Systemic sclerosis or scleroderma is a severe debilitating autoimmune disease with no known cure that is characterized by a hardening of the skin, but it can also affect internal organs, leading to their failure. 80% of patients with this pathology are women, a statistic that worsens as it is the autoimmune disease with the highest associated mortality, reaching between 50 and 80% 10 years after diagnosis.
A study carried out by researchers from the López-Neyra Institute of Parasitology and Biomedicine (IPBLN) of Granada, belonging to the Higher Council for Scientific Research (CSIC) in Spain, has shown the relationship between the number of copies of the C4 gene and the risk of development of scleroderma in women. This discovery is a first step to understand what molecular mechanisms are involved in the development of the disease.
The key to this research, directed by Javier Martín, a researcher at IPBLN, lies in the C4 complement gene, which produces the protein of the same name. This protein, among other functions, helps to eliminate dead cells and cellular debris (which can cause damage where they are deposited). This gene is located in a key area of DNA for the study of immunologically-based diseases, such as autoimmune diseases: lupus erythematosus and rheumatoid arthritis.
The innovation of the study with respect to previous research is that the C4 gene has a protective effect and this effect is greater when there are more copies of the gene. In addition, in men there is a greater amount of these proteins compared to women. In some cases, such as C4, sex acts as a lens that magnifies the effects of genetic variation, explain the first authors of the study, Martin Kerick and Marialbert Acosta-Herrera, both IPBLN researchers.
This may be one of the factors responsible for the greater presence of the disease in women than in men. “It is known that there are diseases that women suffer from much more than men, and this is complex to explain. In this case, we see how genetics can be one of those possible reasons,” explains Javier Martín.
In the new study, one of the genetic factors apparently responsible for scleroderma affecting more women has been discovered. (Illustration: Amazings/NCYT)
These discoveries are relevant in the clinical dimension as there is the potential to modulate the amount of C4 in serum, increasing its protection in those patients who need it. This fact is of great importance, especially in reproductive age, which is where the greatest presence occurs in women than in men. In addition, it can be taken into account for those diseases whose therapeutic targets are complement genes such as C4, thus being able to minimize treatment-related adverse effects.
To achieve these results, the research group led by Professor Javier Martín from the IPBLN carried out a genetic study with more than 9,000 patients with this disease in 2022, analyzing the number of copies of this gene and comparing it in patients and healthy people, as well as between men and women. women. In addition, they have reported its relationship with gene expression levels, as well as the amount of total protein that appears in serum.
The study is entitled “Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis”. And it has been published in the academic journal Genomic Medicine. (Source: CSIC)