GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors

Serum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discover genetic variants affecting BCHE activity, and to clarify whether the associations between BCHE activity and cardiometabolic risk factors are caused by variation in BCHE or whether BCHE variation is secondary to the metabolic abnormalities. We measured serum BCHE in adolescents and adults from three cohorts of Australian twin and family studies. The genotypes from approximately 2.4 million single-nucleotide polymorphisms (SNPs) were available in 8791 participants with BCHE measurements. We detected significant associations with BCHE activity at three independent groups of SNPs at the BCHE locus (P = 5.8 x 10(-262), 7.8 x 10(-47), 2.9 x 10(-12)) and at four other loci: RNPEP (P = 9.4 x 10(-16)), RAPH1-ABI2 (P = 4.1 x 10(-18)), UGT1A1 (P = 4.0 x 10(-8)) and an intergenic region on chromosome 8 (P = 1.4 x 10(-8)). These loci affecting BCHE activity were not associated with metabolic risk factors. On the other hand, SNPs in genes previously associated with metabolic risk had effects on BCHE activity more often than can be explained by chance. In particular, SNPs within FTO and GCKR were associated with BCHE activity, but their effects were partly mediated by body mass index and triglycerides, respectively. We conclude that variation in BCHE activity is due to multiple variants across the spectrum from uncommon/large effect to common/small effect, and partly results from (rather than causes) metabolic abnormalities.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Ambient temperature and risk of cardiovascular hospitalization: An updated systematic review and meta-analysis

The association between temperatures and risk of cardiovascular mortality has been recognized but the association drawn from previous meta-analysis was weak due to the lack of sufficient studies. This paper presented a review with updated reports in the literature about the risk of cardiovascular hospitalization in relation to different temperature exposures and examined the dose–response relationship of temperature-cardiovascular hospitalization by change in units of temperature, latitudes, and lag days. The pooled effect sizes were calculated for cold, heat, heatwave, and diurnal variation using random-effects meta-analysis, and the dose–response relationship of temperature-cardiovascular admission was modelled using random-effect meta-regression. The Cochrane Q-test and index of heterogeneity (I2) were used to evaluate heterogeneity, and Egger's test was used to evaluate publication bias. Sixty-four studies were included in meta-analysis. The pooled results suggest that for a change in temperature condition, the risk of cardiovascular hospitalization increased 2.8% (RR, 1.028; 95% CI, 1.021–1.035) for cold exposure, 2.2% (RR, 1.022; 95% CI, 1.006–1.039) for heatwave exposure, and 0.7% (RR, 1.007; 95% CI, 1.002–1.012) for an increase in diurnal temperature. However no association was observed for heat exposure. The significant dose–response relationship of temperature — cardiovascular admission was found with cold exposure and diurnal temperature. Increase in one-day lag caused a marginal reduction in risk of cardiovascular hospitalizations for cold exposure and diurnal variation, and increase in latitude was associated with a decrease in risk of cardiovascular hospitalizations for diurnal temperature only. There is a significant short-term effect of cold exposure, heatwave and diurnal variation on cardiovascular hospitalizations. Further research is needed to understand the temperature-cardiovascular relationship for different climate areas.

Prediction of individual genetic risk to prostate cancer using a polygenic score

BACKGROUND Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction. Prostate 75:1467–1474, 2015. © 2015 Wiley Periodicals, Inc.

Protocol for assessing maternal, environmental and epigenetic risk factors for dental caries in children

Background Expenditure on dental and oral health services in Australia is $3.4 billion AUD annually. This is the sixth highest health cost and accounts for 7 % of total national health expenditure. Approximately 49 % of Australian children aged 6 years have caries experience in their deciduous teeth and this is rising. The aetiology of dental caries involves a complex interplay of individual, behavioural, social, economic, political and environmental conditions, and there is increasing interest in genetic predisposition and epigenetic modification. Methods The Oral Health Sub-study; a cross sectional study of a birth cohort began in November 2012 by examining mothers and their children who were six years old by the time of initiation of the study, which is ongoing. Data from detailed questionnaires of families from birth onwards and data on mothers’ knowledge, attitudes and practices towards oral health collected at the time of clinical examination are used. Subjects’ height, weight and mid-waist circumference are taken and Body Mass Index (BMI) computed, using an electronic Bio-Impedance balance. Dental caries experience is scored using the International Caries Detection and Assessment System (ICDAS). Saliva is collected for physiological measures. Salivary Deoxyribose Nucleic Acid (DNA) is extracted for genetic studies including epigenetics using the SeqCap Epi Enrichment Kit. Targets of interest are being confirmed by pyrosequencing to identify potential epigenetic markers of caries risk. Discussion This study will examine a wide range of potential determinants for childhood dental caries and evaluate inter-relationships amongst them. The findings will provide an evidence base to plan and implement improved preventive strategies.

Human health risk assessment of heavy metals in urban stormwater

Toxic chemical pollutants such as heavy metals (HMs) are commonly present in urban stormwater. These pollutants can pose a significant risk to human health and hence a significant barrier for urban stormwater reuse. The primary aim of this study was to develop an approach for quantitatively assessing the risk to human health due to the presence of HMs in stormwater. This approach will lead to informed decision making in relation to risk management of urban stormwater reuse, enabling efficient implementation of appropriate treatment strategies. In this study, risks to human health from heavy metals were assessed as hazard index (HI) and quantified as a function of traffic and land use related parameters. Traffic and land use are the primary factors influencing heavy metal loads in the urban environment. The risks posed by heavy metals associated with total solids and fine solids (<150µm) were considered to represent the maximum and minimum risk levels, respectively. The study outcomes confirmed that Cr, Mn and Pb pose the highest risks, although these elements are generally present in low concentrations. The study also found that even though the presence of a single heavy metal does not pose a significant risk, the presence of multiple heavy metals could be detrimental to human health. These findings suggest that stormwater guidelines should consider the combined risk from multiple heavy metals rather than the threshold concentration of an individual species. Furthermore, it was found that risk to human health from heavy metals in stormwater is significantly influenced by traffic volume and the risk associated with stormwater from industrial areas is generally higher than that from commercial and residential areas.

Long-term effects of physical activity level on changes in healthy body mass index over 12 years in young adult women

Objectives To examine the effects of overall level and timing of physical activity (PA) on changes from a healthy body mass index (BMI) category over 12 years in young adult women. Patients and Methods Participants in the Australian Longitudinal Study on Women's Health (younger cohort, born 1973-1978) completed surveys between 2000 (age 22-27 years) and 2012 (age 34-39 years). Physical activity was measured in 2000, 2003, 2006, and 2009 and was categorized as very low, low, active, or very active at each survey, and a cumulative PA score for this 9-year period was created. Logistic regression was used to examine relationships between PA accumulated across all surveys (cumulative PA model) and PA at each survey (critical periods PA model), with change in BMI category (from healthy to overweight or healthy to obese) from 2000 to 2012. Results In women with a healthy BMI in 2000, there were clear dose-response relationships between accumulated PA and transition to overweight (P=.03) and obesity (P<.01) between 2000 and 2012. The critical periods analysis indicated that very active levels of PA at the 2006 survey (when the women were 28-33 years old) and active or very active PA at the 2009 survey (age 31-36 years) were most protective against transitioning to overweight and obesity. Conclusion These findings confirm that maintenance of very high PA levels throughout young adulthood will significantly reduce the risk of becoming overweight or obese. There seems to be a critical period for maintaining high levels of activity at the life stage when many women face competing demands of caring for infants and young children.