Epidemiology Indiana University Richard M. Fairbanks School of Public Health Indianapolis IN.

Background Recent evidence suggests that racial/ethnic differences in circulating levels of free or bioavailable 25-hydroxy vitamin D (25[ OH ]D) rather than total 25( OH )D may explain apparent racial disparities in cardiovascular disease ( CVD ). We prospectively examined black-white differences in the associations of total, free, and bioavailable 25( OH )D, vitamin D-binding protein, and parathyroid hormone levels at baseline with incident CVD (including nonfatal myocardial infarction, nonfatal stroke, and CVD death) in postmenopausal women. Methods and Results We conducted a case-cohort study among 79 705 postmenopausal women, aged 50 to 79 years, who were free of CVD at baseline in the WHI-OS (Women's Health Initiative Observational Study). A subcohort of 1300 black and 1500 white participants were randomly chosen as controls; a total of 550 black and 1500 white women who developed incident CVD during a mean follow-up of 11 years were chosen as cases. We directly measured total 25( OH )D, vitamin D-binding protein, albumin, parathyroid hormone, and calculated free and bioavailable 25( OH )D. Weighted Cox proportional hazards models were used to examine their associations with CVD risk. Although vitamin D-binding protein and total, free, and bioavailable 25( OH )D were not significantly associated with CVD risk in black or white women, a significant positive association between parathyroid hormone and CVD risk persisted in white women (hazard ratio comparing the highest quartile with the lowest, 1.37; 95% CI , 1.06-1.77) but not in black women (hazard ratio comparing the highest quartile with the lowest, 1.12; 95% CI, 0.79-1.58), independent of total, free, and bioavailable 25( OH )D or vitamin D-binding protein. Conclusions Circulating levels of vitamin D biomarkers are not related to CVD risk in either white or black women. Higher parathyroid hormone levels may be an independent risk factor for CVD in white women.
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http://dx.doi.org/10.1161/JAHA.118.011021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405652PMC
February 2019

Changes in physical and mental health are associated with cardiovascular disease incidence in postmenopausal women.

Age Ageing 2019 05;48(3):448-453

Department of Medicine, School of Medicine, Stanford University, Stanford, USA.

Background: physical and mental health are important risk factors for cardiovascular disease (CVD) incidence and death among postmenopausal women. The objective of this study was to assess whether changes in physical and mental health were associated with CVD incidence and death.

Methods: in the Women's Health Initiative Observational Study, 48,906 women (50-79 years) had complete data at baseline on physical and mental health (assessed with Short Form-36) and key covariates. Changes in self-reported physical and mental health were calculated between baseline and year 3. Incident CVD and death between year 3 and end of the study were verified with medical records.

Results: over a median 8.2-year follow-up, 2,319 women developed CVD, and 1,571 women died, including 361 CVD deaths. Women with continued poor health and those with worsened health had significantly increased risk of CVD incidence, CVD-specific death and all-cause death relative to women with continued good health. Both major and minor declines in physical health were associated with an increased risk of these outcomes relative to women with no change in physical health. Only major declines in mental health were associated with poor prognosis.

Conclusions: changes in physical and mental health over 3 years were independently associated with subsequent CVD events.
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http://dx.doi.org/10.1093/ageing/afy213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453231PMC
May 2019

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

JAMA Intern Med 2018 09;178(9):1231-1240

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1001/jamainternmed.2018.2875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142964PMC
September 2018

Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women.

JAMA Cardiol 2018 08;3(8):712-720

Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, National Cancer Institute Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland.

Importance: APOL1 genotypes are associated with kidney diseases in African American individuals and may influence cardiovascular disease and mortality risk, but findings have been inconsistent.

Objective: To discern whether high-risk APOL1 genotypes are associated with cardiovascular disease and stroke in postmenopausal African American women, who are at high risk for these outcomes.

Design, Setting, And Participants: The Women's Health Initiative is a prospective cohort that enrolled 161 838 postmenopausal women into clinical trials and an observational study between 1993 and 1998. This study includes 11 137 African American women participants who had a clinical event from enrollment to June 2014. Data analyses were completed from January 2017 to August 2017.

Exposures: The variants of APOL1 were genotyped or imputed from whole-exome sequencing.

Main Outcomes And Measures: Incident coronary heart disease, stroke and heart failure subtypes, and overall and cause-specific mortality were adjudicated from hospital records and death certificates. Estimated incidence rates were determined for each outcome and hazard ratios (HR) and 95% CIs for the associations of APOL1 groups with outcomes.

