Aromatase (CYP19A1) gene variants, sex steroid levels, and late-life depression.

BACKGROUND: Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. METHODS: This population-based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. RESULTS: Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p-values .01 to .0005). Three SNPs were associated with an increased risk of late-life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. CONCLUSIONS: Variants of the CYP19A1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.

Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study.

BACKGROUND: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. METHODS AND RESULTS: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy. CONCLUSIONS: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.

Sex hormone-binding globulin and thrombin generation in women using hormonal contraception.

OBJECTIVES: We investigated the impact of serum sex hormone-binding globulin (SHBG) on thrombin generation (TG) in women according to hormonal contraception. PATIENTS AND METHODS: A cross-sectional study of SHBG and TG measured via calibrated automated thrombography was conducted in 150 healthy women, including 75 users of combined oral contraceptives (COC), 22 users of progestin-only contraceptives (POC) and 53 nonusers. RESULTS: COC but not POC-users had significantly higher SHBG levels compared with nonusers. In hormonal contraceptive users, SHBG was positively associated with both activated protein C (APC) resistance and baseline TG, and protein S and prothrombin were important mediators. CONCLUSION: These data provide further evidence that SHBG may be used as a biomarker in assessing prothrombotic profile of hormonal contraception.

Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen.

BACKGROUND AND PURPOSE: The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. METHODS: We set up a nested case-control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01-2.49) in oral estrogen users and 0.83 (0.56-1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81). CONCLUSIONS: Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Estrogen receptor polymorphisms and incident dementia: the prospective 3C study.

BACKGROUND: Genetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors. METHODS: The association between five ESR α (ESR1) and ß (ESR2) polymorphisms with 7-year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate-adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association. RESULTS: Among women, the CC genotype of ESR1rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03-2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE ε4 allele (adjusted HR: 3.24, 95% CI: 1.81-5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37-2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men. CONCLUSIONS: Although there was only weak support for a gender-specific association between the common ESR1rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE ε4 allele.

Low testosterone and the risk of dementia in elderly men: Impact of age and education.

OBJECTIVE: The objective of this study was to examine the association of plasma estradiol and testosterone with risk for dementia in elderly men. METHODS: Within the population based Three-City study, including 3650 men age 65 years and older, a case-cohort design was set up after 4-years of follow-up. Baseline plasma levels of total 17-ß estradiol (Total-E2), total testosterone (total-T) and bioavailable testosterone (bio-T) were measured for all cases of incident dementia (n=105) and for a random sample of the cohort (n=413). Cox regression models were used to estimate multivariate steroid sex hormone-associated hazard ratios (HR) and 95% confidence intervals of dementia. RESULTS: There was a reverse J-shaped relationship between total-T and risk for dementia (P=.007). Compared with the median tertile, the HRs associated with total-T in the lower and upper tertile were increased (HR, 2.33; P=.026; HR, 1.9, P=.126; respectively). Low bio-T was associated with a greater risk for dementia (HR for one standard deviation of decreasing log(bio-T), 1.29; 95% confidence interval, 1.03-1.62). An interaction was found between bio-T and age (P<.0001), and bio-T and education (P=.044). Risk for dementia associated with low bio-T was greater in older men (80 years or older) than in younger men (younger than 80 years; HR, 3.11; P=.011 vs. HR, 1.07, P=.715, respectively) and in men with high level of education compared with those with low level of education (HR, 2.32; P=.0002 vs. HR, 0.95; P=.790, respectively). No significant association was found between Total-E2 and dementia. CONCLUSIONS: Low levels of testosterone are associated with a risk for dementia in elderly men. The association between low bio-T and dementia may be more relevant to men 80 years or older and men with a high level of education.

Endogenous oestradiol as a positive correlate of plasma fibrinogen among older postmenopausal women: a population-based study (the Three-City cohort study).

BACKGROUND: Plasma fibrinogen is a strong predictor of ischaemic arterial disease in women. Sex steroid hormones including hormone therapy may play an important role in the development of cardiovascular disease. However, whether endogenous sex steroid hormones influence the plasma fibrinogen concentrations among postmenopausal women remains unclear. OBJECTIVES: To investigate the association of plasma fibrinogen levels with endogenous sex steroid hormones and sex hormone binding globulin (SHBG) among postmenopausal women. METHODS: We used data from the French prospective Three-City cohort study that included 9294 noninstitutionalized men and women over 65 years of age. Total 17ß-oestradiol (E2, pg/ml), total testosterone (T, ng/ml), SHBG (nm) and fibrinogen (g/l) were measured in stored plasmas in a subcohort of 602 randomly selected postmenopausal women who used neither hormone medication nor anticoagulation therapy. Multivariate linear regression models were used to estimate the regression coefficients assessed in fibrinogen unit by 1 SD increase in log-distribution of sex steroid hormones and SHBG. RESULTS: E2 but neither T nor SHBG was positively associated with plasma fibrinogen levels (ß = 0·148, P < 0·001). Adjustment for cardiovascular risk factors including diabetes made no substantial change to the results (ß = 0·145, P < 0·001). The association of fibrinogen with E2 was stronger among women with body mass index over 25 kg/m(2) compared with those with normal weight (ß = 0·156, P < 0·001 and ß = 0·092, P = 0·02, respectively, P for interaction = 0·04). CONCLUSION: E2 emerges as a positive and independent correlate of plasma fibrinogen among postmenopausal women, especially in subjects who are overweight. These findings suggest a deleterious effect of endogenous oestrogens on cardiovascular risk profile among postmenopausal women.