Sjögren’s syndrome leading to differential gene expression in males and females and functional impact on the immune system

Sjögren’s disease has among the highest observed female-to-male ratios of rheumatic diseases, around 9:1. Genetics play an important role in the disease, and genetic variations that associate with Sjögren’s disease have been identified. Notably, there is no difference in the frequency of these genetic variations between women and men in the general population. However, the risk of developing Sjögren’s disease is much higher if the carrier is a woman. In this project we have identified genes that are thus associated with the disease and expressed differently in women and men. We also characterize their role in the disease pathogenesis disease. In all, this project gives novel insight into the molecular basis as to why Sjögren’s disease develops more often in women compared to men, and may open the door to personalized medicine and development of therapeutic strategies better tailored to each sex.

Sjögren’s disease has among the highest observed female-to-male ratios of rheumatic diseases, around 9:1. Genetics play an important role in the disease, and genetic variations that associate with Sjögren’s disease have been identified. Notably, there is no difference in the frequency of these genetic variations between women and men in the general population. However, the risk of developing Sjögren’s disease is much higher if the carrier is a woman. In this project we have identified genes that are thus associated with the disease and expressed differently in women and men. We also characterize their role in the pathogenesis of Sjögren's disease to understand why there is a difference in the risk of developing Sjögren’s disease if the carrier of the disease-associated genetic variants is a woman compared to if it is a man.

In summary, this project gives novel insight into the molecular basis as to why Sjögren’s disease develops so much more often in women compared to men. The results will be applicable also to other systemic rheumatic diseases, and the data generated can open the door to personalized medicine and development of therapeutic strategies better tailored to each sex by targeting relevant regulators and pathways.

• Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME; PRECISESADS Clinical Consortium, Shiboski CH; Sjögren’s International Collaborative Clinical Alliance (SICCA), Wahren-Herlenius M, Ng WF; UK Primary Sjögren’s Syndrome Registry, Sivils KL, Adrianto I, Nordmark G, Lessard CJ. Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells. Nature Communications 2022, Jul 27;13(1):4287. doi: 10.1038/s41467-022-30773-y.
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• Sarkar I, Davies R, Aarebrot AK, Solberg SM, Petrovic A, Joshi AM, Bergum B, Brun JG, Hammenfors D, Jonsson R, Appel S. Aberrant signaling of immune cells in Sjögren’s syndrome patient subgroups upon interferon stimulation. Front Immunol 2022, 13:854183. doi: 10.3389/fimmu.2022.854183.
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• Thorlacius, G.E., Björk, A. & Wahren-Herlenius, M. Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies. Nat Rev Rheumatol (2023). doi.org/10.1038/s41584-023-00932-6
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