Risk of Adverse Cardiovascular Outcomes in Postmenopausal Women with Inflammatory Bowel Disease.

BACKGROUND: Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear. METHODS: We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.). RESULTS: Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76). CONCLUSIONS: Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women.

Infertility and risk of postmenopausal breast cancer in the women's health initiative.

PURPOSE: Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25 years of follow-up). METHODS: At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy. RESULTS: We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%). CONCLUSION: These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

Adverse pregnancy outcomes and risk of type 2 diabetes in postmenopausal women.

BACKGROUND: Although gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established. OBJECTIVE: This study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women. STUDY DESIGN: The Women's Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with medication from baseline (1993-1998) to March 2021. This study used logistic regression to examine the associations of any and individual adverse pregnancy outcomes with diabetes mellitus. Stratified analyses were performed to assess effect modification by body mass index, race and ethnicity, education, parity, breastfeeding, and age at first birth. RESULTS: This analysis included 49,717 women without a history of diabetes mellitus at enrollment who had a least 1 pregnancy and responded to the questionnaire about adverse pregnancy outcomes. After adjusting for body mass index, demographic, lifestyle, and reproductive factors, gestational diabetes mellitus (odds ratio, 2.26; 95% confidence interval, 1.94-2.63), high birthweight (odds ratio, 1.30; 95% confidence interval, 1.18-1.44), and hypertensive disorders of pregnancy (odds ratio, 1.18; 95% confidence interval, 1.08-1.30) were independently associated with higher odds of type 2 diabetes mellitus, whereas preterm birth and low birthweight were not associated with diabetes mellitus risk. A history of ≥2 adverse pregnancy outcomes was associated with higher odds of type 2 diabetes mellitus (odds ratio, 1.55; 95% confidence interval, 1.28-1.88). This study further observed higher odds of type 2 diabetes mellitus (odds ratio, 3.69; 95% confidence interval, 2.38-5.70) among women with a history of both gestational diabetes mellitus and hypertensive disorders of pregnancy than those without any adverse pregnancy outcomes. CONCLUSION: Postmenopausal women with a history of gestational diabetes mellitus, those delivering high-birthweight infants, or those with hypertensive disorders of pregnancy are at risk of future type 2 diabetes mellitus. In addition, women with ≥2 conditions had an augmented risk and might be prioritized for screening and prevention efforts for type 2 diabetes mellitus.

Hysterectomy, oophorectomy and risk of non-Hodgkin's lymphoma.

Hysterectomy is associated with an increased risk for adverse health outcomes. However, its connection to the risk of non-Hodgkin's lymphoma (NHL) remains unclear. The aims of our study were to investigate the associations between hysterectomy, oophorectomy and risk of NHL and its major subtypes (eg, diffuse large B-cell lymphoma [DLBCL]), and whether these associations were modified by exogenous hormone use. Postmenopausal women (n = 141,621) aged 50-79 years at enrollment (1993-1998) from the Women's Health Initiative were followed for an average of 17.2 years. Hysterectomy and oophorectomy were self-reported at baseline. Incident NHL cases were confirmed by central review of medical records and pathology reports. During the follow-up period, a total of 1719 women were diagnosed with NHL. Hysterectomy, regardless of oophorectomy status, was associated with an increased risk of NHL (hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.05-1.44). Oophorectomy was not independently associated with NHL risk after adjusting for hysterectomy. When stratified by hormone use, the association between hysterectomy and NHL risk was confined to women who had never used hormone therapy (HR = 1.35, 95% CI: 1.06-1.71), especially for DLBCL subtype (P for interaction = .01), and to those who had undergone hysterectomy before the age of 55. Our large prospective study showed that hysterectomy was a risk factor of NHL. Findings varied by hormone use. Future studies incorporating detailed information on the types and indications of hysterectomy may deepen our understanding of the mechanisms underlying DLBCL development and its potential interactions with hormone use.

Preterm birth, birthweight, and subsequent risk for depression.

An individual's birthweight, a marker of in utero exposures, was recently associated with certain psychiatric conditions. However, studies investigating the relationship between an individual's preterm birth status and/or birthweight and risk for depression during adulthood are sparse; we used data from the Women's Health Initiative (WHI) to investigate these potential associations. At study entry, 86,925 postmenopausal women reported their birthweight by category (<6 lbs., 6-7 lbs. 15 oz., 8-9 lbs. 15 oz., or ≥10 lbs.) and their preterm birth status (full-term or ≥4 weeks premature). Women also completed the Burnham screen for depression and were asked to self-report if: (a) they had ever been diagnosed with depression, or (b) if they were taking antidepressant medications. Linear and logistic regression models were used to estimate unadjusted and adjusted effect estimates. Compared to those born weighing between 6 and 7 lbs. 15 oz., individuals born weighing <6 lbs. (ßadj = 0.007, P < 0.0001) and ≥10 lbs. (ßadj = 0.006, P = 0.02) had significantly higher Burnam scores. Individuals born weighing <6 lbs. were also more likely to have depression (adjOR 1.21, 95% CI 1.11-1.31). Individuals born preterm were also more likely to have depression (adjOR 1.18, 95% CI 1.02-1.35); while attenuated, this association remained in analyses limited to only those reportedly born weighing <6 lbs. Our research supports the role of early life exposures on health risks across the life course. Individuals born at low or high birthweights and those born preterm may benefit from early evaluation and long-term follow-up for the prevention and treatment of mental health outcomes.

