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A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren’s Syndrome

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Abstract

Systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and Sjögren’s syndrome are four major autoimmune rheumatic diseases characterized by the presence of autoantibodies, caused by a dysregulation of the immune system that leads to a wide variety of clinical manifestations. These conditions present complex etiologies strongly influenced by multiple environmental and genetic factors. The human leukocyte antigen (HLA) region was the first locus identified to be associated and still represents the strongest susceptibility factor for each of these conditions, particularly the HLA class II genes, including DQA1, DQB1, and DRB1, but class I genes have also been associated. Over the last two decades, the genetic component of these disorders has been extensively investigated and hundreds of non-HLA risk genetic variants have been uncovered. Furthermore, it is widely accepted that autoimmune rheumatic diseases share molecular disease pathways, such as the interferon (IFN) type I pathways, which are reflected in a common genetic background. Some examples of well-known pleiotropic loci for autoimmune rheumatic diseases are the HLA region, DNASEL13, TNIP1, and IRF5, among others. The identification of the causal molecular mechanisms behind the genetic associations is still a challenge. However, recent advances have been achieved through mouse models and functional studies of the loci. Here, we provide an updated overview of the genetic architecture underlying these four autoimmune rheumatic diseases, with a special focus on the HLA region.

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Funding

This work was supported by the Spanish Ministry of Science and Innovation (RTI20181013 [32-B-100] to JM and PID2020-113776 Gb-I00 to MEAR), Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013 to JM), the Consejería de Salud y Familias (PE-0297–2019 to MEAR), and the Consejería de Transformación económica, industria, conocimiento y universidades (PY20-00473 to MEAR). LOF was funded by the Spanish Ministry of Science and Innovation through the Juan de la Cierva Incorporacion program (ref. IJC2019-040746-I).

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Authors and Affiliations

  1. Institute of Parasitology and Biomedicine López-Neyra, CSIC, Parque Tecnológico de La Salud, 18016, Granada, Spain

    Lourdes Ortíz-Fernández & Javier Martín

  2. GENYO. Center for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Av de la Ilustración 114, Parque Tecnológico de La Salud, 18016, Granada, Spain

    Marta E. Alarcón-Riquelme

  3. Institute for Environmental Medicine, Karolinska Institutet, 171 77, Solna, Sweden

    Marta E. Alarcón-Riquelme

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  1. Lourdes Ortíz-Fernández
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  3. Marta E. Alarcón-Riquelme
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Ortíz-Fernández, L., Martín, J. & Alarcón-Riquelme, M.E. A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren’s Syndrome. Clinic Rev Allerg Immunol 64, 392–411 (2023). https://doi.org/10.1007/s12016-022-08951-z

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