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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 A comparison of meta-aggregation and meta-ethnography as qualitative review methods(Lippincott Williams & Wilkins, 2013) Lockwood, C.; Pearson, A.Item Open Access A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample(Public Library of Science, 2011) Obeidat, M.; Wain, L.; Shrine, N.; Kalsheker, N.; Soler Artigas, M.; Repapi, E.; Burton, P.; Johnson, T.; Ramasamy, A.; Zhao, J.-H.; Zhai, G.; Huffman, J.; Vitart, V.; Albrecht, E.; Igl, W.; Hartikainen, A.-L.; Pouta, A.; Cadby, G.; Hui, J.; Palmer, L.; et al.; Semple, M.G.RATIONALE Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). OBJECTIVES To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. METHODS We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. RESULTS The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers. CONCLUSIONS Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.Item Open Access A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome(BioMed Central, 2013) Peters, K.; Beilby, J.; Cadby, G.; Warrington, N.; Bruce, D.; Davis, W.; Davis, T.; Wiltshire, S.; Knuiman, M.; McQuillan, B.; Palmer, L.; Thompson, P.; Hung, J.Background: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. Methods: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. Results: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). Conclusions: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.Item Metadata only A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance(Nature Publishing Group, 2012) Palmer, L.; Manning, A.K.; Hivert M-, F.; Scott, R.A.; Grimsby, J.L.; Bouatia-Naji, N.; Chen, H.; Rybin, D.; Liu C-, T.; Bielak, L.F.; Prokopenko, I.; Amin, N.; Barnes, D.; Cadby, G.; Hottenga J-, J.; Ingelsson, E.; Jackson, A.U.; Johnson, T.; Kanoni, S.; Ladenvall, C.; et al.Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.Item Metadata only A genome-wide association meta-analysis identifies new childhood obesity loci(Nature Publishing Group, 2012) Bradfield, J.; Taal, H.; Timpson, N.; Scherag, A.; Lecoeur, C.; Warrington, N.; Hypponen, E.; Holst, C.; Valcarcel, B.; Thiering, E.; Salem, R.; Schumacher, F.; Cousminer, D.; Sleiman, P.; Jianhua, Z.; Berkowitz, R.; Vimaleswaran, K.; Ivonne, J.; Pennell, C.; Evans, D.; et al.Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10−6 in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10−9; odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10−9; OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI.Item Open Access A genome-wide association search for type 2 diabetes genes in African Americans(Public Library of Science, 2012) Palmer, N.; McDonough, C.; Hicks, P.; Roh, B.; Wing, M.; Sandy An, S.; Hester, J.; Cooke, J.; Bostrom, M.; Rudock, M.; Talbert, M.; Lewis, J.; DIAGRAM Consortium,; MAGIC Consortium,; Ferrara, A.; Lu, L.; Ziegler, J.; Sale, M.; Divers, J.; Shriner, D.; et al.; Kronenberg, F.African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P,0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P,0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P,2.561028). SNP rs7560163 (P=7.061029, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P,0.05) and reached more nominal levels of significance (P,2.561025) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.Item Open Access A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling(Company of Biologists, 2022) Stables, J.; Green, E.K.; Sehgal, A.; Patkar, O.L.; Keshvari, S.; Taylor, I.; Ashcroft, M.E.; Grabert, K.; Wollscheid-Lengeling, E.; Szymkowiak, S.; McColl, B.W.; Adamson, A.; Humphreys, N.E.; Mueller, W.; Starobova, H.; Vetter, I.; Shabestari, S.K.; Blurton-Jones, M.M.; Summers, K.M.; Irvine, K.M.; et al.Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/− mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.Item 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 A Transgenic Line That Reports CSF1R Protein Expression Provides a Definitive Marker for the Mouse Mononuclear Phagocyte System(The American Association of Immunologists, 2020) Grabert, K.; Sehgal, A.; Irvine, K.M.; Wollscheid-Lengeling, E.; Ozdemir, D.D.; Stables, J.; Luke, G.A.; Ryan, M.D.; Adamson, A.; Humphreys, N.E.; Sandrock, C.J.; Rojo, R.; Verkasalo, V.A.; Mueller, W.; Hohenstein, P.; Pettit, A.R.; Pridans, C.; Hume, D.A.The proliferation, differentiation, and survival of cells of the mononuclear phagocyte system (MPS; progenitors, monocytes, macrophages, and classical dendritic cells) are controlled by signals from the M-CSF receptor (CSF1R). Cells of the MPS lineage have been identified using numerous surface markers and transgenic reporters, but none is both universal and lineage restricted. In this article, we report the development and characterization of a CSF1R reporter mouse. A FusionRed (FRed) cassette was inserted in-frame with the C terminus of CSF1R, separated by a T2A-cleavable linker. The insertion had no effect of CSF1R expression or function. CSF1R-FRed was expressed in monocytes and macrophages and absent from granulocytes and lymphocytes. In bone marrow, CSF1R-FRed was absent in lineage-negative hematopoietic stem cells, arguing against a direct role for CSF1R in myeloid lineage commitment. It was highly expressed in marrow monocytes and common myeloid progenitors but significantly lower in granulocyte-macrophage progenitors. In sections of bone marrow, CSF1R-FRed was also detected in osteoclasts, CD169+ resident macrophages, and, consistent with previous mRNA analysis, in megakaryocytes. In lymphoid tissues, CSF1R-FRed highlighted diverse MPS populations, including classical