Somatic Mutations and Clonal Hematopoiesis as Drivers of Age-Related Cardiovascular Risk

Purpose of Review Clonal hematopoiesis of indeterminate potential (CHIP) has been identifed as a novel cardiovascular risk factor. Here we review the relationship of lifestyle and environmental risk factors predisposing to somatic mutations and CHIP and provide an overview on age-related cardiovascular outcomes. Recent Findings CHIP has been associated with accelerated atherosclerosis and cardiovascular disease in both epidemiologi cal and experimental studies. The most commonly mutated candidate driver genes are DNMT3A, TET2, JAK2, and ASXL1. The underlying mechanisms appear predominantly related to infammatory pathways. Although age is the dominant risk factor for developing CHIP, emerging evidence suggests that other factors such as smoking, obesity/type 2 diabetes, or an unhealthy diet play a role in the occurrence of somatic mutations. Summary Evidence suggests a strong link between vascular risk factors, somatic hematopoietic mutations, and age-related cardiovascular disease. Further studies on CHIP biology are required to identify targeted interventions for risk reduction in patients with CHIP and inform the utility of screening strategies

Genetic Determinants for Body Iron Store and Type 2 Diabetes Risk in US Men and Women

Background: High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk. Methodology/Principal Findings Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses’ Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P = 3.47×10−6), TF with transferrin (P = 0.0002 to 1.72×10−10); and HFE with ferritin (P = 0.017 to 1.6×10−8), sTfR (P = 0.007 to 7.9×10−6), and transferrin (P = 0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR = 0.81; 95% CI = 0.66–0.98; P = 0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk. Conclusions/Significance: The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study

Update in hormone therapy use in menopause

The original report from the Women's Health Initiative (WHI) changed our understanding of the benefits and risks of hormone therapy. Since that time, reanalysis of the WHI and additional data from other studies have further refined these concepts. Here we provide an update on recent advances in the field. Menopausal hormone therapy continues to have a clinical role in the management of vasomotor symptoms. However, our understanding of the role of hormones in cardiovascular disease and breast cancer continues to evolve. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy are described. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Finally, we discuss new advances in hormone therapy that will likely lead to a more favorable benefit-to-risk ratio, enabling safer effective menopausal symptom relief. O ver the past several decades, a large number of observational studies suggested that the use of hormone therapy in menopause not only relieved vasomotor symptoms, but also reduced the risk of several chronic medical conditions such as osteoporosis and cardiovascular disease. However, in 2002, the results of a prospective randomized trial, the Women's Health Initiative (WHI), demonstrated that many of the benefits identified in observational studies were not present in a population randomized to treatment; some hypothesized that the previously purported benefits may have been due not to the therapy but rather to confounding and selection biases, as well as other methodological limitations. In response to the findings of the WHI and other randomized trials, menopausal hormone therapy (MHT) use declined dramatically. The WHI confirmed a decreased risk of osteoporosis and fractures in menopausal women assigned to hormone therapy; it also confirmed an increased risk of breast cancer previously identified in women who use combination estrogen plus progestin (E ϩ P) hormone therapy. However, the WHI trial also revealed that women assigned to MHT had an increase in coronary disease, stroke, and venous thromboembolic events. In the past few years, there has been renewed interest in the risks of MHT, especially that of breast cancer as well as the apparent elevation, rather than reduction, in the risk of coronary events. Since the original publication of the WHI results in 2002, a large number of subsequent studies have looked at these concepts in detail. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy have all recently been described. Here we provide an overview of recent developments in this field, including the central role of timing of initiation. Coronary Heart Disease (CHD) The original report from the WHI demonstrated that women randomized to conjugated equine estrogens (CEEs) combined with medroxyprogesterone acetat

Walnut Consumption Is Associated with Lower Risk of Type 2 Diabetes in Women12

Walnuts are rich in polyunsaturated fatty acids and have been shown to improve various cardiometabolic risk factors. We aimed to investigate the association between walnut intake and incident type 2 diabetes in 2 large cohort studies: the Nurses’ Health Study (NHS) and NHS II. We prospectively followed 58,063 women aged 52–77 y in NHS (1998–2008) and 79,893 women aged 35–52 y in NHS II (1999–2009) without diabetes, cardiovascular disease, or cancer at baseline. Consumption of walnuts and other nuts was assessed every 4 y using validated food frequency questionnaires. Self-reported type 2 diabetes was confirmed by a validated supplemental questionnaire. We documented a total of 5930 incident type 2 diabetes cases during 10 y of follow-up. In the multivariable-adjusted Cox proportional hazards model without body mass index (BMI), walnut consumption was associated with a lower risk of type 2 diabetes, and the HRs (95% CIs) for participants consuming 1–3 servings/mo (1 serving = 28 g), 1 serving/wk, and ≥2 servings/wk of walnuts were 0.93 (0.88–0.99), 0.81 (0.70–0.94), and 0.67 (0.54–0.82) compared with women who never/rarely consumed walnuts (P-trend < 0.001). Further adjustment for updated BMI slightly attenuated the association and the HRs (95% CIs) were 0.96 (0.90–1.02), 0.87 (0.75–1.01), and 0.76 (0.62–0.94), respectively (P-trend = 0.002). The consumption of total nuts (P-trend < 0.001) and other tree nuts (P-trend = 0.03) was also inversely associated with risk of type 2 diabetes, and the associations were largely explained by BMI. Our results suggest that higher walnut consumption is associated with a significantly lower risk of type 2 diabetes in women