Needs assessment of menopause education in United States obstetrics and gynecology residency training programs.

OBJECTIVE: This study aimed to assess the variance in menopause education, educational resources, and the needs of obstetrics and gynecology (ObGyn) residency programs by conducting a national survey of program directors (PDs). METHODS: In 2022, an institutional review board-approved Web-based Qualtrics survey was designed and distributed electronically to 145 US ObGyn residency PDs. The survey consists of 15 questions. The main outcomes are reported using descriptive statistics. RESULTS: The survey was completed by 99 of 145 PDs (68.3%). Almost all participants (92.9%) strongly agreed that residents nationwide should have access to a standardized menopause curriculum that could be utilized in their programs. Only 31.3% reported having a menopause curriculum in their residency program. Of the programs with a menopause curriculum, 96.8% reported using lectures, 77.4% reported assigned readings, and 74.2% had either dedicated menopause clinics or other clinics with a high volume of menopausal patients. Of all programs surveyed, only 29.3% reported that trainees had dedicated time assigned to a menopause clinic. A total of 83 of 99 PDs agreed or strongly agreed that their programs needed more menopause educational resources, and most (89.7%) stated they were likely or very likely to use self-paced menopause modules that include performance feedback if available. CONCLUSIONS: Data from the needs assessment questionnaire revealed that menopause education and resources vary across residency programs, with the majority lacking a dedicated menopause curriculum. Most PDs expressed a desire for more educational resources and standardized training materials, and preferred to access an online national menopause curriculum.

Association of maternal birth weight and maternal preterm birth with subsequent risk for adverse reproductive outcomes: The Women's Health Initiative.

BACKGROUND: Advancements in medical technology and pharmacologic interventions have drastically improved survival of infants born preterm and low birth weight, but knowledge regarding the long-term health impacts of these individuals is limited and inconsistent. AIM: To investigate whether an individual's birthweight or history of being born preterm increases the risk of an adverse reproductive outcome. STUDY DESIGN: Nested case-control study within the Women's Health Initiative. SUBJECTS: 79,934 individuals who self-reported their personal birthweight category and/or preterm birth status. OUTCOMES MEASURES: Self-reported pregnancy outcomes: subfertility, miscarriage, stillbirth, preeclampsia, gestational diabetes, gestational hypertension, preterm birth, low birthweight infant, high birthweight infant. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR). RESULTS: After adjustments, individuals reporting their birthweight <6lbs. were 20 % more likely to have a stillbirth or 70 % more likely to have a low birthweight infant and were less likely to have a full-term birth or high birthweight infant during their pregnancy. Individuals reporting a birthweight ≥10 lbs. were more likely to have a high birthweight infant (OR 3.49, 95 % CI 2.73-4.39) and less likely to have a low birthweight infant (OR 0.64, 95 % CI 0.47-0.82). Individuals born preterm were at increased risk for infertility, miscarriage, preeclampsia, gestational diabetes, and delivering a preterm or low birthweight infant. CONCLUSIONS: As more individuals born preterm and/or low birthweight survive to adulthood, the incidence and prevalence of poor reproductive outcomes may increase. Women born at extremes of birthweight and prematurity may need to be monitored more closely during their own pregnancies.

Association of Later-Life Weight Changes With Survival to Ages 90, 95, and 100: The Women's Health Initiative.

BACKGROUND: Associations of weight changes and intentionality of weight loss with longevity are not well described. METHODS: Using longitudinal data from the Women's Health Initiative (N = 54 437; 61-81 years), we examined associations of weight changes and intentionality of weight loss with survival to ages 90, 95, and 100. Weight was measured at baseline, year 3, and year 10, and participants were classified as having weight loss (≥5% decrease from baseline), weight gain (≥5% increase from baseline), or stable weight (<5% change from baseline). Participants reported intentionality of weight loss at year 3. RESULTS: A total of 30 647 (56.3%) women survived to ≥90 years. After adjustment for relevant covariates, 3-year weight loss of ≥5% vs stable weight was associated with lower odds of survival to ages 90 (OR, 0.67; 95% CI, 0.64-0.71), 95 (OR, 0.65; 95% CI, 0.60-0.71), and 100 (OR, 0.62; 95% CI, 0.49-0.78). Compared to intentional weight loss, unintentional weight loss was more strongly associated with lower odds of survival to age 90 (OR, 0.83; 95% CI, 0.74-0.94 and OR, 0.49; 95% CI, 0.44-0.55, respectively). Three-year weight gain of ≥5% vs stable weight was not associated with survival to age 90, 95, or 100. The pattern of results was similar among normal weight, overweight, and obese women in body mass index (BMI)-stratified analyses. CONCLUSIONS: Weight loss of ≥5% vs stable weight was associated with lower odds of longevity, more strongly for unintentional weight loss than for intentional weight loss. Potential inaccuracy of self-reported intentionality of weight loss and residual confounding were limitations.