dendritic cells. Whole mount imaging of nonlymphoid tissues in mice with combined CSF1R-FRed/Csf1r-EGFP confirmed the restriction of CSF1R expression to MPS cells. The two markers highlight the remarkable abundance and regular distribution of tissue MPS cells, including novel macrophage populations within tendon and skeletal muscle and underlying the mesothelial/serosal/capsular surfaces of every major organ. The CSF1R-FRed mouse provides a novel reporter with exquisite specificity for cells of the MPS.Item Metadata only A vision for chronic disease prevention and intervention research: report from a workshop(Canadian Public Health Association, 2014) Ashbury, F.D.; Little, J.; Ioannidis, J.P.A.; Kreiger, N.; Palmer, L.J.; Relton, C.; Taylor, P.The Population Studies Research Network of Cancer Care Ontario hosted a strategic planning workshop to establish an agenda for a prevention intervention research program in Ontario, including priority topics for investigation and design considerations. The two-day workshop included: presentations on background papers developed to facilitate participants' preparation for and discussions in the workshop; keynote presentations on intervention research concerning primary prevention of chronic diseases, design and study implementation considerations; a dedicated session on critical and creative thinking to stimulate participation and discussion topics; breakout groups to identify, discuss and present study ideas, designs, implementation considerations; and a consensus process to discuss and identify recommendations for research priorities and next steps. The retreat yielded the following recommendations: 1) develop an intervention research agenda that includes working with existing large-scale cohorts; 2) develop an intervention research agenda that includes novel research designs that could target individuals or groups; and 3) develop an intervention research agenda in which studies collect data on costs, define stakeholders, and ensure clear strategies for stakeholder engagement and knowledge transfer. The Population Studies Research Network will develop options from these recommendations and release a call for proposals in 2014 for intervention research pilot projects that reflect these recommendations. Pilot projects will be evaluated based on their fit with the retreat's recommendations, and their potential to scale up to full studies and application in practice. = Le reseau de recherche " Etude de la population " d'Action Cancer Ontario a organise un atelier de planification strategique afin de fixer l'agenda d'un programme de recherche d'intervention sur la prevention en Ontario, y compris les themes prioritaires a aborder et les elements a considerer dans le plan d'etude. L'atelier de deux jours incluait : des presentations sur les documents de base elabores pour faciliter la preparation des participants et leurs discussions durant l'atelier; des allocutions sur la recherche d'intervention axee sur la prevention primaire des maladies chroniques, le plan d'etude et les elements a considerer dans la mise en oeuvre de l'etude; une seance consacree a la pensee critique et creatrice pour stimuler la participation et les sujets de discussion; la formation de petits groupes pour cerner, discuter et presenter des idees d'etude, des plans d'etude et des elements a considerer pour la mise en oeuvre; et un exercice de consensus pour discuter des priorites de recherche et de la suite des choses et formuler des recommandations. Ces journees de reflexion ont produit les recommandations suivantes : 1) elaborer un agenda pour la recherche d'intervention incluant l'utilisation des cohortes a grande echelle existantes; 2) elaborer un agenda pour la recherche d'intervention incluant des plans de recherche novateurs qui pourraient cibler des particuliers ou des groupes; et 3) elaborer un agenda pour la recherche d'intervention avec des etudes pour recueillir des donnees sur les couts, identifier les acteurs du milieu et presenter des strategies claires pour la mobilisation des acteurs et le transfert des connaissances. Le reseau de recherche " Etude de la population " formulera des options a partir de ces recommandations et lancera un appel de propositions en 2014 pour des projets-pilotes de recherche d'intervention qui refletent ces recommandations. Les projets-pilotes seront evalues selon leur degre de correspondance avec les recommandations de l'atelier, leur potentiel de transformation en etudes completes et leurs possibilites de mise en pratique.Item Open Access Action research in radiography: what it is and how it can be conducted(Wiley, 2013) Munn, Z.; Pearson, A.; Jordan, Z.; Murphy, F.; Pilkington, D.Action research is a form of research that investigates and describes a social or work situation with the aim of achieving a change which results in improvement. This article emphasizes the potential for action research to be a useful research method in radiography. A search was conducted to determine the extent to which action research has been utilized in radiography. Although action research has been used in a number of health-care settings, there are no published examples of action research being utilized in a clinical medical imaging department. Action research is discussed in detail, along with an example guide for an action research study. Action research has been identified as a useful way to affect change, to involve radiographers in the research process, and to introduce evidence-based practice to radiography.Item Metadata only Adherence to recommended Australian sexually transmitted infections screening guidelines among