Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.

PURPOSE: Primary ovarian insufficiency before the age of 40 years affects 1% of the female population and is characterized by permanent cessation of menstruation. Genetic causes include FMR1 expansion mutations. Previous studies have estimated mutation prevalence in clinical referrals for primary ovarian insufficiency, but these are likely to be biased as compared with cases in the general population. The prevalence of FMR1 expansion mutations in early menopause (between the ages of 40 and 45 years) has not been published. METHODS: We studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46 years. We determined the prevalence of premutation (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in women with primary ovarian insufficiency (n = 254) and early menopause (n = 1,881). RESULTS: The prevalence of the premutation was 2.0% in primary ovarian insufficiency, 0.7% in early menopause, and 0.4% in controls, corresponding to odds ratios of 5.4 (95% confidence interval = 1.7-17.4; P = 0.004) for primary ovarian insufficiency and 2.0 (95% confidence interval = 0.8-5.1; P = 0.12) for early menopause. Combining primary ovarian insufficiency and early menopause gave an odds ratio of 2.4 (95% confidence interval = 1.02-5.8; P = 0.04). Intermediate alleles were not significant risk factors for either early menopause or primary ovarian insufficiency. CONCLUSION: FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of primary ovarian insufficiency and early menopause.

Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study.

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.

Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) are potentially at increased risk of cardiovascular (CV) diseases due to well-established risk factors, including insulin resistance, obesity and type 2 diabetes mellitus (T2DM). However, data showing excess CV events in this population are still lacking. We investigated the incidence and prevalence of CV events in a cohort of women with PCOS. DESIGN: Retrospective cohort study (total follow-up >12,000 person-years). SETTING: Leicester, Leicestershire and Rutland (Total Female population of 434,859), UK. PARTICIPANTS: Two thousand three hundred and one women with PCOS (mean age = 29.6 years) attending a speciality clinic in Leicestershire, UK. MAIN OUTCOMES MEASURES: T2DM, myocardial infarction (MI), angina, heart failure (HF), stroke and CV-related death. RESULTS: Incidence of T2DM, MI, angina, HF, stroke and CV death was respectively 3.6, 0.8, 1.0, 0.3, 0.0 and 0.4 per 1000 person-years. At the end of follow-up, the prevalence of MI in the age groups 45-54, 55-64 and >65 years was 1.9%, 6.0% and 27.3% and of angina was 2.6%, 6.0% and 27.3%, respectively. Age-group-specific odds ratios for the prevalence of MI and angina compared to the local female population ranged between 2.6 (95% CI: 1.0-6.3) and 12.9 (CI: 3.4-48.6) with the highest ratio being for MI in the group >65 years old. Age, history of hypertension and smoking had significant correlations with CV outcomes in the PCOS patients. CONCLUSION: We have shown a high incidence and age-group-specific prevalence of T2DM, MI and angina in the women with PCOS, with over a quarter having had MI or angina in those >65 years. These findings should be considered in the treatment strategies and long-term planning for women with PCOS.

The impact of diet and lifestyle management strategies for obstructive sleep apnoea in adults: a systematic review and meta-analysis of randomised controlled trials.

PURPOSE: To systematically evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity, Obstructive Sleep Apnoea (OSA) parameters and quality of life (QoL) in adults with OSA. METHODS: Electronic databases were searched to identify randomised controlled trials published in English with an intervention based on dietary weight loss, exercise and/or lifestyle programme in adults with OSA. Meta-analyses were conducted using random-effects models. RESULTS: Twelve studies met the inclusion criteria with nine comparing similar interventions. Diet and diet plus continuous positive airway pressure (CPAP) therapy were compared in three studies (n = 261), and intensive lifestyle programmes and routine care were compared in six studies (n = 483). Diet with CPAP therapy reduced weight by -2.64 kg (95 % Confidence Interval (CI) -3.98, -1.30, I (2) = 0 %) compared with diet alone. No differences were observed for QoL or Epworth Sleepiness Scale. A significant reduction in weight was seen in participants receiving an intensive lifestyle intervention of -5.65 kg (95 % CI -10.91, -0.40, I(2) = 95.7 %) compared with controls. Reductions were also observed for waist circumference (-5.80 cm, 95 % CI -8.64, -2.96, I(2) = 77.7 %), body mass index (BMI) (-2.33 kg/m(2), 95 % CI -3.41, -1.24, I(2) = 78.8 %) and the Apnoea Hypopnoea Index (AHI) (-4.55 events/h, 95 % CI -7.12, -1.98, I(2) = 54.4 %) but with high levels of heterogeneity. CONCLUSIONS: Intensive lifestyle management can significantly reduce obesity indices and improve AHI. Future research is required to investigate this effect due to a limited number of studies identified.

