Yanzhong Wang

Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome

Summary Background A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity. Methods We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study. Findings Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis. Interpretation The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation. Funding British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.

Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers

We analysed 148 primary breast cancers using BAC-arrays containing 287 clones representing cancer-related gene/loci to obtain genomic molecular portraits. Gains were detected in 136 tumors (91.9%) and losses in 123 tumors (83.1%). Eight tumors (5.4%) did not have any genomic aberrations in the 281 clones analysed. Common (more than 15% of the samples) gains were observed at 8q11–qtel, 1q21–qtel, 17q11–q12 and 11q13, whereas common losses were observed at 16q12–qtel, 11ptel–p15.5, 1p36–ptel, 17p11.2–p12 and 8ptel–p22. Patients with tumors registering either less than 5% (median value) or less than 11% (third quartile) total copy number changes had a better overall survival (log-rank test: P=0.0417 and P=0.0375, respectively). Unsupervised hierarchical clustering based on copy number changes identified four clusters. Women with tumors from the cluster with amplification of three regions containing known breast oncogenes (11q13, 17q12 and 20q13) had a worse prognosis. The good prognosis group (Nottingham Prognostic Index (NPI) ⩽3.4) tumors had frequent loss of 16q24–qtel. Genes significantly associated with estrogen receptor (ER), Grade and NPI were used to build k-nearest neighbor (KNN) classifiers that predicted ER, Grade and NPI status in the test set with an average misclassification rate of 24.7, 25.7 and 35.7%, respectively. These data raise the prospect of generating a molecular taxonomy of breast cancer based on copy number profiling using tumor DNA, which may be more generally applicable than expression microarray analysis.

A variational Bayesian mixture modelling framework for cluster analysis of gene-expression data

MOTIVATION Accurate subcategorization of tumour types through gene-expression profiling requires analytical techniques that estimate the number of categories or clusters rigorously and reliably. Parametric mixture modelling provides a natural setting to address this problem. RESULTS We compare a criterion for model selection that is derived from a variational Bayesian framework with a popular alternative based on the Bayesian information criterion. Using simulated data, we show that the variational Bayesian method is more accurate in finding the true number of clusters in situations that are relevant to current and future microarray studies. We also compare the two criteria using freely available tumour microarray datasets and show that the variational Bayesian method is more sensitive to capturing biologically relevant structure.

The impact of comprehensive geriatric assessment interventions on tolerance to chemotherapy in older people

Background:Although comorbidities are identified in routine oncology practice, intervention plans for the coexisting needs of older people receiving chemotherapy are rarely made. This study evaluates the impact of geriatrician-delivered comprehensive geriatric assessment (CGA) interventions on chemotherapy toxicity and tolerance for older people with cancer.Methods:Comparative study of two cohorts of older patients (aged 70+ years) undergoing chemotherapy in a London Hospital. The observational control group (N=70, October 2010–July 2012) received standard oncology care. The intervention group (N=65, September 2011–February 2013) underwent risk stratification using a patient-completed screening questionnaire and high-risk patients received CGA. Impact of CGA interventions on chemotherapy tolerance outcomes and grade 3+ toxicity rate were evaluated. Outcomes were adjusted for age, comorbidity, metastatic disease and initial dose reductions.Results:Intervention participants undergoing CGA received mean of 6.2±2.6 (range 0–15) CGA intervention plans each. They were more likely to complete cancer treatment as planned (odds ratio (OR) 4.14 (95% CI: 1.50–11.42), P=0.006) and fewer required treatment modifications (OR 0.34 (95% CI: 0.16–0.73), P=0.006). Overall grade 3+ toxicity rate was 43.8% in the intervention group and 52.9% in the control (P=0.292).Conclusions:Geriatrician-led CGA interventions were associated with improved chemotherapy tolerance. Standard oncology care should shift towards modifying coexisting conditions to optimise chemotherapy outcomes for older people.

