Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans

Background: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms ( SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort ( 1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF- II levels. Results: Both offspring's and mother's H19 2992C> T SNP genotypes showed associations with offspring birthweight ( P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels ( P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype ( P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight ( P = 0.04) and higher cord blood IGF-II levels ( P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies ( P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight ( P = 0.04) and with mother's glucose levels ( P = 0.01) in first pregnancies. Conclusion: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index

Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers

Understanding asthma phenotypes: the World Asthma Phenotypes (WASP) international collaboration.

The World Asthma Phenotypes (WASP) study started in 2016 and has been conducted in five centres, in the UK, New Zealand, Brazil, Ecuador and Uganda. The objectives of this study are to combine detailed biomarker and clinical information in order to 1) better understand and characterise asthma phenotypes in high-income countries (HICs) and low and middle-income countries (LMICs), and in high and low prevalence centres; 2) compare phenotype characteristics, including clinical severity; 3) assess the risk factors for each phenotype; and 4) assess how the distribution of phenotypes differs between high prevalence and low prevalence centres. Here we present the rationale and protocol for the WASP study to enable other centres around the world to carry out similar analyses using a standardised protocol. Large collaborative and integrative studies like this are essential to further our understanding of asthma phenotypes. The findings of this study will help elucidate the aetiological mechanisms of asthma and might potentially identify new causes and guide the development of new treatments, thereby enabling better management and prevention of asthma in both HICs and LMICs

Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer

The aim of this study was to ascertain if oestrogen receptor ( ER) status predicts for pathological complete response (pCR) to neoadjuvant chemotherapy in operable breast cancer, and the effects of pCR on survival. Using a single-institution database, 435 patients were identified, who received neoadjuvant chemotherapy for operable breast cancer and were eligible for the analysis. Patients whose tumours were ER negative were more likely to achieve a pCR than patients who were ER positive (21.6 vs 8.1%,

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes.

AIMS/HYPOTHESIS: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. MATERIALS AND METHODS: Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) > or =0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. RESULTS: Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF > or = 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype. CONCLUSIONS/INTERPRETATION: Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes

A genome-wide association study for corneal curvature identifies the platelet-derived growth factor receptor alpha gene as a quantitative trait locus for eye size in white Europeans

2012-2013 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Total Catch of a Red-Listed Marine Species Is an Order of Magnitude Higher than Official Data

Accurate information on total catch and effort is essential for successful fisheries management. Officially reported landings, however, may be underestimates of total catch in many fisheries. We investigated the fishery for the nationally red-listed European lobster (Homarus gammarus) in south-eastern Norway. Probability-based strip transect surveys were used to count buoys in the study area in combination with catch per unit effort data obtained independently from volunteer catch diaries, phone interviews, and questionnaires. We estimate that recreational catch accounts for 65% of total catch in the study area. Moreover, our results indicate that only a small proportion (24%) of lobsters landed commercially were sold through the legal market and documented. Total estimated lobster catch was nearly 14 times higher than reported officially. Our study highlights the need for adequate catch monitoring and data collection efforts in coastal areas, presents a clear warning to resource managers that illegal, unreported and unregulated (IUU) fisheries in coastal areas should not be ignored, and shows the potential impact of recreational fisheries

Tamoxifen resistance in early breast cancer: statistical modelling of tissue markers to improve risk prediction

BACKGROUND: For over two decades, the Nottingham Prognostic Index (NPI) has been used in the United Kingdom to calculate risk scores and inform management about breast cancer patients. It is derived using just three clinical variables - nodal involvement, tumour size and grade. New scientific methods now make cost-effective measurement of many biological characteristics of tumour tissue from breast cancer biopsy samples possible. However, the number of potential explanatory variables to be considered presents a statistical challenge. The aim of this study was to investigate whether in ER+ tamoxifen-treated breast cancer patients, biological variables can add value to NPI predictors, to provide improved prognostic stratification in terms of overall recurrence-free survival (RFS) and also in terms of remaining recurrence free while on tamoxifen treatment (RFoT). A particular goal was to enable the discrimination of patients with a very low risk of recurrence. METHODS: Tissue samples of 401 cases were analysed by microarray technology, providing biomarker data for 72 variables in total, from AKT, BAD, HER, MTOR, PgR, MAPK and RAS families. Only biomarkers screened as potentially informative (i.e., exhibiting univariate association with recurrence) were offered to the multivariate model. The multiple imputation method was used to deal with missing values, and bootstrap sampling was used to assess internal validity and refine the model. RESULTS: Neither the RFS nor RFoT models derived included Grade, but both had better predictive and discrimination ability than NPI. A slight difference was observed between models in terms of biomarkers included, and, in particular, the RFoT model alone included HER2. The estimated 7-year RFS rates in the lowest-risk groups by RFS and RFoT models were 95 and 97%, respectively, whereas the corresponding rate for the lowest-risk group of NPI was 89%. CONCLUSION: The findings demonstrate considerable potential for improved prognostic modelling by incorporation of biological variables into risk prediction. In particular, the ability to identify a low-risk group with minimal risk of recurrence is likely to have clinical appeal. With larger data sets and longer follow-up, this modelling approach has the potential to enhance an understanding of the interplay of biological characteristics, treatment and cancer recurrence. British Journal of Cancer (2010) 102, 1503 - 1510. doi:10.1038/sj.bjc.6605627 www.bjcancer.co

Minding the gap: The importance of active facilitation in moving boundary objects from in-theory to in-use as a tool for knowledge mobilisation

The Health Inequalities Assessment Toolkit (HIAT) was developed to support those involved in health research to integrate a focus on health inequalities. Our study focuses on bringing together the concepts of boundary objects (BO) and brokers-as-bricoleurs to explain the implementation of the HIAT within a research capacity building programme. Exploring the extent to which (i) the HIAT operated as a BO and (ii) the ideal conditions to nurture and enhance its effectiveness during knowledge mobilisation. We employed a qualitative approach to analyse: semi-structured focus groups and telephone interviews; secondary data from an evaluation of the wider research programme within which the capacity building was situated. Data was thematically analysed incorporating the properties of a BO: meaningfulness, convergence, resonance and authenticity. Four main themes identified: (1) Generating convergence through creating a focus (2) Reconciling differences to create a common language (3) Workshop facilitators: boundary brokers-as-bricoleurs, (4) Thoughts into action. The HIAT operated as a BO, enabling individuals across the different project teams to galvanise around the issue of health inequalities, explore collaboratively and incorporate equity within service evaluations. Highlighting the importance of involving brokers with an ability to improvise and mobilise around the HIAT, using their expertise to translate and interpret across boundaries and emphasise shared goals. Reflecting on this, a modified tool with additional resources beyond socio-economic causes has been launched as a forum to consider health inequalities from diverse perspectives for use beyond UK health and social care research

The measurement and therapeutic implications of circulating tumour cells in breast cancer

Circulating tumours cells (CTCs) represent an important biologic link in the spread of breast cancer from primary to metastatic disease. CTCs are strong predictors of prognosis in patients with metastatic breast cancer. Research to date has focused on development of methods with adequate sensitivity and specificity to reproducibly identify these rare events. Future research will focus on the biologic phenotypes of these cells with goals to understand mechanisms of metastasis, to identify novel therapeutic targets, and to monitor response to therapy