Body mass index, exercise, and other lifestyle factors in relation to age at natural menopause: analyses from the breakthrough generations study.

The authors examined the effect of women's lifestyles on the timing of natural menopause using data from a cross-sectional questionnaire used in the United Kingdom-based Breakthrough Generations Study in 2003-2011. The analyses included 50,678 women (21,511 who had experienced a natural menopause) who were 40-98 years of age at study entry and did not have a history of breast cancer. Cox competing risks proportional hazards models were fitted to examine the relation of age at natural menopause to lifestyle and anthropometric factors. Results were adjusted for age at reporting, smoking status at menopause, parity, and body mass index at age 40 years, as appropriate. All P values were 2-sided. High adult weight (P(trend) < 0.001), high body mass index (P(trend) < 0.001), weight gain between the ages of 20 and 40 years (P(trend) = 0.01), not smoking (P < 0.001), increased alcohol consumption (P(trend) < 0.001), regular strenuous exercise (P < 0.01), and not being a vegetarian (P < 0.001) were associated with older age at menopause. Neither height nor history of an eating disorder was associated with menopausal age. These findings show the importance of lifestyle factors in determining menopausal age.

Familial concordance for height and its components: analyses from the Breakthrough Generations Study.

OBJECTIVES: To assess familial resemblance for height, arm span, and components of these, and differences between concordance for short and tall heights. METHODS: We examined whether female relatives were similar for six anthropometric measurements (height, arm span, leg, trunk and arm length, and leg:trunk length ratio). Subjects were 31,622 related individuals aged 16-102 yr participating in the UK Breakthrough Generations Study. Height and arm span were self-reported, limb and trunk length were measured in a subset (N = 508) by study investigators, and paternal height was reported by the daughter. Data were analyzed using correlations and Poisson regression. RESULTS: Correlation coefficients within families were 0.4 for height, 0.3 for arm span, and 0.5 for leg length, trunk length, leg:trunk ratio, and arm length. Women had a relative risk (RR) of being short (i.e., in the lowest height quintile) of 2.3 (95% confidence interval [CI] = 2.1-2.5) if their mother was short, 2.1 (95% CI = 1.9-2.3) if their father was short, and 3.7 (95% CI = 3.4-4.0) if both parents were short. RRs of being tall (i.e., in the highest height quintile) were 2.3 (95% CI = 2.1-2.5), 2.4 (95% CI = 2.2-2.6), and 4.4 (95% CI = 4.1-4.8) if their mother, father or both were tall, respectively. CONCLUSIONS: We have shown, for the first time, that leg:trunk length ratio and arm length aggregate within families. Concordance seemed to be stronger for tall than short heights.

Secular trends in age at menarche in women in the UK born 1908-93: results from the Breakthrough Generations Study.

Menarcheal age decreased over time in Western countries until cohorts born in the mid-20th century. It then stabilised, but limited data are available for recent cohorts. Menarche data were collected retrospectively by questionnaire in 2003-10 from 94,170 women who were participating in the Breakthrough Generations Study, aged 16-98 years, born 1908-93 and resident in the UK. Average menarcheal age declined from women born in 1908-19 (mean=13.5 years) to those born in 1945-49 (mean=12.6 years). It was then stable for several birth cohorts, but resumed its downward trend in recent cohorts (mean=12.3 years in 1990-93 cohort). Trends differed between socio-economic groups, but the recent decline was present in each group. In conclusion, menarcheal age appears to have decreased again in recent cohorts after a period of stabilisation.

Familial concordance for age at menarche: analyses from the Breakthrough Generations Study.

Age at menarche is correlated within families, but estimates of the heritability of menarcheal age have a wide range (0.45-0.95). We examined the familial resemblance for age at menarche and the extent to which this is due to genetic and shared environmental factors. Between 2003 and 2010 data were retrospectively collected by questionnaire from participants within the UK-based Breakthrough Generations Study. These analyses included 25,970 female participants aged 16-98 with at least one female relative who was also a study participant. A woman's menarche was significantly delayed for each yearly increase in the menarcheal age of her monozygotic twin (average increase = 7.2 months, P < 0.001), dizygotic twin (average increase = 3.0 months, P = 0.03), older sister (average increase = 3.3 months, P < 0.001), mother (average increase = 3.4 months, P < 0.001), maternal grandmother (average increase = 1.5 months, P = 0.04), maternal aunt (average increase = 1.4 months, P < 0.001) and paternal aunt (average increase = 3.0 months, P < 0.001). There was not a significant association between the menarcheal ages of half-sister pairs or of paternal grandmother-granddaughter pairs, based on small numbers. Heritability was estimated as 0.57 [95% confidence interval 0.53, 0.61]. Shared environmental factors did not have an effect in the model. In conclusion, approximately half of the variation in age at menarche was attributable to additive genetic effects with the remainder attributable to non-shared environmental effects.