Results: The mean (SD) age of participants was 61.7 (7.1) years. Carriers of high-risk APOL1 variants (n = 1370; 12.3%) had higher prevalence of hypertension, use of cholesterol-lowering medications, and reduced estimated glomerular filtration rate (eGFR). After a mean (SD) of 11.0 (3.6) years, carriers of high-risk APOL1 variants had a higher incidence rate of hospitalized heart failure with preserved ejection fraction (HFpEF) than low-risk carriers did but showed no differences for other outcomes. In adjusted models, there was a significant 58% increased hazard of hospitalized HFpEF (HR, 1.58 [95% CI, 1.03-2.41]) among carriers of high-risk APOL1 variants compared with carriers of low-risk APOL1 variants. The association with HFpEF was attenuated (HR = 1.50 [95% CI, 0.98-2.30]) and no longer significant when adjusting for baseline eGFR.

Conclusions And Relevance: Status as a carrier of a high-risk APOL1 genotype was associated with HFpEF hospitalization among postmenopausal women, which is partly accounted for by baseline kidney function. These findings do not support an association of high-risk APOL1 genotypes with coronary heart disease, stroke, or mortality in postmenopausal African American women.
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http://dx.doi.org/10.1001/jamacardio.2018.1827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143074PMC
August 2018

A Case-control Study to Evaluate the Prevalence of Nonalcoholic Fatty Liver Disease Among Patients with Moderate-to-severe Psoriasis.

J Clin Aesthet Dermatol 2018 Jun 1;11(6):33-37. Epub 2018 Jun 1.

Drs. Awosika, Rengifo-Pardo, and Ehrlich are with the Department of Dermatology, The George Washington Medical Faculty Associates in Washington, DC.

International case-control studies have demonstrated that psoriasis is associated with an increased prevalence of nonalcoholic fatty liver disease (NAFLD). The purpose of the present study was to establish an association of psoriasis and NAFLD in patients attending a dermatology clinic center in the United States. This was an observational, case-control study. The study setting was an outpatient dermatology clinic of the George Washington Medical Faculty Associates in Washington DC. One hundred fifty-one adult patients with psoriasis and 51 control subjects were recruited. NAFLD was diagnosed by ultrasonography after excluding secondary causes of liver disease. Regression analysis was used to assess the associations between: 1) NAFLD and psoriasis and 2) metabolic syndrome components and NAFLD among psoriasis patients. NAFLD was more prevalent in patients with psoriasis (21.2% vs. 7.8%, <0.04). However, psoriasis was not associated with NAFLD when matching for age, sex, and body mass index (BMI) (odds ratio: 2.63, 95% confidence interval [CI]: 0.51-13.6; =0.25). As compared to patients with psoriasis but without NAFLD, those with NAFLD were more likely to have obesity (BMI: 34.9 vs. 27.2, 95% CI: 32.4-37.5 vs. 25.9-28.5; <0.01). NAFLD in patients with psoriasis was also associated with select components of metabolic syndrome, including hyperglycemia and hyperlipidemia. Our findings show there is an association of psoriasis with NAFLD. Our findings also suggest an increased presence of metabolic syndrome components in patients with psoriasis and NAFLD. NCT00930384.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011871PMC
June 2018

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

Circ Heart Fail 2018 05;11(5):e004642

Division of Cardiology, University of California San Francisco (L.K.).

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 (<0.0001, interaction of race/ethnicity and RF number =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 (<0.0001) but differed by racial/ethnic group (interaction =0.001). The number of RFs was not associated with the risk of death after developing HF in any group (=0.25; interaction =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.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935135PMC
May 2018

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

Cancer Med 2018 05 2;7(5):2121-2130. Epub 2018 Apr 2.

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

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.
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http://dx.doi.org/10.1002/cam4.1368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943473PMC
May 2018

An analysis of the association between statin use and risk of endometrial and ovarian cancers in the Women's Health Initiative.

Gynecol Oncol 2018 03 13;148(3):540-546. Epub 2018 Feb 13.

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.

Background: Statins have anti proliferative activity in vitro against endometrial and ovarian cancer and can affect levels of reproductive hormones. We analyzed data from the Women's Health Initiative (WHI) to assess whether statins are associated with risk of endometrial and ovarian cancer.

Methods: The WHI study included 161,808 postmenopausal women in which incident cases of endometrial (n = 1377) and ovarian cancer (n = 763) were identified over an average of 10.8 (SD + 3.3) years. Information on statin use and risk factors was collected at baseline and follow-up. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of statin use and risk of endometrial and ovarian cancer. All statistical tests were two-sided.

Results: Statins were used at baseline by 7.5% women and by up to 25% at year nine. The multivariable adjusted HR for risk of endometrial cancer for baseline statin use was 0.74, 95% C.I. 0.59-0.94 and for ovarian cancer was 1.15, 95% C.I. 0.89-1.50. In time-dependent models, statins were not associated with endometrial cancer (HR 0.91, 95% C.I. 0.76-1.08) however there was an increased risk of ovarian cancer (HR 1.30, 95% CI 1.04-1.62), largely attributed to the effect of the hydrophilic statin, pravastatin (1.89, 95% CI 1.24-2.88).

