Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only ~45% of FJHN probands, indicating the involvement of other genetic loci in ~55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a ~5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a ~5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10-10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10-9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10-14, OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10-14, OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. © 2011 Nature America, Inc. All rights reserved.

A genome-wide asociation study identifies new psoriasis susceptibility loci and an interaction betwEn HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertOk a genome-wide asociation study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified asociations at eight previously unreported genomic loci. Seven loci harbored genes with recognized iMune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These asociations were replicated in 9,079 European samples (six loci with a combined P < 5-10 -8 and two loci with a combined P < 5-10-7). We also report compeLing evidence for an interaction betwEn the HLA-C and ERAP1 loci (combined P = 6.95-10-6). ERAP1 plays an important role in MHC claS I peptide proceSing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk aLele. Our findings implicate pathways that integrate epidermal barrier dysfunction with iNate and adaptive iMune dysregulation in psoriasis pathogenesis.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P 10 800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10 19) and 21q22 (rs2242944; P = 8.3 × 10 20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10 8) and IL1R2 (rs2310173; P = 4.8 × 10 7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10 14) and ERAP1 (rs27434; P = 5.3 × 10 12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility. © 2010 Nature America, Inc. All rights reserved.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P 1 × 10 5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10 17), 16q22 (CDH1 and CDH3; P = 2.8 × 10 8) and 7q31 (LAMB1; P = 3.0 × 10 8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis. © 2009 Nature America, Inc. All rights reserved.

Genome-wide association studies and musculoskeletal diseases

Bone and joint diseases are major causes of morbidity and mortality worldwide, and their prevalence is increasing as the average population age increases. Most common musculoskeletal diseases show significant heritability, and few have treatments that prevent disease or can induce true treatment-free, disease-free remission. Furthermore, despite valiant efforts of hypothesis-driven research, our understanding of the etiopathogenesis of these conditions is, with few exceptions, at best moderate. Therefore, there has been a long-standing interest in genetics research in musculoskeletal disease as a hypothesis-free method for investigating disease etiopathogenesis. Important contributions have been made through the identification of monogenic causes of disease, but the holy grail of human genetics research has been the identification of the genes responsible for common diseases. The development of genome-wide association (GWA) studies has revolutionized this field, and led to an explosion in the number of genes identified that are definitely involved in musculoskeletal disease pathogenesis. However, this approach will not identify all common disease genes, and although the current progress is exciting and proves the potential of this research discipline, other approaches will be required to identify many of the types of genetic variation likely to be involved.

Base material characterisation of spoil piles at BMA coal mines

This project was an initiation to investigate slaking induced properties detrition of spoil pile materials with overburden pressure and time. The changes in the material properties over time are important parameters that control the behaviour and performance of the piles. The time dependent mechanical and hydraulic properties reported together with mineralogical changes. One chamber designed to apply slaking in the laboratory and geotechnical investigation conducted to fulfil the objective of this project.

Breastmilk-saliva interactions boost innate immunity by regulating the oral microbiome in early infancy