South Asian individuals at high risk of type 2 diabetes have lower plasma vitamin C levels than white Europeans.

Individuals of South Asian origin are at high risk of developing type 2 diabetes; the relationship between this risk and diet remains to be investigated fully. Furthermore, fruit and vegetable intake remains low throughout the world and previous data suggest that intake is associated with risk of diabetes. The aim of this research study was to compare plasma vitamin C concentrations, measured as a biomarker for fruit and vegetable intake, in South Asian and white European individuals. Participants recruited as part of the Let's Prevent Diabetes Study provided samples for the quantification of plasma vitamin C. We compared vitamin C levels by ethnicity using multiple regression, both unadjusted and adjusted for confounders, including glycaemic status. Mean plasma vitamin C was significantly lower in the South Asian participants compared with white European participants (34.5 (sd 19·8) v. 39·9 (sd 22·1) µmol/l, respectively; P ≤ 0·0001). Significantly fewer South Asian individuals consumed five portions of fruit and vegetables per d, as determined by a plasma vitamin C concentration of ≥ 50 µmol/l (23·2 % (n 58) v. 31·4 % (n 558); P = 0·01). Vitamin C reflects habitual fruit and vegetable consumption; thus results suggest that South Asians have lower fruit and vegetable intake. However, it cannot be excluded that vitamin C is utilised differently. Dietary advice specifically targeting the South Asian population should be developed.

Effect of physical activity measurement type on the association between walking activity and glucose regulation in a high-risk population recruited from primary care.

BACKGROUND: We investigate associations of self-reported and objectively assessed walking activity with measures of glucose regulation in a multi-ethnic population at high risk of type 2 diabetes. METHODS: This study reports data from a 2009-2011 screening programme for impaired glucose regulation (IGR) within a high-risk primary care population in Leicestershire, UK; 2532 participants (38% women, 8% South Asian) with a mean age of 64 ± 8 years and an average BMI of 32.1 ± 5.6 kg/m(2) were included. Walking activity was measured by self-report (International Physical Activity Questionnaire) and objectively (pedometer). Glucose regulation assessments included 2h post-challenge glucose, fasting glucose and HbA1c. RESULTS: Higher levels of self-reported walking activity and pedometer steps were associated with lower 2h post-challenge glucose after controlling for several known confounding variables, including BMI. Similarly, when categorized in tertiles, both measures were associated with a lower odds of having any form of IGR; odds ratio for lowest vs highest tertile was 0.64 (0.51-0.80) for self-report and 0.69 (0.55-0.87) for pedometer steps. There was no significant difference between self-reported and objective measures in the strength of associations with glucose regulation; associations with self-report were maintained when further adjusted for pedometer steps. Stronger associations between self-reported walking activity and glucose regulation were observed in South Asians compared with White Europeans. CONCLUSIONS: Self-reported and objectively measured walking activity were equally associated with indices of glucose regulation. Associations with self-reported walking activity were maintained when further adjusted for pedometer steps, suggesting that self-reported walking activity may measure facets of physical activity that are beyond total volume.

Joint prevalence of diabetes, impaired glucose regulation, cardiovascular disease risk and chronic kidney disease in South Asians and White Europeans.

BACKGROUND: Multiple vascular risk factors may confer very high risk, but the degree of commonality between risk factors is unclear, particularly among ethnic minorities. Furthermore, it is unknown what impact this commonality will have on the UK-based NHS Health Check Programme; a vascular disease prevention programme that screens individuals aged 40-74 years. We estimated the joint prevalence of diabetes, impaired glucose regulation (IGR), high cardiovascular disease (CVD) risk and chronic kidney disease (CKD) among White Europeans and South Asians who would be eligible for the Programme. METHODS: Cross-sectional data were analysed for 3707 participants (23.6% South Asian) in a screening study set in Leicestershire, UK. Diabetes and IGR were screen-detected. CKD may have been diagnosed previously. IGR was defined as impaired fasting glucose and/or impaired glucose tolerance, and high CVD risk as 10 year risk greater than 20%. RESULTS: Among males, South Asians had higher prevalence than White Europeans of diabetes (9.0% vs. 3.9%, respectively, p<0.001), IGR (12.5% vs. 9.2%, p = 0.06), and high CVD risk (39.1% vs. 33.1%, p = 0.03), but lower prevalence of CKD (1.5% vs. 4.6%, p<0.01). Among females, South Asians had higher prevalence than White Europeans of diabetes (7.4% vs. 3.3%, p<0.001), but lower prevalence of CKD (3.7% vs. 13.0%, p <0.001) and CVD risk (2.4% vs. 4.6%, p = 0.03), and a non-significant difference in IGR prevalence. At least one risk factor was diagnosed in 34% of participants, and all of them in 0.4%, suggesting that 723,589-734,589 more individuals each year will require monitoring following implementation of the Health Check Programme. CONCLUSIONS: The collective prevalence of risk factors for vascular disease in this population was high, but there was little overlap between the risk factors, and prevalence differed by ethnicity. This has implications for service delivery and resources, and should be considered when planning screening and intervention programmes.