The effects of socioeconomic status on stroke risk and outcomes

The latest evidence on socioeconomic status and stroke shows that stroke not only disproportionately affects low-income and middle-income countries, but also socioeconomically deprived populations within high-income countries. These disparities are reflected not only in risk of stroke but also in short-term and long-term outcomes after stroke. Increased average levels of conventional risk factors (eg, hypertension, hyperlipidaemia, excessive alcohol intake, smoking, obesity, and sedentary lifestyle) in populations with low socioeconomic status account for about half of these effects. In many countries, evidence shows that people with lower socioeconomic status are less likely to receive good-quality acute hospital and rehabilitation care than people with higher socioeconomic status. For clinical practice, better implementation of well established treatments, effective management of risk factors, and equity of access to high-quality acute stroke care and rehabilitation will probably reduce inequality substantially. Overcoming barriers and adapting evidence-based interventions to different countries and health-care settings remains a research priority.

Socioeconomic status and telomere length: the West of Scotland Coronary Prevention Study

Background: It has been hypothesised that socioeconomically deprived people age more rapidly than their more advantaged counterparts and this is biologically manifest in shorter telomeres. However, in the very few studies conducted, substantial uncertainty exists regarding this relationship. Methods: In the present investigation, 1542 men in the West of Scotland Coronary Prevention Study responded to a series of enquiries about their socioeconomic position (educational attainment, employment status, area-based deprivation), had their physical stature measured (a proxy for early life social circumstances) and provided a blood specimen from which leucocyte DNA was extracted and telomere length derived. Results: There was no strong evidence that any of these four indices of socioeconomic position was robustly related to telomere length. The only exception was employment status: men who reported being out of work had significantly shorter telomeres than those who were employed (p = 0.007). Conclusion: In this cross-sectional study—the largest to date to examine the relationship—we found little evidence of an association between socioeconomic status and telomere length.

Age and Ethnic Disparities in Incidence of Stroke Over Time The South London Stroke Register

Background and Purpose— Data on continuous monitoring of stroke risk among different age and ethnic groups are lacking. We aimed to investigate age and ethnic disparities in stroke incidence over time from an inner-city population–based stroke register. Methods— Trends in stroke incidence and before-stroke risk factors were investigated with the South London Stroke Register, a population-based register covering a multiethnic population of 357 308 inhabitants. Age-, ethnicity-, and sex-specific incidence rates with 95% confidence intervals were calculated, assuming a Poisson distribution and their trends over time tested by the Cochran–Armitage test. Results— Four thousand two hundred forty-five patients with first-ever stroke were registered between 1995 and 2010. Total stroke incidence reduced by 39.5% during the 16-year period from 247 to 149.5 per 100 000 population (P<0.0001). Similar declines in stroke incidence were observed in men, women, white groups, and those aged >45 years, but not in those aged 15 to 44 years (12.6–10.1; P=0.2034) and black groups (310.1–267.5; P=0.3633). The mean age at stroke decreased significantly from 71.7 to 69.6 years (P=0.0001). The reduction in prevalence of before-stroke risk factors was mostly seen in white patients aged >55 years, whereas an increase in diabetes mellitus was observed in younger black patients aged 15 to 54 years. Conclusions— Total stroke incidence decreased during the 16-year time period. However, this was not seen in younger age groups and black groups. The advances in risk factor reduction observed in white groups aged >55 years failed to be transferred to younger age groups and black groups.

Differences in Outcome and Predictors Between Ischemic and Intracerebral Hemorrhage The South London Stroke Register

