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    ABSTRACT: Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women's Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30x10⁻⁶), GCKR (rs1260326, p=1.63x10⁻⁶), ZNF259-APOA5 (rs651821, p=7.17x10⁻⁶) with plasma viscosity; andat CSF1 (rs333948, p=8.88x10⁻⁶) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10⁻⁷) and plasma viscosity (p=1.63x10⁻⁶), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10⁻²) and plasma viscosity (p<1.00x10⁻⁵). Triglyceride associated variants were overrepresented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.
    Thrombosis and Haemostasis 10/2013; 110(5):995-1003.
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    ABSTRACT: Within medical research there is an increasing trend toward deriving multiple types of data from the same individual. The most effective prognostic prediction methods should use all available data, since this maximizes the amount of information used. In this paper we consider a variety of learning strategies to boost prediction performance based on the use of all available data.Implementation: We consider data integration via the use of multiple kernel learning (MKL) supervised learning methods. We propose a scheme in which feature selection by statistical score is performed separately per data type and by pathway membership. We further consider the introduction of a confidence measure for the class assignment, both to remove some ambiguously labelled datapoints from the training data and to implement a cautious classifier which only makes predictions when the associated confidence is high. We use the METABRIC dataset (Curtis et al, 2012) for breast cancer, with prediction of survival at 2000 days from diagnosis. Predictive accuracy is improved by using kernels which exclusively use those genes, as features, which are known members of particular pathways. We show that yet further improvements can be made by using a range of additional kernels based on clinical covariates such as ER-status. Using this range of measures to improve prediction performance, we show that the test accuracy on new instances is nearly 80%, though predictions are only made on 69.2% of the patient cohort. J.Seoane@bristol.ac.uk.
    Bioinformatics 10/2013;
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    ABSTRACT: Lower maternal vitamin D status in pregnancy may be associated with increased offspring cardiovascular risk in later life, but evidence for this is scant. We examined associations of maternal total 25-hydroxyvitamin D (25(OH)D) in pregnancy with offspring cardiovascular risk factors assessed in childhood and adolescence. A longitudinal, prospective study. The study was based on data from mother-offspring pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective population-based birth cohort (N=4109). Offspring cardiovascular risk factors were measured in childhood (mean age 9.9 years) and in adolescence (mean age 15.4 years): blood pressure, lipids, apolipoproteins (at 9.9 years only), glucose and insulin (at 15.4 years only), C reactive protein (CRP), and interleukin 6 (at 9.9 years only) were measured. After adjustments for potential confounders (maternal age, education, body mass index (BMI), smoking, physical activity, parity, socioeconomic position, ethnicity, and offspring gestational age at 25(OH)D sampling; gender, age, and BMI at outcome assessment), maternal 25(OH)D was inversely associated with systolic blood pressure (-0.48 mm Hg difference per 50 nmol/L increase in 25(OH)D; 95% CI -0.95 to -0.01), Apo-B (-0.01 mg/dL difference; 95% CI -0.02 to -0.001), and CRP (-6.1% difference; 95% CI -11.5% to -0.3%) at age 9.9 years. These associations were not present for risk factors measured at 15.4 years, with the exception of a weak inverse association with CRP (-5.5% difference; 95% CI -11.4% to 0.8%). There was no strong evidence of associations with offspring triglycerides, glucose or insulin. Our findings suggest that fetal exposure to 25(OH)D is unlikely to influence cardiovascular risk factors of individuals later in life.
    Heart (British Cardiac Society) 10/2013;
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    ABSTRACT: Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption we performed a population based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals respectively from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2,446,724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of fifteen independent loci, with ten loci reaching genome-wide significance (p<5x10(-8)) for 'age at first tooth' and eleven loci for 'number of teeth'. Together these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including a SNP in the protein-coding region of BMP4 (rs17563, P= 9.080x10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
    Human Molecular Genetics 09/2013; 22(18):3807-3817.
