School of Translational Health Science
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Item Metadata only The transforming growth factor-β1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD)(Oxford University Press (OUP), 2004) Celedón, J.C.; Lange, C.; Raby, B.A.; Litonjua, A.A.; Palmer, L.J.; DeMeo, D.L.; Reilly, J.J.; Kwiatkowski, D.J.; Chapman, H.A.; Laird, N.; Sylvia, J.S.; Hernandez, M.; Speizer, F.E.; Weiss, S.T.; Silverman, E.K.Although cigarette smoking is the primary environmental risk factor, genetic risk factors likely influence the development of chronic obstructive pulmonary disease (COPD). Linkage analysis between short-tandem repeat markers on chromosome 19 and COPD phenotypes was followed by association analysis of single nucleotide polymorphisms in a gene on chromosome 19q [transforming growth factor-beta1 (TGFB1)] and COPD phenotypes in a family-based sample and a case-control study (cases with severe COPD and control subjects with significant history of smoking but no COPD). Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the Boston Early-Onset COPD Study, there was significant evidence of linkage between chromosome 19q and pre-bronchodilator (pre-BD) FEV(1) (LOD=3.30) and suggestive evidence of linkage between chromosome 19q and other COPD phenotypes. In these families, a SNP in the promoter region of TGFB1 (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957) were significantly associated with pre- and post-BD FEV(1) (P<0.05). Among smokers in the COPD cases and control subjects, two SNPs in the promoter region of TGFB1 (rs2241712 and rs1800469) and one SNP in exon 1 of TGFB1 (rs1982073) were significantly associated with COPD (PItem Metadata only Spontaneous ventilation pneumothorax(Australian Society of Anaesthetists, 2008) Runciman, W.B.; Hibbert, P.D.Item Metadata only Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomization(Kluwer Academic Publ, 2008) CRP CHD Genetics Collaboration,; Danesh, J.; Hingorani, A.; Wensley, F.; Casas, J.; Smeeth, L.Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known to be associated with circulating concentrations, thereby utilising these variants as proxies for circulating CRP levels. By analysing data from several studies examining the association between relevant CRP polymorphisms and CHD risk, the present collaboration will undertake a Mendelian randomisation analysis to help assess the likelihood of any causal relevance of CRP levels to CHD risk. A central database is being established containing individual data on CRP polymorphisms, circulating CRP levels, and major coronary outcomes as well as age, sex and other relevant characteristics. Associations between CRP polymorphisms or haplotypes and CHD will be evaluated under different circumstances. This collaboration comprises, at present, about 37,000 CHD outcomes and about 120,000 controls, which should yield suitably precise findings to help judge causality. This work should advance understanding of the relevance of low-grade inflammation to CHD and indicate whether or not CRP itself is involved in long-term pathogenesis.Item Metadata only Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population(Springer-Verlag, 2008) Carter, K.; Hung, J.; Powell, B.; Wiltshire, S.; Foo, B.; Leow, Y.; McQuillan, B.; Jennens, M.; McCaskie, P.; Thompson, P.; Beilby, J.; Palmer, L.The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) in the Interleukin-1 (IL-1) gene family are associated with central obesity and metabolic syndrome in a coronary heart disease population. The IL-1α C-889T (rs1800587) and IL-1β +3954 (rs1143634) SNPs were studied in a Western Australian coronary heart disease (CHD) population (N = 556). Subjects who were TT homozygous at either SNP had larger waist circumference (IL-1α: 1.8 cm greater, P = 0.04; IL-1β: 4 cm greater, P = 0.0004) compared with major allele homozygotes. Individuals with two copies of the IL-1α:IL-1β T:T haplotype had greater waist circumference (4.7 cm greater, P = 0.0001) compared to other haplotypes. There was a significant interaction between the IL-1β SNP and BMI level on waist circumference (P = 0.01). When the cohort was stratified by median BMI, TT carriers for IL-1β with above median BMI had greater waist circumference (6.1 cm greater, P = 