Background and Purpose— Few population-based studies describing functional outcome between ischemic stroke and intracerebral hemorrhage (ICH) in the short- and long-term are available. Knowledge of the natural history and factors associated with poor outcome is important in providing prognostic information and resource allocation. Methods— Data were collected within the population-based South London Stroke Register between 1995 and 2011. Baseline data were collection of sociodemographic factors, case mix, risk factors before stroke, and acute stroke processes, with outcomes at 7 days, 3 months, 1 year, 5 years, and 10 years after stroke. Logistic regression was used to determine factors associated with poor outcome (dead and dependency: Barthel index <15). Results— Age and incontinence were associated with poor outcome at 3 months, 1 year, 5 years, and 10 years in ICH, whereas age, incontinence, failed swallow, atrial fibrillation, and diabetes mellitus were associated with poor outcome in ischemic stroke. ICH was more likely to have poorer outcomes at 3 months (odds ratio, 2.2; 95% confidence interval [CI], 1.8–2.8) and 1 year (odds ratio, 2.1; 95% CI, 1.7–2.6) but not at 5 years (odds ratio, 1.1; 95% CI, 0.8–1.4) or 10 years (odd ratio, 0.8; 95% CI, 0.57–1.22); however, the improvement of functional outcome from day 7 to 3 months was significantly greater for ICH (regression coefficient: 1.8; 95% CI, 1.1–2.6; P<0.0001). Conclusions— ICH has poorer outcomes up to 5 years after stroke. The improvement of functional outcome up to 3 months was significantly greater with ICH. Identification of factors associated with poor outcome may be used for clinical predictions.

Trends and Survival Between Ethnic Groups After Stroke The South London Stroke Register

Background and Purpose— To identify trends and differences between ethnic groups in survival after first-ever stroke and examine factors influencing survival. Methods— Population-based stroke register of first in a lifetime strokes between 1995 and 2010. Baseline data were collection of sociodemographic factors, stroke subtype, case mix, risk factors before stroke, and receipt of effective acute stroke processes. Survival curves were estimated with Kaplan-Meier methods, and survival analyses were undertaken using Cox Proportional-hazards models. Results— Survival improved significantly over this 16-year period (P<0.0001). Black Caribbean and black African had a reduced risk of all-cause mortality compared with white patients (hazard ratio, 0.85 [95% confidence interval, 0.74–0.98] and 0.61 [0.49–0.77], respectively) after adjustment for confounders. This survival advantage of black Caribbean/black African over white mainly existed in older patients (over 65). Recent stroke, being black Caribbean/black African, and stroke unit admission were associated with better survival. Conclusions— Survival has improved in a multiethnic population over time. The independent survival advantage of black Caribbean and black African over White group in those aged over 65 may be a healthy migrant effect of first generation migrants. The increase in admission to a stroke unit may contribute to the improvement in survival after stroke.

PMC42, a breast progenitor cancer cell line, has normal-like mRNA and microRNA transcriptomes

IntroductionThe use of cultured cell lines as model systems for normal tissue is limited by the molecular alterations accompanying the immortalisation process, including changes in the mRNA and microRNA (miRNA) repertoire. Therefore, identification of cell lines with normal-like expression profiles is of paramount importance in studies of normal gene regulation.MethodsThe mRNA and miRNA expression profiles of several breast cell lines of cancerous or normal origin were measured using printed slide arrays, Luminex bead arrays, and real-time reverse transcription-polymerase chain reaction.ResultsWe demonstrate that the mRNA expression profiles of two breast cell lines are similar to that of normal breast tissue: HB4a, immortalised normal breast epithelium, and PMC42, a breast cancer cell line that retains progenitor pluripotency allowing in-culture differentiation to both secretory and myoepithelial fates. In contrast, only PMC42 exhibits a normal-like miRNA expression profile. We identified a group of miRNAs that are highly expressed in normal breast tissue and PMC42 but are lost in all other cancerous and normal-origin breast cell lines and observed a similar loss in immortalised lymphoblastoid cell lines compared with healthy uncultured B cells. Moreover, like tumour suppressor genes, these miRNAs are lost in a variety of tumours. We show that the mechanism leading to the loss of these miRNAs in breast cancer cell lines has genomic, transcriptional, and post-transcriptional components.ConclusionWe propose that, despite its neoplastic origin, PMC42 is an excellent molecular model for normal breast epithelium, providing a unique tool to study breast differentiation and the function of key miRNAs that are typically lost in cancer.