Conclusions: There was a reduction in risk of endometrial cancer among statin users at baseline but not in time-dependent models. Pravastatin use was associated with an increased risk of ovarian cancer. Analyses of larger numbers of cases are needed to evaluate these findings.
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http://dx.doi.org/10.1016/j.ygyno.2018.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896309PMC
March 2018

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

JAMA 2017 09;318(10):927-938

Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York.

Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.

Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials.

Design, Setting, And Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.

Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).

Main Outcomes And Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.

Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.

Conclusions And Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.

Trial Registration: clinicaltrials.gov Identifier: NCT00000611.
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http://dx.doi.org/10.1001/jama.2017.11217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728370PMC
September 2017

Higher Lipophilic Index Indicates Higher Risk of Coronary Heart Disease in Postmenopausal Women.

Lipids 2017 08 8;52(8):687-702. Epub 2017 Jul 8.

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

Fatty acids (FAs) are essential components of cell membranes and play an integral role in membrane fluidity. The lipophilic index [LI, defined as the sum of the products between FA levels and melting points (°C), divided by the total amount of FA: [Formula: see text]] is thought to reflect membrane and lipoprotein fluidity and may be associated with the risk of coronary heart disease (CHD). Therefore, we examined the associations of dietary and plasma phospholipid (PL) LI with CHD risk among postmenopausal women. We determined dietary LI for the cohort with completed baseline food frequency questionnaires and free of prevalent cardiovascular diseases in the Women's Health Initiative (WHI) observational study (N = 85,563). We additionally determined plasma PL LI in a matched case-control study (N = 2428) nested within the WHI observational cohort study. Cox proportional hazard regression and multivariable conditional logistic regression were used to calculate HRs/ORs for CHD risk between quartiles of LI after adjusting for potential sources of confounding and selection bias. Higher dietary LI in the cohort study and plasma PL LI in the case-control study were significantly associated with increased risk of CHD: HR = 1.18 (95% CI 1.07-1.31, P for trend <0.01) and OR = 1.76 (95% CI 1.33-2.33, P for trend <0.01) comparing extreme quartiles and adjusting for potential confounders. These associations still persisted after adjusting for the polyunsaturated to saturated fat ratio. Our study indicated that higher LI based on either dietary or plasma measurements, representing higher FA lipophilicity, was associated with elevated risk of CHD among postmenopausal women.
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http://dx.doi.org/10.1007/s11745-017-4276-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903800PMC
August 2017

Associations of Biomarker-Calibrated Sodium and Potassium Intakes With Cardiovascular Disease Risk Among Postmenopausal Women.

Am J Epidemiol 2017 Nov;186(9):1035-1043

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.
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http://dx.doi.org/10.1093/aje/kwx238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860327PMC
November 2017

Change in Physical Activity and Sitting Time After Myocardial Infarction and Mortality Among Postmenopausal Women in the Women's Health Initiative-Observational Study.

J Am Heart Assoc 2017 May 15;6(5). Epub 2017 May 15.

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

Background: How physical activity (PA) and sitting time may change after first myocardial infarction (MI) and the association with mortality in postmenopausal women is unknown.

Methods And Results: Participants included postmenopausal women in the Women's Health Initiative-Observational Study, aged 50 to 79 years who experienced a clinical MI during the study. This analysis included 856 women who had adequate data on PA exposure and 533 women for sitting time exposures. Sitting time was self-reported at baseline, year 3, and year 6. Self-reported PA was reported at baseline through year 8. Change in PA and sitting time were calculated as the difference between the cumulative average immediately following MI and the cumulative average immediately preceding MI. The 4 categories of change were: maintained low, decreased, increased, and maintained high. The cut points were ≥7.5 metabolic equivalent of task hours/week versus <7.5 metabolic equivalent of task hours/week for PA and ≥8 h/day versus <8 h/day for sitting time. Cox proportional hazard models estimated hazard ratios and 95% CIs for all-cause, coronary heart disease, and cardiovascular disease mortality. Compared with women who maintained low PA (referent), the risk of all-cause mortality was: 0.54 (0.34-0.86) for increased PA and 0.52 (0.36-0.73) for maintained high PA. Women who had pre-MI levels of sitting time <8 h/day, every 1 h/day increase in sitting time was associated with a 9% increased risk (hazard ratio=1.09, 95% CI: 1.01, 1.19) of all-cause mortality.

Conclusions: Meeting the recommended PA guidelines pre- and post-MI may have a protective role against mortality in postmenopausal women.
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http://dx.doi.org/10.1161/JAHA.116.005354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524089PMC
May 2017
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