The co-occurrence and cumulative prevalence of hypertension, rheumatoid arthritis, and hypothyroidism in preterm-born women in the Women's Health Initiative.

Emerging evidence suggests that preterm-born individuals (<37 weeks gestation) are at increased risk of developing chronic health conditions in adulthood. This study compared the prevalence, co-occurrence, and cumulative prevalence of three female predominant chronic health conditions - hypertension, rheumatoid arthritis [RA], and hypothyroidism - alone and concurrently. Of 82,514 U.S. women aged 50-79 years enrolled in the Women's Health Initiative, 2,303 self-reported being born preterm. Logistic regression was used to analyze the prevalence of each condition at enrollment with birth status (preterm, full term). Multinomial logistic regression models analyzed the association between birth status and each condition alone and concurrently. Outcome variables using the 3 conditions were created to give 8 categories ranging from no disease, each condition alone, two-way combinations, to having all three conditions. The models adjusted for age, race/ethnicity, and sociodemographic, lifestyle, and other health-related risk factors. Women born preterm were significantly more likely to have any one or a combination of the selected conditions. In fully adjusted models for individual conditions, the adjusted odds ratios (aORs) were 1.14 (95% CI, 1.04, 1.26) for hypertension, 1.28 (1.12, 1.47) for RA, and 1.12 (1.01, 1.24) for hypothyroidism. Hypothyroidism and RA were the strongest coexisting conditions [aOR 1.69, 95% CI (1.14, 2.51)], followed by hypertension and RA [aOR 1.48, 95% CI (1.20, 1.82)]. The aOR for all three conditions was 1.69 (1.22, 2.35). Perinatal history is pertinent across the life course. Preventive measures and early identification of risk factors and disease in preterm-born individuals are essential to mitigating adverse health outcomes in adulthood.

Associations of maternal preterm birth with subsequent risk for type 2 diabetes in women from the women's health initiative.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women's Health Initiative (n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.

Association of Social Support with Mild Cognitive Impairment and Dementia Among Older Women: The Women's Health Initiative Memory Study.

BACKGROUND: Social support may be a modifiable risk factor for cognitive impairment. However, few long-term, large prospective studies have examined associations of various forms of social support with incident mild cognitive impairment (MCI) and dementia. OBJECTIVE: To examine associations of perceived social support with incident MCI and dementia among community-dwelling older women. METHODS: This prospective cohort study included 6,670 women from the Women's Health Initiative Memory Study who were cognitively unimpaired at enrollment. We used Cox proportional hazards models to assess associations between perceived social support with incident MCI, dementia, or either MCI/dementia during an average 10.7 (SD = 6.1)-year follow-up. Modelling was repeated for emotional/information support, affection support, tangible support, and positive social interaction subscales of social support. RESULTS: Among 6,670 women (average age = 70 years [SD = 3.8]; 97.0% non-Hispanic/Latina; 89.8% White), greater perceived social support was associated with lower risk of MCI/dementia after adjustment for age, ethnicity, race, hormone therapy, education, income, diabetes, hypertension, and body mass index (Tertile [T]3 versus T1: HR = 0.85, 95% CI 0.74-0.99; ptrend = 0.08). Associations were significant for emotional/information support (T3 versus T1: HR = 0.84, 95% CI 0.72-0.97; ptrend = 0.04) and positive social interaction (T3 versus T1: HR = 0.85, 95% CI 0.73-0.99; ptrend = 0.06) subscales. Associations were attenuated and not significant after adjustment for depressive symptom severity. OBJECTIVE: Perceived social support, emotional/information support, and positive social interaction were associated with incident MCI/dementia among older women. Results were not significant after adjustment for depressive symptom severity. Improving social support may reduce risk of MCI and dementia in older women.

The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women's Health Initiative clinical trials.

OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

The association between incidentally found breast arterial calcification on routine screening mammography and the development of coronary artery disease and stroke: results of a 10-year prospective study.

