Common genetic variants contribute to risk of transposition of the great arteries

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

The effects of golimumab treatment on systolic and diastolic left ventricular function in ankylosing spondylitis

SC Heslinga,1,2 TC Konings,3 IE van der Horst-Bruinsma,1,2 O Kamp,3 VP van Halm,3,4 HACM de Bruin-Bon,4 MJ Peters,5 MT Nurmohamed1,2 1Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands; 2Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands; 3Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands; 4Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands; 5Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands Background: Diastolic left ventricular (LV) dysfunction appears more prevalent in ankylosing spondylitis (AS). The effects of tumor necrosis factor alpha (TNF-α) blocking therapy, a strong and effective anti-inflammatory drug, on diastolic LV function in AS are unknown. The objective of the study was to find the effects of 1-year treatment with golimumab 50 mg subcutaneously once per month on systolic and diastolic LV dysfunction in AS patients.Methods: Forty consecutive AS patients were treated with TNF-α blocking therapy for 1 year. Transthoracic echocardiography was performed in all patients at baseline and after 1 year of treatment.Results: Diastolic LV function improved after treatment in four out of six (67%) AS patients who completed follow-up (P=0.125), and did not develop or worsen in any of the other patients. Treatment with TNF-α blocking therapy had no effect on systolic LV function.Conclusion: These findings give support to the hypothesis that diastolic LV dysfunction improves during treatment with TNF-α blocking therapy. Keywords: ankylosing spondylitis, cardiovascular disease, anti-TN

Measuring Relationships between Doctor Densities and Patient Visits: A Dog’s Breakfast of Small Area Health Geographies

A number of small area geographies are used in Australia to investigate primary care relevant outcomes/behaviours and to manage the supply of Primary Care Providers (PCP) that influence these outcomes. However, very little research exists on the choice of a small area geography suitable for these purposes. We evaluated a large basket of Australian small area geographies to determine which geography is optimal for investigating relationships between PCP supply and the use of PCP services. We used linked data to evaluate the relationship between PCP supply and the likelihood of a patient visiting a PCP, after adjusting for individual level covariates. PCP supply was measured at different geographies including Local Government Areas (LGAs), Primary Health Networks (PHNs), Statistical Areas-1/2/3 and Remoteness Areas. Overall, the strongest relationships between PCP density and PCP use were found when LGAs were used to measure PCP density. Large geographies such as PHNs also detected strong relationships while custom built geographies such as Primary Care Service Areas were not significantly better than the rest. Existing geographies such as LGAs may be suitable for investigating the effect of PCP supply at state or national scales

Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis

Virulence-linked pathways in opportunistic pathogens are putative therapeutic targets that may be associated with less potential for resistance than targets in growth-essential pathways. However, efficacy of virulence-linked targets may be affected by the contribution of virulence-related genes to metabolism. We evaluate the complex interrelationships between growth and virulence-linked pathways using a genome-scale metabolic network reconstruction of Pseudomonas aeruginosa strain PA14 and an updated, expanded reconstruction of P. aeruginosa strain PAO1. The PA14 reconstruction accounts for the activity of 112 virulence-linked genes and virulence factor synthesis pathways that produce 17 unique compounds. We integrate eight published genome-scale mutant screens to validate gene essentiality predictions in rich media, contextualize intra-screen discrepancies and evaluate virulence-linked gene distribution across essentiality datasets. Computational screening further elucidates interconnectivity between inhibition of virulence factor synthesis and growth. Successful validation of selected gene perturbations using PA14 transposon mutants demonstrates the utility of model-driven screening of therapeutic targets