A Design for Life: is scleroderma in the genes?

What is the link between our genetic code and developing scleroderma? Researchers from Spain have recently studied genetic alterations and established a connection with the pathways that dictate the clinical features of scleroderma. The study is significant because increasing our understanding of the genetic pathway could be a faster route towards identifying effective new therapies for this complex condition.

Our DNA is our molecular design for life, which provides the instructions for us to fulfil our biological potential. In some medical conditions it is well-documented that certain small changes in a person’s genes may make them more likely to develop that particular condition e.g. breast cancer. However, whilst genes have been identified that are associated with scleroderma, it is less clear how these influence and cause the condition to develop and worsen. A recent study from a group in Spain has examined genetic alterations in individuals with scleroderma, mapping them to the pathways which dictate the clinical features of the condition.

The findings of this work are encouraging, since increasing our understanding of the genetic pathway of scleroderma may well open avenues for new and targeted therapies in the not-too-distant future.

Those living with systemic sclerosis will agree that it is a complex condition, where no two cases are exactly the same. Part of the variation in experiences results from the differing expression of the three hallmarks of scleroderma; fibrosis caused by the excessive production of collagen, autoimmunity and damage to the small blood vessels.  To better understand the interplay between these factors and therefore develop more effective treatments, scientists must examine the route of the condition – the genetic code.

Our genetic code is formed from DNA, a highly complex molecule found in every cell of the body (with the exception of mature red blood cells). At its core, DNA is made from four molecules (known as bases), each referred to by a letter: A, C, G or T. These bases are strung together in a long chain and housed on strand-like structures called chromosomes, found within the nucleus.

Genes are comparatively small sections of DNA, which are considered to be units of inheritance – determining how certain characteristics like eye colour, hair colour and even your risk of developing medical conditions are passed down through generations. Genes instruct our cells to make ‘proteins’ needed for growth, repair and other specialised functions in a process known as gene expression. Whilst each cell contains exactly the same DNA, how this is expressed differs between cell types, as different genes are switched ‘on’ and ‘off’ altering which proteins are made in each cell.

This variation in the proteins produced enables cells to be specialised for specific purposes. For example, B cells are a type of cell found in the blood that make antibodies capable of fighting infections. The fibroblasts found in our skin and connective tissues make an entirely different molecule, collagen, which is needed for strength. Too much collagen can cause the ‘stiffness’ characteristic of scleroderma. Both cell types contain the same DNA but switch on and off certain genes leading to the production of different molecules.

Previous research has unearthed some of the specific genes believed to be linked to scleroderma, however this in itself does not offer enough information about the pathway from genes to symptoms, which is essential in the development of new treatments.

Single Nucleotide Polymorphisms – Spot the difference!

In addition to linking genes to medical conditions, recent scientific research has identified the importance of single nucleotide polymorphisms (SNPs) in the causation of autoimmune conditions. SNPs are small, single base changes within the DNA sequence associated with a particular medical condition. They are commonly identified through what is known as a Genome Wide Associations Studies (GWAS). This method whilst sounding complicated basically involves playing ‘spot the difference’ between the DNA of individuals with a certain medical condition and a ‘healthy’ control group; i.e., looking for key changes in individuals with a condition but not in those without it. Many GWAS have been carried out within cancer research and in relation to autoimmune conditions such as  lupus and rheumatoid arthritis identifying changes associated with these conditions (2), (3). More recently, these studies have been carried out in scleroderma.  

Less than 2% of our DNA is responsible for forming the blueprint for our bodies. The rest is non-coding, affectionately known as ‘junk’ DNA. Most SNPs identified by GWAS occur in these non-gene coding regions of DNA, meaning that their role in the mechanisms underpinning disease development is unclear. Recently, work from a research team based at the University of Granada in Spain sought to understand the impact of SNPs associated with scleroderma and their link to the immune responses, fibrosis and the blood vessels abnormalities, by understanding how these SNPs affect gene expression, in a process called an eQTL analysis.  

Can SNPS help us develop treatments to ‘SNP’ scleroderma in the bud?

The study compared DNA taken from the white blood cells of those with scleroderma and healthy controls to identify relevant eQTLs, before mapping these to the genes whose expression they regulated.  Their analysis identified 64 eQTLs specific to scleroderma which mapped to 134 eGenes associated with the three hallmarks of scleroderma mentioned earlier: 122 linked to immune cell responses, 27 to fibrosis, and 16 to blood vessel abnormalities. The team found an overlap between these categories, which is not surprising given that these features are closely linked, re-enforcing how complex the pathology of scleroderma is.

The work could lead to a greater understanding of the pathways underpinning disease, potentially accelerating the development of targeted therapies. The research team examined whether there were any ongoing clinical trials testing drugs that target the protein products of the relevant eGenes – and seven were identified. This opens up the possibility of drug repurposing for scleroderma treatment – a more time and cost-effective way of introducing a new therapy to those in need. Additionally, the 64 eQTLs that are specific to those with scleroderma indicate additional mechanisms activating eQTLs in disease, suggesting potential treatment routes if these pathways can be illuminated.  

In the journey to more precise treatments, more in-depth study of specific eQTL and eGene targets will be necessary, however the results from this study are an optimistic first step towards potential new and effective treatments for people living with systemic sclerosis.  


1. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus - PubMed   (nih.gov)

2. Systematic identification of trans eQTLs as putative drivers of known disease associations - PubMed (nih.gov)

    3.   Profiling RNA-Seq at multiple resolutions markedly increases the number of causal eQTLs in autoimmune disease -  PubMed (nih.gov)