Is Systemic Sclerosis Genetic?

Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.

What if your immune system, which is supposed to protect you, mistakenly attacked your own body? That’s exactly what happens in autoimmune conditions like scleroderma. The name Sclerosis comes from Greek and means “hard skin,”reflecting one of its most visible symptoms. Systemic Sclerosis or scleroderma is, however, more than a skin condition.

Understanding what causes scleroderma is important to managing it, and that includes looking at both genetic factors and non-genetic triggers like environmental exposures, immune system activity, and lifestyle. This may help in early recognition, better treatment choices, and long-term care.

What Is Systemic Sclerosis (Scleroderma)?

Scleroderma usually refers to thethickened skin patches, but systemic sclerosis (SSc) is a condition that may affect many internal organs and may lead to significant health problems.

SSc may affect internal organs when the body produces too much collagen, a protein meant to support and strengthen tissues. This excess leads to thickening and scarring, or fibrosis, not only on the skin but throughout the body.

This condition is a type of connective tissue disease that may impact the skin, blood vessels, and various organs. Its exact cause is unknown, but research suggests it involves a mix of immune system imbalance, abnormal blood vessel function, and the overproduction of collagen. This overproduction leads to hardening and scarring of tissues.

Understanding the root causes of systemic sclerosis may lead to better treatment and management strategies.

Two Main Types of Scleroderma

Scleroderma is typically divided into two major types:

Localized Scleroderma: This form affects only the skin and nearby tissues. It may cause thickened, hardened patches of skin but does not usually involve internal organs. Unlike systemic sclerosis, localized scleroderma is rarely linked to Raynaud phenomenon or severe symptoms. About half of those with this type may test positive for antinuclear antibodies (ANA). Localized scleroderma is not linked to increased risk of death.
Systemic Sclerosis: This more serious type affects both the skin and internal organs, including the lungs, digestive system, heart, kidneys, and more. It is connected to higher risks of complications and health issues.

What Are the Symptoms of Systemic Sclerosis?

Symptoms may differ widely depending on the type and severity. Common signs of systemic sclerosis include:

Skin thickening and hardening: The skin may become tight, shiny, and harder to move. It often begins in the fingers and hands and may spread.
Sclerodactyly: Fingers may look shiny, tapered, and stiff, limiting movement.
Raynaud phenomenon: Fingers or toes may change color (white, blue, then red) in response to cold or stress due to narrowed blood vessels. This is often the earliest sign.
Ulcers on fingers: Poor circulation may lead to painful open sores on the fingertips that heal slowly.
Telangiectasia: Small red blood vessels may become visible on the face, lips, and hands.
Calcinosis: Hard calcium lumps may form under the skin, especially over bony areas like elbows or knees.

Heredity and Genetic and Epigenetic Factors in Systemic Sclerosis

Studies suggest that systemic sclerosis affects between 0.6 to 5.6 people per 100,000 annually and is more common in women than men in Europe & North America. Despite being less common in men, males tend to experience more severe complications, especially affecting the heart and lungs. The disease not only poses a high risk of mortality due to these complications but also affects patients’ emotional and social well-being and adds economic strain. Because SSc presents with a wide range of symptoms and has a significant impact on quality of life, early diagnosis and treatment are essential. Understanding the disease’s complex causes is also key to developing better, more targeted therapies.

Both genetic and environmental factors play a role in who develops SSc. For example, first-degree relatives of people with SSc have a 1.6% chance of developing it—much higher than the general population’s 0.026%. However, the low match rate of 4.7% in twins shows that environmental triggers are also important. The disease behaves differently among racial/ethnic groups as well. SSc is more common in people of European descent than in Asians.

Sex hormones are also involved, estrogen may increase autoimmunity, while androgens and progesterone may offer some protection. Another layer of complexity comes from differences in gut bacteria between sexes, which may influence risk. Lastly, the study points to epigenetic factors, especially issues with X chromosome inactivation (XCI), as contributors to why more women are affected. In females with SSc, abnormal or skewed XCI can cause immune-related genes to be overactive. Altogether, this study highlights how genetics, hormones, environmental exposures, gut health, and epigenetic changes all interact in the development and severity of systemic sclerosis.

Another study by Salazar and Mayes, shares that SSc or systemic sclerosis does not follow simple inheritance patterns but arises from the interplay of various genetic loci and environmental triggers. Key genes with SSC associated variants implicated include IRF5, STAT4, TNFSF4 (OX40L), PTPN22, and CD247, all involved in immune regulation and signaling pathways that contribute to disease susceptibility and severity.

Beyond genetics, epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA dysregulation play critical roles in modulating gene expression without altering the DNA sequence. For example, hypermethylation of the Fli1 gene reduces its expression, promoting collagen overproduction and fibrosis, a hallmark of SSc. These epigenetic changes often occur early in disease progression and may serve as valuable biomarkers.

Advances in genomic technologies, including genome-wide association studies (GWAS) and gene expression profiling, have deepened understanding of these factors and opened avenues for personalized medicine. By integrating genetic and epigenetic data, researchers aim to develop targeted therapies that improve management and outcomes for patients with systemic sclerosis.

Is There a Cure for Systemic Sclerosis?

There is currently no cure for systemic sclerosis. However, several treatment strategies may help manage symptoms, reduce complications, and improve overall quality of life:

Immunosuppressive medications such as methotrexate, mycophenolate mofetil, or cyclophosphamide may calm the immune system and slow tissue scarring (fibrosis), particularly in the lungs and skin.
Vasodilators or medications to improve blood flow are often used for people with Raynaud phenomenon to reduce episodes and lower the risk of sores or tissue damage.
Physical therapy may help maintain joint flexibility and relieve stiffness, especially in areas affected by skin tightening.
Regular monitoring of vital organs through pulmonary function tests, heart scans, and kidney assessments may help detect complications early.

With a combination of medications, supportive therapies, and careful monitoring, many people with systemic sclerosis may live fuller, more manageable lives despite the challenges.