Steroid-sensitive nephrotic syndrome (SSNS) is a rare, mostly childhood kidney disease defined by selective proteinuria, hypoalbuminaemia and minimal histological changes without Ig deposits. It has been postulated that SSNS is immune mediated and involves T-cell dysregulation. Association studies with HLA class-2 alleles are small or limited to an exome array on a South Asian population. Building on our GWAS in membranous nephropathy (MN), (Stanescu et al, NEJM 2011, 364: 616) and a first set of data obtained by GWAS and NGS in 425 and 96 SSNS patients, respectively, our objectives are to identify additional gene variants by GWAS, to sequence the GWAS-tagged loci by NGS, and to investigate the functional significance of the relevant gene variants. This project is very innovative because it combines multi-ethnic and family studies, full sequencing of GWAS-tagged loci, functional studies, and clinical correlations in deeply phenotyped cohorts, as well as a comparison with risk variants in MN. This study comprises 5 workpackages. WP 1: GWAS discovery of new SNPs associated with SSNS We have tripled the number of enrolled patients (non-Chinese available for the current study: 375 patients; Chinese: 500 patients; grand total, 1,400 patients including already studied patients) to discover new SNPs, particularly in non-HLA-D associated loci. WP 2: Deep genotyping of relevant loci by NGS: HLA-D and beyond Our first aim is to provide a fine mapping of loci tagged by GWAS within HLA-D locus and outside of it. Studies will include logistic regression analysis of top SNPs, and identification of ethnicity-specific SNPs which may explain part of the geographic heterogeneity of SSNS, as well as common, trans-ethnic SNPs, which may be associated with key pathways affecting the immune system or the podocyte. A second objective is to compare these data with those in MN (220 patients sequenced, unpublished results) because of shared characteristics with SSNS. WP 3: Family studies Our objective is to discover variants associated with 22 families of SSNS, which may reveal a strong effect of a rare variant of a gene involved as a common variant in sporadic cases. We aim to identify coding variants (mutations) by whole exome studies (WES) as well as non-coding and coding variants within HLA-D locus and outside of it, by targeted sequencing of candidate genes and loci. WP 4: Functional studies of relevant gene variants They will depend on the findings of genetic studies, which may provide clues to permeability factor(s) or to altered signaling pathways. Two lines of research can already be envisaged: • Characterization of regulatory and coding SNPs: We expect to find disease-associated non-coding SNPs within regulatory sequences as well as SNPs in the coding regions. Computational approaches will first guide the design of functional assays. We will use 41 glomerular transcriptomes from SSNS patients to correlate tag and regulatory SNPs with actual transcriptional changes in the glomerulus. • Identification of HLA-class 2 molecules: the road toward identification of T-cell epitopes: We will characterize risk allelotypes, haplotypes and amino acids on HLA class-2 molecules, and we will use the relevant anti-allelotype antibodies to immunoprecipitate the circulating HLA class-2 peptide complexes followed by mass spectometry analysis. WP 5: Clinical correlations Correlations will be established between clinical presentation (demography) and outcome, and genotype (alleles of top SNPs, risk allelotypes and amino acids). With our deeply phenotyped, multi-ethnic cohort also including adult patients (30% of the Spanish and 60% of the Chinese cohorts), we have the unique opportunity to establish correlations with response to treatment depending on age and ethnicity. These studies will contribute to SSNS pathogenesis and hopefully provide new disease biomarkers and drug targets.

Antimicrobial resistance (AMR) and particularly resistance to antibiotics (ABR) has become one of the most complex public health challenges globally. Estimates have suggested that by 2050 AMR will be responsible for 10 million deaths, of which 4.73 million are in Asia, with an associated reduction of 2% to 3.5% in Gross Domestic Product (GDP) that will cost the world up to 100 trillion USD. Our collaborative research and training programme will bring together international experts at leading universities in China and the UK to tackle antibiotic resistance, the type of AMR that is the most pressing concern for human health. China is estimated to be the second largest consumer of antibiotics in the world, with widespread and often inessential use in both humans and livestock. Widespread consumption leads to antibiotic residues in water and soil that may exacerbate the development and transmission of resistance through organisms and chemicals in the environment. Studies have investigated the epidemiology and pattern of drug-resistant infections in China, but the size of the health and economic burdens caused by ABR on a national level and the role of the environment in the development and transmission of drug resistance are still unclear. Most ABR research in China has focused on specific bacteria in hospital patients, selected food animals, or isolated determinants. Better evidence and broader understanding of environmental, community, economic and health care drivers and burdens of ABR based on a systems perspective that recognises interactions between these areas is urgently needed, as are evaluation tools to measure the effectiveness of different ABR-reducing intervention strategies. Due to a dense population, an intensive livestock breeding industry and massive antibiotic use, Eastern China is a key region for controlling antibiotic use and ABR. Our research aims to bridge these key evidence gaps and strengthen disciplinary and methodological research skills, through a set of closely linked projects that will generate the holistic knowledge which is needed to design, deliver and monitor targeted strategies to limit ABR in China and comparable settings. We will also establish sustainable partnerships with cross-disciplinary research expertise that is currently lacking in China and strengthen capacity in policy-relevant research. Since antibiotic resistant infections and their genetic components spread rapidly through international travel, research into ways of reducing the burden of ABR in China is important not only for populations in China and the wider Asian region, but globally. Through three linked programmes of work based at three leading universities in China, supported by UK academics from a wide range of disciplines, we will: 1. Estimate the economic burden of AMR and determine the cost-effectiveness of potential intervention strategies 2. Design and evaluate a tailored intervention to modify antibiotic prescribing behaviour among health professionals and reduce antibiotic consumption among outpatients 3. Measure human exposure to antibiotics from environmental and livestock sources, estimate their health effects & develop tools for risk assessment and monitoring of environmental exposures to antibiotics and antibiotic-resistant genes 4. Gather evidence on current patterns of antibiotic use and the implementation of ABR-related policies and regulations at local, regional and national levels 5. Produce evidence-based recommendations on optimising antibiotic use, monitoring ABR and assessing the success of strategies to reduce ABR in China 6. Build cross-institutional and international collaborative groups to increase China's research capacity in a range of relevant disciplines and methodologies, as well as in the design and conduct of inter-disciplinary research.