0.007) compared to baseline carriers, whilst no significant association was seen in the below median group. Similarly, when the cohort was stratified by median fibrinogen level (IL-1α interaction P = 0.01; IL-1β interaction P = 0.04), TT carriers for both SNPs in the above median fibrinogen group had greater waist circumference (IL-1α 2.7 cm greater, P = 0.007; IL-1β 3.3 cm greater, P = 0.003) compared with major allele homozygotes. This association was not seen in the below median group. Also, we found a trend of increased metabolic syndrome for IL-1β TT homozygotes (P = 0.07). In conclusion, our findings suggest that in a CHD population IL-1 gene polymorphisms may be involved in increased central obesity, and the genetic influences are more evident among patients who have a higher level of obesity or inflammatory markers.Item Metadata only Investigating the association between K198N coding polymorphism in EDN1 and hypertension, lipoprotein levels, the metabolic syndrome and cardiovascular disease(Springer-Verlag, 2008) Wiltshire, S.; Powell, B.; Jennens, M.; McCaskie, P.; Carter, K.; Palmer, L.; Thompson, P.; McQuillan, B.; Hung, J.; Beilby, J.Endothelin-1 is a potent vasoconstrictor in the body. Previous studies have identified associations between the coding polymorphism K198N and hypertension, systolic blood pressure and HDL levels. We sought to examine the evidence for these associations and, additionally, the association between K198N, insulin resistance, metabolic syndrome and coronary artery disease (CAD). We used generalised linear modelling to test K198N for association with hypertension and systolic blood pressure, lipid levels, insulin resistance scores and metabolic syndrome in a general cross-sectional community sample. Mean carotid intima media thickness and risk of carotid plaque were examined in the general population sample, and Gensini score was examined in a sample of patients with CAD. A case/control sample was used to examine the association of K198N with risk of CAD. There was no significant evidence for association between K198N and hypertension, systolic blood pressure, lipid levels, insulin resistance or metabolic syndrome in either population. The minor allele was marginally associated with increased mean IMT levels (P = 0.02) in the general population sample, although not with CAD in the case/control study or with the severity of disease in patients with CAD. In conclusion, we found no robust evidence for the associations between K198N and hypertension, systolic blood pressure or HDL levels seen in previous studies.Item Metadata only 15-lipoxygenase gene variants are associated with carotid plaque but not carotid intima-media thickness(Springer-Verlag, 2008) McCaskie, P.; Beilby, J.; Hung, J.; Chapman, C.; McQuillan, B.; Powell, B.; Thompson, P.; Palmer, L.The major underlying cause of CHD is atherosclerosis, and oxidised LDL is known to play an important role in its development. We examined the role of three single nucleotide polymorphisms (SNPs) in the 15-lipoxygenase gene (ALOX15), in atherosclerosis. We genotyped three SNPs in the ALOX15 promoter in two Western Australian samples—1,111 community-based individuals and 556 with CHD. SNPs and haplotypes were tested for an association with carotid plaque, intima-media thickness and risk of CHD. The −611GG genotype was associated with increased likelihood of carotid plaque in CHD patients (OR = 4.01, 95%CI = 1.39–11.53, P = 0.005) and the C alleles of the G-220C and G-189C SNPs were associated with decreased likelihood of plaque among cases (OR = 0.66, 95%CI = 0.43–0.99, P = 0.05 and OR = 0.51, 95%CI = 0.34–0.78, P = 0.002 respectively). The GGG haplotype was associated with increased risk of carotid plaque in CHD patients (OR = 5.77, 95%CI = 1.82–18.29, P = 0.0007) and in community-based individuals under 53 years (OR = 4.15, 95%CI = 1.23–14.08, P = 0.02). No association was observed between ALOX15 SNPs or haplotypes and intima-media thickness. This study is novel as it is the first to examine the association between 15-lipoxygenase polymorphisms and atherosclerotic indicators. These findings suggest a possible role of ALOX15 polymorphisms in focal plaque formation.Item Metadata only The apolipoprotein AII rs5082 variant is associated with reduced risk of