The association of the triglyceride-to-HDL cholesterol ratio with insulin resistance in White European and South Asian men and women.

INTRODUCTION: There is recent interest surrounding the use of the triglyceride-to-HDL cholesterol ratio as a surrogate marker of insulin resistance in clinical practice, as it may identify people at high risk of developing diabetes or its complications. However, it has been suggested using this lipid ratio may not be appropriate for measuring insulin resistance in African-Americans, particularly women. We investigated if this inconsistency extended to South Asian women in a UK multi-ethnic cohort of White Europeans and South Asians. METHODS: Cross-sectional analysis was done of 729 participants from the ADDITION-Leicester study from 2005 to 2009. The association between tertiles of triglyceride-to-HDL cholesterol ratio to fasting insulin, homeostatic model of assessment for insulin resistance (HOMA1-IR), quantitative insulin sensitivity check index (QUICKI) and glucose: insulin ratio was examined with adjustment for confounding variables. RESULTS: Incremental tertiles of the triglyceride-to-HDL cholesterol ratio demonstrated a significant positive association with levels of fasting insulin, HOMA1-IR, glucose: insulin ratio and a negative association with QUICKI in White European men (n = 255) and women (n = 250) and South Asian men (n = 124) (all p<0.05), but not South Asian women (n = 100). A significant interaction was demonstrated between sex and triglyceride-to-HDL cholesterol ratio tertiles in South Asians only (p<0.05). The area under the receiver operating characteristic curve for triglyceride-to-HDL cholesterol ratio to detect insulin resistance, defined as the cohort HOMA1-IR ≥ 75(th) percentile (3.08), was 0.74 (0.67 to 0.81), 0.72 (0.65 to 0.79), 0.75 (0.66 to 0.85) and 0.67 (0.56 to 0.78) in White European men and women, South Asian men and women respectively. The optimal cut-points for detecting insulin resistance were 0.9-1.7 in mmol/l (2.0-3.8 in mg/dl) for the triglyceride-to-HDL ratio. CONCLUSION: In South Asian women the triglyceride-to-HDL cholesterol ratio was not associated with insulin resistance; therefore there may be limitations in its use as a surrogate marker in this group.

A Comparative Analysis of Biomarker Expression and Molecular Subtypes of Pure Ductal Carcinoma In Situ and Invasive Breast Carcinoma by Image Analysis: Relationship of the Subtypes with Histologic Grade, Ki67, p53 Overexpression, and DNA Ploidy.

There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS). We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs) by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.

Familial concordance for age at natural menopause: results from the Breakthrough Generations Study.

OBJECTIVE: Existing estimates of the heritability of menopause age have a wide range. Furthermore, few studies have analyzed to what extent familial similarities might reflect shared environment, rather than shared genes. We therefore analyzed familial concordance for age at natural menopause and the effects of shared genetic and environmental factors on this concordance. METHODS: Participants were 2,060 individuals comprising first-degree relatives, aged 31 to 90 years, and participating in the UK Breakthrough Generations Study. Menopause data were collected using a self-administered questionnaire and analyzed using logistic regression and variance-components models. RESULTS: Women were at an increased risk of early menopause (≤45 y) if their mother (odds ratio, 6.2; P < 0.001) or non-twin sister (odds ratio, 5.5; P < 0.001) had had an early menopause. Likewise, women had an increased risk of late menopause (≥54 y) if their relative had had a late menopause (mother: odds ratio, 6.1; P < 0.01; non-twin sister: odds ratio, 2.3; P < 0.001). Estimated heritability was 41.6% (P < 0.01), with an additional 13.6% (P = 0.02) of the variation in menopause age attributed to environmental factors shared by sisters. CONCLUSIONS: We confirm that early menopause aggregates within families and show, for the first time, that there is also strong familial concordance for late menopause. Both genes and shared environment were the source of variation in menopause age. Past heritability estimates have not accounted for shared environment, and thus, the effect of genetic variants on menopause age may previously have been overestimated.