Introduction Xanthine oxidase (XO) is distributed in mammals largely in the liver and small intestine, but also is highly active in milk where it generates hydrogen peroxide (H2O2). Adult human saliva is low in hypoxanthine and xanthine, the substrates of XO, and high in the lactoperoxidase substrate thiocyanate, but saliva of neonates has not been examined. Results Median concentrations of hypoxanthine and xanthine in neonatal saliva (27 and 19 μM respectively) were ten-fold higher than in adult saliva (2.1 and 1.7 μM). Fresh breastmilk contained 27.3±12.2 μM H2O2 but mixing baby saliva with breastmilk additionally generated >40 μM H2O2, sufficient to inhibit growth of the opportunistic pathogens Staphylococcus aureus and Salmonella spp. Oral peroxidase activity in neonatal saliva was variable but low (median 7 U/L, range 2–449) compared to adults (620 U/L, 48–1348), while peroxidase substrate thiocyanate in neonatal saliva was surprisingly high. Baby but not adult saliva also contained nucleosides and nucleobases that encouraged growth of the commensal bacteria Lactobacillus, but inhibited opportunistic pathogens; these nucleosides/bases may also promote growth of immature gut cells. Transition from neonatal to adult saliva pattern occurred during the weaning period. A survey of saliva from domesticated mammals revealed wide variation in nucleoside/base patterns. Discussion and Conclusion During breast-feeding, baby saliva reacts with breastmilk to produce reactive oxygen species, while simultaneously providing growth-promoting nucleotide precursors. Milk thus plays more than a simply nutritional role in mammals, interacting with infant saliva to produce a potent combination of stimulatory and inhibitory metabolites that regulate early oral–and hence gut–microbiota. Consequently, milk-saliva mixing appears to represent unique biochemical synergism which boosts early innate immunity.

Podcast: Community wide interventions for increasing physical activity

If the amount of physical activity in a society increased, it should improve public health; but uncertainties remain about how to achieve this. Professor Philip Baker from the Queensland University of Technology in Australia describes the findings from the January 2015 update of the Cochrane review of the evidence on community-wide interventions.

#20 [updated] Community wide interventions for increasing physical activity - Clinical Version

People who are physically active have higher levels of health related fitness, and a lower risk profile for developing a number of disabling medical conditions and chronic diseases. However, despite considerable evidence of the benefits of regular physical activity, global levels of physical inactivity remain stubbornly high. In response, governments are looking to find ways to increase the physical activity of their populations.

Laboratories transformation

BACKGROUND OR CONTEXT Laboratories provide the physical spaces for engineering students to connect with theory and have a personal hands-on learning experience. Learning space design and development is well established in many universities however laboratories are often not part of that movement. While active, collaborative and group learning pedagogies are all key words in relation to these new spaces the concepts have always been central to laboratory based learning. The opportunity to build on and strengthen good practice in laboratories is immense. In the 2001 review “Universities in Crisis” many references are made to the decline of laboratories. One such comment in the review was made by Professor Ian Chubb (AVCC), who in 2013, as Chief Scientist for Australia, identifies the national concern about STEM education and presents a strategic plan to address the challenges ahead. What has been achieved and changed in engineering teaching and research laboratories in this time? PURPOSE OR GOAL A large number of universities in Australia and New Zealand own laboratory and other infrastructure designed well for the era they were built but now showing signs of their age, unable to meet the needs of today’s students, limiting the effectiveness of learning outcomes and presenting very low utilisation rates. This paper will present a model for new learning space design that improves student experience and engagement, supporting academic aims and significantly raising the space utilisation rate. APPROACH A new approach in laboratory teaching and research including new management has been adopted by the engineering disciplines at QUT. Flexibility is an underpinning principle along with the modularisation of fixed teaching and learning equipment, high utilisation of spaces and dynamic pedagogical approaches. The revitalised laboratories and workshop facilities are used primarily for the engineering disciplines and increasingly for integrated use across many disciplines in the STEM context. The new approach was built upon a base of an integrated faculty structure from 2005 and realised in 2010 as an associated development with the new Science and Engineering Centre (SEC). Evaluation through student feedback surveys for practical activities, utilisation rate statistics and uptake by academic and technical staff indicate a very positive outcome. DISCUSSION Resulting from this implementation has been increased satisfaction by students, creation of social learning and connecting space and an environment that meets the needs and challenges of active, collaborative and group learning pedagogies. Academic staff are supported, technical operations are efficient and laboratories are effectively utilised. RECOMMENDATIONS/IMPLICATIONS/CONCLUSION Future opportunities for continuous improvement are evident in using the student feedback to rectify faults and improve equipment, environment and process. The model is easily articulated and visible to other interested parties to contribute to sector wide development of learning spaces.