coronary artery disease in an Australian male population(Elsevier Ireland, 2008) Xiao, J.; Zhang, F.; Wiltshire, S.; Hung, J.; Jennens, M.; Beilby, J.; Thompson, P.; McQuillan, B.; McCaskie, P.; Carter, K.; Palmer, L.; Powell, B.Abstract not availableItem Metadata only Polymorphisms of the interleukin-6 gene promoter and abdominal aortic aneurysm(Elsevier, 2008) Smallwood, L.; Allcock, R.; van Bockxmeer, F.; Warrington, N.; Palmer, L.; Iacopetta, B.; Norman, P.Abstract not availableItem Metadata only Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes(Wiley-Liss, 2008) Peters, K.; Wiltshire, S.; Henders, A.; Dragovic, M.; Badcock, J.; Chandler, D.; Howell, S.; Ellis, C.; Bouwer, S.; Montgomery, G.; Palmer, L.; Kalaydjieva, L.; Jablensky, A.Abstract not availableItem Metadata only Angiotensinogen gene T235 variant: a marker for the development of persistent microalbuminuria in children and adolescents with type 1 diabetes mellitus(Elsevier, 2008) Gallego, P.; Shephard, N.; Bulsara, M.; van Bockxmeer, F.; Powell, B.; Beilby, J.; Arscott, G.; Le Page, M.; Palmer, L.; Davis, E.; Jones, T.; Choong, C.Abstract not availableItem Metadata only Celestial3D: a novel method for 3D visualization of familial data(Oxford University Press, 2008) Loh, A.; Wiltshire, S.; Emery, J.; Carter, K.; Palmer, L.Traditional two-dimensional (2D) software programs for drawing pedigrees are limited when dealing with extended pedigrees. In successive generations, the number of individuals grows exponentially, leading to an unworkable amount of space required in the horizontal direction for 2D displays. In addition, it is not always possible to place closely related individuals near each other due to the lack of space in 2Ds. To address these issues we have developed three-dimensional (3D) pedigree drawing techniques to enable clearer visualization of extended pedigrees. Currently no other methods are available for displaying extended pedigrees in 3Ds. We have made freely available a software tool—‘Celestial3D’—that implements these novel techniques.Item Metadata only Bile acids modulate store-operated CA2+ channels and stromal interaction molecule1 (STIM1) distribution in liver cells(Elsevier Science, 2008) Aromataris, E.C.; Castro, J.; Rychkov, G.Y.; Barritt, G.J.; 43rd Annual Meeting of the European Association for the Study of the Liver (23 Apr 2008 - 27 Apr 2008 : Milan, Italy)Item Metadata only The epistemology of patient safety research(Blackwell Publishing, 2008) Runciman, W.B.; Ross Baker, G.; Michel, P.; Jauregui, I.L.; Lilford, R.J.; Andermann, A.; Flin, R.; Weeks, W.B.Patient safety has only recently been subjected to wide-spread systematic study. Healthcare differs from other high risk industries in being more diverse and multi-contextual, and less certain and regulated. Also many patient safety problems are low-frequency events associated with many, varied contributing factors. The subject of this paper is the epistemology of patient safety (the science of the method of finding out about patient safety). Patient safety research is considered here on the background of a risk management framework which requires researchers to: • Understand the context - as a subset of healthcare quality, services and systems research, with technical and human behavioural (cultural) components and a range of external and internal organisational influences, a wide range of research disciplines is necessary • Identify the risks - identify the things that go wrong and the frequency and nature of different types of incidents from sources such as medical record review, observational studies, audit, incident and medico-legal reports • Analyse the risks - deconstruct the things that go wrong, identifying contributing factors and trying to detect trends and patterns in contributing factors, detection, mitigation factors, ameliorating factors and actions taken to reduce risk • Evaluate the risks - decide on priorities, identifying preventive and corrective strategies and judging the risk- and cost-benefit of potential corrective strategies such as standardisation or simplification of a process or device • Manage the risk - evaluate and scope preventive and/or corrective strategies and then implement these, or place the problem on a risk register pending solution, or accept