OBJECTIVE: The objective of this study is to assess whether the presence of breast arterial calcifications (BACs) found on routine mammography is prospectively associated with the development of cardiovascular disease (CVD) events after 10 years of follow-up. METHODS: Women presenting for screening mammography were enrolled in this prospective cohort. Baseline data were collected including history of CVD and CVD risk factors. Mammograms were assessed for the presence or absence of BAC. Participants completed questionnaires 10 years after baseline that assessed the development of CVD (coronary artery disease [CAD] and stroke) and CVD risk factors. RESULTS: Of the 1,995 participants who enrolled at baseline, complete 10-year follow-up data were available for 1,039; of those, 114 (11.0%) were BAC-positive and 925 (89.0%) were BAC-negative at baseline. After controlling for age, BAC-positive women were more likely to develop CAD (odds ratio, 3.14; 95% confidence interval, 1.86-5.27; P < 0.001) compared with BAC-negative women after 10 years of follow-up. After controlling for age, BAC-positive women were more likely to have had a stroke (odds ratio, 5.10; 95% CI, 1.82-14.30) compared with BAC-negative women after 10 years. CONCLUSIONS: The presence of BAC on routine screening mammography was associated with a significantly increased risk of developing CAD and stroke after 10 years of follow-up. Additional large prospective, population-based studies are needed to confirm BAC as a predictor of future CVD events and its utility in stratifying a woman's risk of CVD.

The severity of individual menopausal symptoms, cardiovascular disease, and all-cause mortality in the Women's Health Initiative Observational Cohort.

OBJECTIVE: The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality. METHODS: In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality. RESULTS: The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality. CONCLUSION: Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions.

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

Low Diastolic Blood Pressure and Mortality in Older Women. Results From the Women's Health Initiative Long Life Study.

BACKGROUND: Recommended systolic blood pressure targets often do not consider the relationship of low diastolic blood pressure (DBP) levels with cardiovascular disease (CVD) and all-cause mortality risk, which is especially relevant for older people with concurrent comorbidities. We examined the relationship of DBP levels to CVD and all-cause mortality in older women in the Women's Health Initiative Long Life Study (WHI-LLS). METHODS: The study sample included 7,875 women (mean age: 79 years) who underwent a blood pressure measurement at an in-person home visit conducted in 2012-2013. CVD and all-cause mortality were centrally adjudicated. Hazard ratios (HRs) were obtained from adjusted Cox proportional hazards models. RESULTS: After 5 years follow-up, all-cause mortality occurred in 18.4% of women. Compared with a DBP of 80 mm Hg, the fully adjusted HR for mortality was 1.33 (95% confidence interval [CI]: 1.04-1.71) for a DBP of 50 mm Hg and 1.67 (95% CI: 1.29-2.16) for a DBP of 100 mm Hg. The HRs for CVD were 1.14 (95% CI: 0.78-1.67) for a DBP of 50 mm Hg and HR 1.50 (95% CI: 1.03-2.17) for a DBP of 100 mm Hg. The nadir DBP associated with lowest mortality risk was 72 mm Hg overall. CONCLUSIONS: In older women, consideration should be given to the potential adverse effects of low and high DBP. Low DBP may serve as a risk marker. DBP target levels between 68 and 75 mm Hg may avoid higher mortality risk.

Infertility and Risk of Heart Failure in the Women's Health Initiative.

BACKGROUND: There is growing recognition that reproductive factors are associated with increased risk of future cardiovascular disease. Infertility has been less well studied, although emerging data support its association with increased risk of cardiovascular disease. Whether infertility is associated with future risk of heart failure (HF) is not known. OBJECTIVES: This study sought to examine the development of HF and HF subtypes in women with and without history of infertility. METHODS: We followed postmenopausal women from the Women's Health Initiative prospectively for the development of HF. Infertility was self-reported at study baseline. Multivariable cause-specific Cox models were used to evaluate the association of infertility with incident overall HF and HF subtypes (heart failure with preserved ejection fraction [HFpEF]: left ventricular ejection fraction of ≥50% vs heart failure with reduced ejection fraction [HFrEF]: left ventricular ejection fraction of <50%]). RESULTS: Among 38,528 postmenopausal women (mean age: 63 ± 7 years), 5,399 (14%) participants reported a history of infertility. Over a median follow-up of 15 years, 2,373 developed incident HF, including 807 with HFrEF and 1,133 with HFpEF. Infertility was independently associated with future risk of overall HF (HR: 1.16; 95% CI: 1.04-1.30; P = 0.006). Notably, when examining HF subtypes, infertility was associated with future risk of HFpEF (HR: 1.27; 95% CI: 1.09-1.48; P = 0.002) but not HFrEF (HR: 0.97; 95% CI: 0.80-1.18). CONCLUSIONS: Infertility was significantly associated with incident HF. This was driven by increased risk of HFpEF, but not HFrEF, and appeared independent of traditional cardiovascular risk factors and other infertility-related conditions. Future research should investigate mechanisms that underlie the link between infertility and HFpEF.