Associations between Benign Cutaneous Nevi and Risk of Type 2 Diabetes Mellitus in Men and Women: Results from Two Prospective Cohort Studies

poster abstractABSTRACT Objective: Previous studies suggest that the number of cutaneous nevi and type 2 diabetes mellitus (T2DM) are both associated with endogenous sex hormone levels. However, no prospective studies have specifically examined the relationship between the number of benign cutaneous nevi and T2DM. Research Design and Methods: We prospectively examined the associations between the number of nevi and risk of T2DM among 23,748 men (1986-2010) from the Health Professionals Follow-up Study (HPFS) and 67,050 women (1989-2010) from the Nurses' Health Study (NHS). Information on the numbers of melanocytic nevi on arms and the incidence of T2DM was collected by validated questionnaires. Results: During 1,831,118 person-years of follow-up, we documented 8748 incident cases of T2DM. After adjustment for age, BMI, and other diabetes risk factors, the number of nevi was significantly associated with increased risk of T2DM. Multivariable-adjusted HRs (95% CIs) for <1, 1-5, 6-14, and ≥15 nevi were 1.00 (reference), 1.02 (0.92, 1.14), 1.10 (0.87, 1.38), and 1.70 (1.22, 2.36), respectively, for men (P trend = 0.03) and 1.00 (reference), 1.15 (1.09, 1.21), 1.25 (1.11, 1.40), and 1.70 (1.38, 2.09), respectively, for women (P trend = 0.019). This positive association remained consistent across subgroups of participants. Conclusions: Mole count may represent a novel marker for development of T2DM in men and women, indicating a unique nevus development-related mechanism, possibly due to altered levels or functions of endogenous steroid sex hormones, in the pathogenesis of T2DM. Further studies are warranted to clarify the relationship of nevogenesis and T2DM and underlying mechanisms

Effect of Combination Folic Acid, Vitamin B6 , and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research

A Randomized Trial of Low-Dose Aspirin in the Prevention of Clinical Type 2 Diabetes in Women

OBJECTIVE—Subclinical inflammation is linked with the development of type 2 diabetes, and epidemiologic data suggest that this association may be stronger in women. Although small clinical studies have shown a prominent hypoglycemic effect of short-term high-dose aspirin, no randomized trials have directly evaluated the efficacy of aspirin in diabetes prevention at doses acceptable for use in routine clinical practice. We evaluated whether chronic low-dose aspirin prevents the development of clinical diabetes among initially healthy American women

Hemoglobin A1c Is Associated With Increased Risk of Incident Coronary Heart Disease Among Apparently Healthy, Nondiabetic Men and Women

Background: Hemoglobin A1c (HbA1c), a time‐integrated marker of glycemic control, predicts risk of coronary heart disease (CHD) among diabetics. Few studies have examined HbA1c and risk of CHD among women and men without clinically elevated levels or previously diagnosed diabetes. Methods and Results: We conducted parallel nested case–control studies among women (Nurses' Health Study) and men (Health Professionals Follow‐up Study). During 14 and 10 years of follow‐up, 468 women and 454 men developed incident nonfatal myocardial infarction (MI) and fatal CHD. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these analyses, participants with a history of diabetes or HbA1c levels ≥6.5% at baseline were excluded. Compared with HbA1c of 5.0% to 3.0 mg/L had a 2.5‐fold higher risk of CHD compared with participants in the lowest categories of both biomarkers. Conclusions: Our findings suggest that HbA1c is associated with CHD risk among apparently healthy, nondiabetic women and men and may be an important early clinical marker of disease risk

Interrelationship Between Alcohol Intake and Endogenous Sex-Steroid Hormones on Diabetes Risk in Postmenopausal Women

OBJECTIVE: We examined whether circulating concentrations of sex hormones, including estradiol, testosterone, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS), were associated with alcohol intake or mediated the alcohol-type 2 diabetes (T2D) association. METHODS: Among women not using hormone replacement therapy and free of baseline cardiovascular disease, cancer, and diabetes in the Women's Health Study, 359 incident cases of T2D and 359 matched controls were chosen during 10 years of follow-up. RESULTS: Frequent alcohol intake (≥1 drink/day) was positively and significantly associated with higher plasma estradiol concentrations in an age-adjusted model (β = 0.14, 95% confidence interval [CI], 0.03, 0.26), compared to rarely/never alcohol intake. After adjusting for additional known covariates, this alcohol-estradiol association remained significant (β = 0.19, 95% CI, 0.07, 0.30). Testosterone (β = 0.13, 95% CI, -0.05, 0.31), SHBG (β = 0.07, 95% CI, -0.07, 0.20), and DHEAS (β = 0.14, 95% CI, -0.04, 0.31) showed positive associations without statistical significance. Estradiol alone or in combination with SHBG appeared to influence the observed protective association between frequent alcohol consumption and T2D risk, with a 12%-21% reduction in odds ratio in the multivariate-adjusted models. CONCLUSIONS: Our cross-sectional analysis showed positive associations between alcohol intake and endogenous estradiol concentrations. Our prospective data suggested that baseline concentrations of estradiol, with or without SHBG, might influence the alcohol-T2D association in postmenopausal women