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    ABSTRACT: An accumulating body of evidence suggests that offspring of mothers with preeclampsia have higher blood pressure during childhood and young adulthood compared with women without preeclampsia. However, the evidence with regard to offspring glucose metabolism and lipids is more scant. We examined whether maternal hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) are associated with a range of cardiometabolic health measures in adolescent offspring. We included data for mother-offspring pairs from a United Kingdom prospective birth cohort (the Avon Longitudinal Study of Parents and Children). Repeat antenatal clinic measures of blood pressure and proteinuria (median 14 and 11, respectively) were used to ascertain maternal preeclampsia (n=53) and gestational hypertension (n=431). Offspring had blood pressure (n=4438), and fasting lipids, insulin, and glucose (n=2888) measured at a mean age of 17 years. There was no strong evidence of differences in fasting insulin, glucose, or lipid concentrations. Systolic and diastolic blood pressures were higher in offspring of mothers with gestational hypertension (mean difference, 2.06 mm Hg; 95% confidence interval, 1.28-2.84 and 1.11 mm Hg; 95% confidence interval, 0.54-1.69, respectively) and preeclampsia (1.12 mm Hg; 95% confidence interval, -0.89-3.12 and 1.71 mm Hg; 95% confidence interval, 0.23-3.17, respectively) compared with offspring of mothers without hypertensive disorders of pregnancy, adjusting for potential confounders (age, sex, maternal age at delivery, household social class, prepregnancy body mass index, parity, and smoking in pregnancy). Results suggest a specific association between maternal hypertensive disorders of pregnancy and offspring blood pressure that may be driven by genetics or familial nongenetic risk factors particular to blood pressure.
    Hypertension 08/2013;
  • International Journal of Epidemiology 08/2013; 42(4):1022-6.
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    ABSTRACT: Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the United Kingdom. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and >2.5m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, p = 5.03 x 10(-10), and rs2769264, p = 2.63 x 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined p = 9.40 x 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, p = 6.40 x 10(-12); rs2120019, p = 1.55 x 10(-18); and rs4826508, p = 1.40 x 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing aminoacids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
    Human Molecular Genetics 05/2013;
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    ABSTRACT: OBJECTIVE: Pregnancy interventions to limit gestational weight gain (GWG) have been proposed as a means of preventing hypertensive disorders of pregnancy (HDP), however it is currently unclear whether GWG has a causal influence on the development of HDP. Thus, we aimed to determine whether GWG in early pregnancy is a risk factor for preeclampsia and gestational hypertension and whether GWG precedes increases in blood pressure in normotensive women across pregnancy. Study design: We examined repeat antenatal clinic measurements of weight and blood pressure (median of 12 and 14 per woman respectively) of 12,522 women in the Avon Longitudinal Study of Parents and Children. RESULTS: Greater pre-pregnancy weight was associated with increased risk of gestational hypertension and preeclampsia (odds ratios (95% confidence interval) per 10kg pre-pregnancy weight: 1.80 (1.70, 1.91) and 1.71 (1.49, 1.95) respectively for women weighing ≤90kg pre-pregnancy; 1.24 (1.03, 1.49) and 1.61 (1.18, 2.19) for women weighing >90kg). Fully-adjusted odds ratios for gestational hypertension and preeclampsia per 200g/week GWG up to 18 weeks were 1.26 (1.16, 1.38) and 1.31 (1.07, 1.62). In normotensive women, GWG in early pregnancy was associated positively with blood pressure change in mid-pregnancy, and negatively with blood pressure change in late pregnancy. In all gestational periods, GWG was positively associated with concurrent blood pressure change. However, there was no evidence that blood pressure changes in any period were associated with subsequent GWG. CONCLUSION: These findings suggest that GWG in early pregnancy may be a potential target for interventions aimed at reducing the risk of HDP.
    American journal of obstetrics and gynecology 05/2013;
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    ABSTRACT: Advances done in "-Omics" technologies in the last 20 years have made available to the researches huge amounts of data spanning a wide variety of biological processes from gene sequences to the metabolites present in a cell at a particular time. The management, analysis and representation of these data have been facilitated by mean of the advances made by biomedical informatics in areas such as data architecture and integration systems. However, despite the efforts done by biologists in this area, research in drug design adds a new level of information by incorporating data related with small molecules, which increases the complexity of these integration systems. Current knowledge in molecular biology has shown that it is possible to use comprehensive and integrative approaches to understand the biological processes from a systems perspective and thatnbsp; pathological processes can be mapped into biological networks. Therefore, current strategies for drug design are focusing on how to interact with or modify those networks to achieve the desired effects on what is called systems chemical biology. In this review several approaches for data integration in systems chemical biology will be analysed and described. Furthermore, because of the increasing relevance of the development and use of nanomaterials and their expected impact in the near future, the requirements of integration systems that incorporate these new data types associated with nanomaterials will also be analysed.
    Current topics in medicinal chemistry 03/2013;
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    ABSTRACT: AimsTo explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors.Methods and resultsWe used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (-4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [-2.0% (-2.1, -1.8)] was not present in the IV analyses [0.6% (-3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [-0.13 kg/m(2) (-0.16, -0.10)] and with triglycerides [-0.4% (-0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m(2) (0.59, 2.15)] and the strong inverse association with triglycerides [-14.9% (-25.6, -4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose.Conclusion Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.
    European Heart Journal 03/2013;
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