Are Keloids Genetic? New Clues on Family Clustering

Keloids are raised scars that grow beyond the original wound, often becoming thick and persistent. They disproportionately affect certain ethnic groups and tend to run in families, suggesting a genetic component. However, their exact inheritance patterns remain unclear, prompting researchers to investigate both genetic and environmental factors.

Recent studies have identified gene variants and biological mechanisms involved in keloid formation. Understanding these factors could lead to improved treatments and preventive strategies.

Collagen Regulation Mechanisms

Keloid formation is tied to disruptions in collagen regulation, particularly an overproduction of type I and type III collagen. Unlike normal wound healing, where collagen synthesis and degradation are balanced, keloids exhibit prolonged fibroblast activity and excessive deposition of disorganized collagen fibers. This imbalance results in a dense, fibrotic structure that extends beyond the original injury, distinguishing keloids from hypertrophic scars, which remain confined to the wound boundary.

Fibroblasts in keloid tissue show heightened sensitivity to growth factors such as transforming growth factor-beta (TGF-β), a cytokine central to collagen synthesis. Increased expression of TGF-β1 and TGF-β2 in keloid fibroblasts leads to sustained activation of downstream pathways, including the SMAD transcription factors. This prolonged signaling enhances collagen gene transcription while suppressing matrix metalloproteinases (MMPs), enzymes responsible for collagen degradation, resulting in excessive extracellular matrix accumulation.

Beyond TGF-β signaling, abnormalities in mechanotransduction pathways also contribute to keloid development. Keloid fibroblasts respond abnormally to mechanical stress, leading to sustained activation of focal adhesion kinase (FAK) and Yes-associated protein (YAP), both of which promote fibroblast proliferation and collagen deposition. This may explain why keloids frequently develop in high-tension areas such as the chest, shoulders, and earlobes. Additionally, dysregulation of the Wnt/β-catenin pathway has been implicated in keloid progression, as increased β-catenin activity enhances fibroblast survival and extracellular matrix production.

Known Gene Variants

Genetic studies have identified several gene variants associated with keloid susceptibility. Genome-wide association studies (GWAS) and linkage analyses have pointed to loci on chromosomes 2q23, 7p11, and 15q21, which harbor genes involved in fibroblast regulation, extracellular matrix remodeling, and wound healing. Among these, NEDD4, a ubiquitin ligase gene on chromosome 15q21, has emerged as a strong candidate due to its role in protein turnover and fibroblast proliferation. Variants in NEDD4 have been linked to altered degradation of growth factor receptors, prolonging signaling pathways that drive excessive collagen deposition.

Another key gene, TGFB1, encodes transforming growth factor-beta 1, a central regulator of fibrosis. Specific single nucleotide polymorphisms (SNPs) within TGFB1, such as rs1800470 and rs1800469, have been associated with increased TGF-β1 expression, correlating with heightened fibroblast activity and extracellular matrix accumulation. These SNPs appear at higher frequencies in keloid-prone populations, particularly individuals of African and East Asian descent, supporting a genetic basis for ethnic disparities in keloid prevalence. Similarly, polymorphisms in SMAD3, a downstream mediator of TGF-β signaling, influence fibroblast responsiveness to profibrotic signals and have been linked to keloid susceptibility.

Variants in genes related to mechanotransduction and cellular adhesion have also been implicated in keloid pathogenesis. ANKRD1, located on chromosome 10q23, encodes a protein that modulates fibroblast adhesion and extracellular matrix stiffness. Mutations in ANKRD1 have been linked to abnormal fibroblast contractility, contributing to persistent keloid growth. Additionally, polymorphisms in PDGFRA, which encodes platelet-derived growth factor receptor alpha, have been associated with increased fibroblast proliferation and collagen synthesis.

Family Clustering Patterns

Keloids frequently appear in multiple generations of the same family, suggesting a hereditary component beyond individual gene variants. Individuals with a first-degree relative affected by keloids are significantly more likely to develop them. This pattern does not follow a simple Mendelian model but suggests a polygenic or multifactorial mode of transmission, where multiple genetic and regulatory elements interact to influence susceptibility. Twin studies reinforce this, with monozygotic twins displaying higher concordance rates than dizygotic twins.

Pedigree analyses across diverse populations show keloid clustering is particularly pronounced in families of African, East Asian, and Hispanic descent. Some cases suggest an autosomal dominant-like pattern with incomplete penetrance, meaning not all individuals carrying susceptibility alleles develop keloids. This indicates that additional factors—such as epigenetic regulation or hormonal influences—affect expression. In some families, keloid severity varies widely, pointing to gene-environment interactions.

The age of onset and anatomical distribution of keloids also exhibit familial trends. Some studies indicate individuals from the same lineage tend to develop keloids at similar life stages, often during adolescence or early adulthood, when hormonal changes may amplify fibroblast activity. Familial clustering also extends to keloid location, with some families exhibiting a predisposition for keloids on specific areas such as the earlobes, chest, or upper back. This suggests inherited variations in skin tension response and fibroblast behavior contribute to site-specific susceptibility.

Environmental Influences On Gene Expression

While genetic predisposition plays a significant role in keloid development, environmental factors shape how these genetic tendencies manifest. Epigenetic modifications, such as DNA methylation and histone acetylation, influence gene expression without altering genetic code. External stimuli like ultraviolet radiation, chronic skin irritation, and mechanical stress can trigger these changes, affecting fibroblast behavior and collagen production. Environmental pressures can amplify fibrosis-related signaling pathways, making genetically susceptible individuals more prone to keloid formation.

Hormonal fluctuations also contribute to keloid development. Elevated estrogen and androgen levels, particularly during puberty and pregnancy, have been linked to increased fibroblast proliferation and extracellular matrix deposition. This may explain why keloids frequently emerge or worsen during these periods. Additionally, higher melanin levels correlate with increased fibroblast sensitivity to external stimuli, which may partially account for the higher prevalence of keloids in individuals with darker skin tones.

Recent Advances In Molecular Studies

Advancements in genetic and molecular research have provided deeper insights into keloid formation, particularly through transcriptomic and proteomic profiling. High-throughput sequencing has revealed distinct gene expression patterns in keloid fibroblasts compared to normal scar tissue. Studies have identified upregulation of fibrotic markers such as COL1A1, COL3A1, and FN1, which encode type I collagen, type III collagen, and fibronectin, respectively. These findings underscore how keloid fibroblasts maintain an active fibrotic state long after wound healing should have ceased.

RNA sequencing has uncovered non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), that regulate fibroblast proliferation and extracellular matrix deposition, offering new potential therapeutic targets.

Single-cell RNA sequencing (scRNA-seq) has provided a deeper understanding of cellular heterogeneity within keloid tissue, revealing distinct fibroblast subpopulations that contribute to persistent collagen production and resistance to apoptosis. Proteomic analyses have reinforced these findings, identifying abnormal protein expression in signaling pathways such as PI3K/AKT and JAK/STAT, both involved in cell survival and proliferation.

These insights have paved the way for experimental treatments targeting specific pathways, including small-molecule inhibitors and monoclonal antibodies designed to suppress excessive fibroblast activity. As molecular research advances, these discoveries bring the field closer to precision medicine approaches that could prevent or mitigate keloid formation based on an individual’s genetic and molecular profile.