asymptomatic men who have sex with men: a best practice implementation project(The Joanna Briggs Institute, 2014) Baynes, A.; McArthur, A.Background: Within Australia, men who have sex with men are disproportionally affected by sexually transmissible infections and human immunodeficiency virus. Evidence suggests that early diagnosis of these infections allows for prompt treatment options, slower disease progression and opportunities for early contact tracing to decrease onwards transmission. Updated 2014 guidelines have some key changes to support early diagnosis. Objectives: The goal of this project was to assess the level of staff compliance with evidence-based criteria, recommended in the Australian Sexually Transmitted Infection and HIV Testing Guidelines 2014, for asymptomatic men who have sex with men attending Canberra Sexual Health Centre, and implement strategies to improve compliance if necessary. Methods: The Joanna Briggs Institute three-phase Practical Application of Clinical Evidence System audit and feedback tool for promoting evidence utilization and change in health care was used. In phase one a project team was established, and 18 evidence based audit criteria were developed. A baseline audit was then conducted. In phase two, barriers underpinning non-compliance were identified and strategies to improve these were identified and implemented. In phase three, a follow up audit was conducted. Results: At baseline, compliance with eight of the audit criteria was high, two were moderate and eight were low. Following implementation of selected strategies, compliance rates increased for all audit criteria except one, which was anticipated. Conclusions: The project demonstrated positive outcomes from the baseline to follow-up audit, with overall improvements in compliance.Item Metadata only Adult cancer survivors' experiences of health care interactions and unmet needs in health care services: a systematic review protocol(The Joanna Briggs Institute, 2014) Hallett, P.; Pearson, A.; Stephenson, M.Review question/objective The aim of this review is to synthesize the best available evidence of adult cancer survivors' experiences interacting with health care practitioners and the health care system and the unmet needs they identify in the provision of services in the healthcare system. Inclusion criteria Types of participants This review will consider studies that include adult survivors (18 years and older) of solid tumors, excluding lymphoma, who are under 60 years of age at time of initial diagnosis. A cancer survivor will be defined as an individual who has concluded primary treatment and may be in remission or cured, but does not have active advanced disease/ metastatic disease or is undertaking palliative treatment. Phenomena of interest This review will consider studies that investigate the experience of cancer survivors, their interactions with the healthcare system and healthcare practitioners, and the unmet needs they experience in the healthcare system over the course of their survivor-ship. The health care system will include health care practitioners within medicine, nursing, allied health and complimentary therapies but will exclude alternative therapies. Context This review will consider studies occurring in any country.Item Open Access An integrated systems biology approach to the study of preterm birth using "-omic" technology - a guideline for research(BioMed Central, 2011) Gracie, S.; Pennell, C.; Ekman-Ordeberg, G.; Lye, S.; McManaman, J.; Williams, S.; Palmer, L.; Kelley, M.; Menon, R.; Gravett, M.Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated “-omics” technologies. The issues to be addressed include: (1) integrated “-omics” approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the “-Omics” Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009.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 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 Antidepressant medication and spontaneous abortion: "No significant association"? clinically significant association!(American Medical Association, 2013) Tufanaru, C.; Jureidini, J.Item Metadata only Apolipoprotein E genotype is associated with serum C-reactive protein but not abdominal aortic aneurysm(Elsevier Ireland, 2010) Golledge, J.; Biros, E.; Cooper, M.; Warrington, N.; Palmer, L.; Norman, P.Abstract not availableItem Metadata only Approaches to evaluate gene-environment interactions underlying the developmental origins of health and disease(S. Karger AG, 2009) Pennell Dr, C.; Palmer, L.; Knight, B.; Relton, C.; Lye, S.; Newnham, J.; Ross, M.Research studies have established a clear relationship between antenatal and postnatal environments and the development of adult diseases including the metabolic syndrome (coronary heart disease, stroke, insulin resistance, type 2 diabetes and dyslipidemia), obesity, neurologic disorders and mental illness [1]. These observations have been confirmed in multiple human populations and in numerous animal studies in multiple species. It is clear that the environment of mother, baby and child is a key contributor to diseases and conditions that account for approximately one third of the global burden of disease in both developed and developing countries. Although adverse antenatal and postnatal environments increase the risk of particular adult diseases, not all individuals exposed to these environments develop these conditions, suggesting that an individual’s genotype may contribute to the eventual outcome. Therefore, it has been suggested that gene-environment interactions underlie the developmental origins of health and disease (DOHaD).