Final Report Summary - GENETICS OF SLE (Genetics of Systemic lupus erythematosus in northern and southern European populations) Executive Summary:Background:Systemic lupus erythematosus (SLE) is a complex autoimmune disease, affecting predominantly young female adults. The prevalence of SLE varies considerably in different populations. The morbidity of the disease is dependent on severity, with approximately one-third of European patients with SLE having renal involvement. There is no cure for the disease; patients require continued medical care and treatment with varying doses of anti-inflammatory and/or immunosuppressive medication. Evidences from epidemiology and linkage analysis indicate that there is a genetic contribution to SLE. The genetic contribution to SLE has been further supported by the successful identification of several disease susceptibility loci showing association with SLE, using a candidate-gene approach and relatively small genome wide association studies (GWAS). Among the SLE susceptibility genes identified by genetic studies, the MHC generated the strongest associations in all of them. However, results of the contributions of non-HLA susceptibility genes have established only a few genes associated with SLE, which confers a modest effect in terms of odds ratios, compared with the well-established HLA genes. The studies were of modest size and each of these GWAS had limited power due to modest sample size and the variability within the “top hits” generated. The positive results obtained attest to the utility of this approach in SLE and we argue that much larger, well-powered GWAs would bring great added value. Existing data provide a small fraction (~8%) of the total genetic risk evident in SLE. A well-powered study will significantly increase the proportion of robust genetic factors and allow a full description of the genetic architecture underlying the disease. In addition, further work is required to determine, firstly, whether which of these variants are the biologically relevant variants and secondly, how these variants causes disease. Moreover, the study of different populations from Europe will allow us to create a comprehensive European genetic map that will greatly facilitate inter-population genetic studies. Aim:The aim of the study was to conduct a large-scale GWAS in SLE including different populations collected from Northern and Southern of Europe. Thereafter, we performed a meta-analysis of these GWAS data with the published GWAS in SLE in northern European populations and then to compare these data with the data of the southern European GWAS. We searched for replication of the novel associations in additional samples available through the SLEGEN consortium. Finally I we have selected the FCGR locus to conduct functional studies that will help to clarify the role of the locus in SLE ethiopathogenesis.Results:We have carried out the largest genome-wide association study of systemic lupus erythematosus to date, comprising 4,078 cases and 8,624 controls, and have undertaken a meta-analysis with two published GWA studies in Europeans, adding a further 1,698 cases and 4,650 controls. We have replicated the novel findings from our meta-analysis, and associations at candidate SLE loci, using an independently genotyped cohort of 1,630 cases and 9,019 further controls. Our analyses have identified 62 signals at 52 loci, increasing the explained proportion of genetic variance in SLE from 8% to 16.3%. We have identified 15 novel lupus susceptibility loci, including two replicated findings in the pseudo-autosomal region of the sex chromosomes, at PCDH11X/Y and SPRY3-VAMP7-IL9R. In addition, I have focused my work in the physiological role of the FCGR genes in SLE. FCGR polymorphisms and Copy Number Variations (CNV) have been previously associated with SLE. In order to pursue the underlying mechanism of SLE disease association with FCGR3B CNV we have established a detailed map of paralogous and allelic sequence variation across the two highly similar segments of the FCGR genomic locus. We have established so far that the functional consequences of the genomic re-organization resulting from FCGR3B deletion include reduced FCGR3B expression on all cell types and ectopic expressionof FcgRIIb, the only inhibitory FcgR on NK cells, most likely driven by FCGR2C regulatory elements in a hybrid FCGR2C/2B gene. Both these effects may contribute additively to SLE risk with reduction of FcgRIIb levels on neutrophils decreasing Ig binding and clearance of immune complexes, and expression of FcgRIIb on NK cells inhibiting the actions of FcgRIIa.