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FRIMEDBIO-Fri prosj.st. med.,helse,biol

The molecular basis of sex-differences in Sjögrens syndrome

Alternative title: Det molekylære grunnlaget for kjønnsforskjeller i Sjögrens syndrom

Awarded: NOK 10.0 mill.

The majority of rheumatic diseases are more common in women than in men. Sjögren?s syndrome is a rheumatic disease in which exocrine organs, primarily the salivary and tear glands, are chronically inflammed. Fatigue and joint pain are also common, and manifestations involving the lungs, nervous and vascular systems may occur. Sjögren?s syndrome has among the highest observed female-to-male ratios, and approximately nine out of ten patients with this chronic inflammatory condition are women. This sex-bias remains poorly understood, even though female sex is the strongest known risk factor for Sjögren?s syndrome. Our proposal aims to clarify the basic immune mechanisms underlying the strong sex bias in Sjögren?s syndrome by using a novel concept. Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with Sjögren?s syndrome, and many of these genetic variants lead to differential gene regulation, so called expression quantitative loci (eQTL) effects. The project is built on the idea that sex is a biological context that may influence the eQTL effects of Sjögren?s syndrome-associated SNPs differentially in women and men. It seeks to identify the genes thus regulated, and to explore their functional impact on the immune system and role in development of autoimmunity and Sjögren's syndrome. This novel idea bridges the specificity of genetic associations with the sex-bias in Sjögren?s syndrome, and together with the proposed functional experiments will lead to a better understanding of the pathogenetic process in this disease. The project is driven by state-of-the art technology and a unique, large biobank of patient-derived tissues. The concept and results of the project will be applicable also to other rheumatic diseases, and will be essential for development of novel treatment approaches and preventive measures better tailored to each sex.

The majority of rheumatic diseases are more common in women than in men. Sjögren’s syndrome is a systemic autoimmune rheumatic disease in which exocrine organs, primarily the salivary and lacrimal glands, are targets of chronic inflammation. Fatigue and arthralgia are also common, and extraglandular manifestations involving the respiratory, nervous and vascular systems may occur. Sjögren’s syndrome has among the highest observed female-to-male ratios, and approximately nine out of ten patients with this chronic inflammatory condition are women. This sex-bias remains poorly understood, even though female sex is the strongest known risk factor for Sjögren’s syndrome. Our proposal aims to clarify the basic immune mechanisms underlying the strong sex bias in Sjögren’s syndrome by using a novel concept. Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with Sjögren’s syndrome, and many of these genetic variants lead to differential gene regulation, so called expression quantitative loci (eQTL) effects. The project is built on the idea that sex is a biological context that may influence the eQTL effects of Sjögren’s syndrome-associated SNPs differentially in women and men. It seeks to identify the genes thus regulated, and to explore their functional impact on the immune system and role in development of autoimmunity and Sjögren's syndrome. This novel idea bridges the specificity of genetic associations with the sex-bias in Sjögren’s syndrome, and together with the proposed functional experiments will lead to a better understanding of the pathogenetic process in this disease. The project is driven by state-of-the art technology and a unique, large biobank of patient-derived tissues. The concept and results of the project will be applicable also to other rheumatic diseases, and will be essential for development of novel treatment approaches and preventive measures better tailored to each sex.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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