that what is needed is unaffordable • Communicate and consult - use interactive sessions, audit, on-going feedback, reminders and patient mediated prompts • Monitor and review the state of the problem - get baseline trends and patterns so that changes can be tracked and properly attributed to an intervention A hierarchy of levels of evidence has been proposed for clinical research and we argue that insufficient weighting has been given to lower ranked levels of research and to qualitative research, although critical interpretive synthesis is now gaining acceptance in mainstream thinking (e.g. by the Cochrane Collaboration). Fundamental challenges remain including how to grasp the elusive concept of patient safety, how to quantify, characterise and cost the problems, how to judge the extent to which harm can be attributed to errors, violations or system failures, how to identify contributing factors and the extent to which they can be implicated, how to judge whether incidents or their precursors are preventable, how to generate strong evidence to make healthcare safer and how to translate research into practice. Future directions include addressing the mundane as well as rare, dramatic events, and developing further research in non-hospital settings and in developing countries. In summary, a mixture of qualitative and quantitative methods, using information from all available data sources and combining retrospective, real time and prospective study designs, is necessary to address some of the more difficult patient safety problems.Item Open Access SimHap GUI: an intuitive graphical user interface for genetic association analysis(BioMed Central, 2008) Carter, K.; McCaskie, P.; Palmer, L.Background: Researchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the SimHap package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool. Results: We have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the SimHap R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress. Conclusion: SimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.Item Metadata only Sequence variants in three loci influence monocyte counts and erythrocyte volume(Elsevier, 2009) Ferreira, M.; Hottenga, J.; Warrington, N.; Medland, S.; Willemsen, G.; Lawrence, R.; Gordon, S.; de Geus, E.; Henders, A.; Smit, J.; Campbell, M.; Wallace, L.; Evans, D.; Wright, M.; Nyholt, D.; James, A.; Beilby, J.; Penninx, B.; Palmer, L.; Frazer, I.; et al.Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p = 8.9 × 10−14). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p = 1.2 × 10−9, 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p = 5.3 × 10−9, 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values = 0.001, 9.9 × 10−5, and 7 × 10−5, respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.Item Metadata only Analyses of associations with asthma in four asthma population samples from Canada and Australia(Springer, 2009) Daly, D.; Lemire, M.; Akhabir, L.; Chan-Yeung, M.; He, J.; McDonald, T.; Stanford, A.; Stefanowicz, D.; Tripp, B.; Zamar, D.; Bosse, Y.; Ferretti, V.; Montpetit, A.; Tessier, M.; Becker, A.; Kozyrskyj, A.; Beilby, J.; McCaskie, P.; Musk, A.; Warrington, N.; et al.Asthma, atopy, and related phenotypes are heterogeneous complex traits, with both genetic and environmental risk factors. Extensive research has been conducted and over hundred genes have been associated with asthma and atopy phenotypes, but many of these findings have failed to replicate in subsequent studies. To separate true associations from false positives, candidate genes need to be examined in large well-characterized samples, using standardized designs (genotyping, phenotyping and analysis). In an attempt to replicate previous associations we amalgamated the power and resources of four studies and genotyped 5,565 individuals to conduct a genetic association study of 93 previously associated candidate genes for asthma and related phenotypes using the same set of 861 single-nucleotide polymorphisms (SNPs), a common genotyping platform, and relatively harmonized phenotypes. We tested for association between SNPs and the dichotomous outcomes of asthma, atopy, atopic asthma, and airway hyperresponsiveness using a general allelic likelihood ratio test. No SNP in any gene reached