Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population

O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

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Kestrel-Prey Dynamic in a Mediterranean Region: The Effect of Generalist Predation and Climatic Factors

[Background] Most hypotheses on population limitation of small mammals and their predators come from studies carried out in northern latitudes, mainly in boreal ecosystems. In such regions, many predators specialize on voles and predator-prey systems are simpler compared to southern ecosystems where predator communities are made up mostly of generalists and predator-prey systems are more complex. Determining food limitation in generalist predators is difficult due to their capacity to switch to alternative prey when the basic prey becomes scarce. [Methodology] We monitored the population density of a generalist raptor, the Eurasian kestrel Falco tinnunculus over 15 years in a mountainous Mediterranean area. In addition, we have recorded over 11 years the inter-annual variation in the abundance of two main prey species of kestrels, the common vole Microtus arvalis and the eyed lizard Lacerta lepida and a third species scarcely represented in kestrel diet, the great white-toothed shrew Crocidura russula. We estimated the per capita growth rate (PCGR) to analyse population dynamics of kestrel and predator species. [Principal Findings] Multimodel inference determined that the PCGR of kestrels was better explained by a model containing the population density of only one prey species (the common vole) than a model using a combination of the densities of the three prey species. The PCGR of voles was explained by kestrel abundance in combination with annual rainfall and mean annual temperature. In the case of shrews, growth rate was also affected by kestrel abundance and temperature. Finally, we did not find any correlation between kestrel and lizard abundances. [Significance] Our study showed for the first time vertebrate predator-prey relationships at southern latitudes and determined that only one prey species has the capacity to modulate population dynamics of generalist predators and reveals the importance of climatic factors in the dynamics of micromammal species and lizards in the Mediterranean region.The Spanish Ministerio de Educación Ciencia (Projects: CGL2004-04479/BOS and CGL2007-61395/BOS) financed the study over the last four years

Factors affecting shrew population dynamic.

<p>Linear relationship between white-toothed shrew density and Eurasian kestrel density of the preceding year (A). Linear relationship between the per capita growth rate and one-year lagged density of shrews (B) and annual ambient temperature (C).</p

Factors affecting kestrel population dynamic.

<p>Linear relationship between the per capita growth rate of Eurasian kestrels and one-year lagged densities of kestrels (A), common voles (B). The linear relationship between the per capita growth rate of kestrels and the trophic term is also showed (C).</p

Lizard and August rainfall relationship.

<p>Hyperbolic relationship between annual abundance of eyed lizards and August precipitation of the preceding year.</p

Kestrel and nest-box numbers.

<p>Inter-annual variation in the number of nest-boxes installed (green line and dots) and the number of Eurasian kestrel pairs breeding (red line and squares) in the study area. The 7-year period in which the number of nest-boxes was constant (short period) and the 11-year period (long period) of trapping prey species were indicated.</p

Inter-annual fluctuation in the abundance of prey species.

<p>Inter-annual variation in the abundance of trapped eyed lizards (A), white-toothed shrews (B) and common voles (C). Black dots represent mean annual values (summer+autumn)/2. Dots inside a circle represent only autumn values. Eyed lizard abundances correspond to summer trappings.</p

Selected vole population-dynamic models.

<p>Per capita growth rate of voles <i>Microtus arvalis</i> (Rv). Log-transformed population densities of voles (V) and kestrels <i>Falco tinnunculus</i> (K) are included in the models. T and R correspond with annual ambient temperature and rainfall, respectively. Bold type represents best models according to Akaike (AICc) criterion.</p

Factors affecting vole population dynamic.

<p>Linear relationship between common vole density and Eurasian kestrel density of the preceding year (A). Linear relationship between the per capita growth rate of common voles and the ratio of vole density to rainfall (B) and annual ambient temperature (C).</p