significance levels that survived correction for all tested SNPs, phenotypes, and genes. Even after relaxing the usual stringent multiple testing corrections by performing a gene-based analysis (one gene at a time as if no other genes were typed) and by stratifying SNPs based on their prior evidence of association, no genes gave strong evidence of replication. There was weak evidence to implicate the following: IL13, IFNGR2, EDN1, and VDR in asthma; IL18, TBXA2R, IFNGR2, and VDR in atopy; TLR9, TBXA2R, VDR, NOD2, and STAT6 in airway hyperresponsiveness; TLR10, IFNGR2, STAT6, VDR, and NPSR1 in atopic asthma. Additionally we found an excess of SNPs with small effect sizes (OR < 1.4). The low rate of replication may be due to small effect size, differences in phenotypic definition, differential environmental effects, and/or genetic heterogeneity. To aid in future replication studies of asthma genes a comprehensive database was compiled and is available to the scientific community at http://genapha.icapture.ubc.ca/.Item Metadata only Matrix metalloproteinase-2 gene variants and abdominal aortic aneurysm(Elsevier, 2009) Smallwood, L.; Warrington, N.; Allcock, R.; van Bockxmeer, F.; Palmer, L.; Iacopetta, B.; Golledge, J.; Norman, P.Abstract not availableItem Metadata only A single-nucleotide polymorphism in the gene encoding osteoprotegerin is associated with diastolic blood pressure in older men(Nature Publishing Group, 2009) Golledge, J.; Biros, E.; Clancy, P.; Cooper, M.; Palmer, L.; Norman, P.Background
Osteoprotegerin (OPG) has been associated with cardiovascular events but currently the mechanisms underlying this association are unknown. OPG is thought to play a role in controlling artery calcification and small studies have suggested that it may influence artery structure. We examined the association between single nucleotide polymorphisms (SNPs) in the gene encoding OPG (tumor necrosis factor receptor superfamily, member 11b, TNFRSF11B), with blood pressure in a large cohort of elderly men.Methods
21 tagging SNPs in the region encoded by TNFRSF11B were examined in 1,071 men recruited in a population-based study of elderly men. Genotyping was carried out using the Illumina Golden Gate assay. SNPs were investigated for their association with resting systolic and diastolic blood pressure after adjusting for other variables using linear regression. The association of SNPs in the region encoded by TNFRSF11B with plasma OPG was assessed in a random subset of 467 men.Results
One SNP, rs11573901, was significantly associated with diastolic blood pressure, after adjusting for other risk factors and multiple testing (coefficient -4.36, P = 0.001). Men with the TC genotype had lower diastolic blood pressure than those with the common cc variation. this snp was not associated with plasma opg in the 467 men in which this was examined.Conclusions
This study suggests that a SNP within the region encoded by TNFRSF11B, which is believed to code for OPG, is associated with blood pressure. The mechanism underlying this observed association is currently unclear.Item Metadata only Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction(Nature Publishing Group, 2009) Gudbjartsson, D.; Bjornsdottir, U.; Halapi, E.; Helgadottir, A.; Sulem, P.; Jonsdottir, G.; Thorleifsson, G.; Helgadottir, H.; Steinthorsdottir, V.; Stefansson, H.; Williams, C.; Hui, J.; Beilby, J.; Warrington, N.; James, A.; Palmer, L.; Koppelman, G.; Heinzmann, A.; Krueger, M.; Boezen, H.; et al.Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10-14, 5.4 x 10-10, 8.6 x 10-17, 1.2 x 10-10 and 6.5 x 10-19, respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10-12) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10-6, 2.2 x 10-5 and 2.4 x 10-4, respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10-8) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).Item Metadata only The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits(Springer, 2009) Webster, R.; Warrington, N.; Weedon, M.; Hattersley, A.; McCaskie, P.; Beilby, J.; Palmer, L.; Frayling, T.AIMS/HYPOTHESIS Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. METHODS The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007). CONCLUSIONS/INTERPRETATION The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.