Is Rosacea Genetic? YES

Is Rosacea Genetic? YES

But it’s more complicated than just that.

Rosacea is a chronic inflammatory skin disorder with a complex etiology that involves both environmental and genetic factors. Research has increasingly pointed to a genetic basis for rosacea, supported by family studies, twin concordance, and genome-wide association studies (GWAS). Below is a detailed overview of the current understanding of the genetic basis of rosacea, including specific genes and their chromosomal locations, based on available scientific evidence.

Genetic Basis of Rosacea

Evidence suggests that genetics play a significant role in rosacea predisposition:

• Family History and Twin Studies: Studies have shown that individuals with a family history of rosacea have a higher risk of developing the condition. For example, a retrospective study found a greater than fourfold increased odds of rosacea in individuals with an affected family member. Twin studies also indicate higher concordance rates among identical twins compared to fraternal twins, supporting a hereditary component.
• Population Trends: Rosacea is more prevalent among individuals of Northern European descent, particularly those with fair skin, suggesting a genetic predisposition tied to specific ancestral groups.

Specific Genes and Chromosomal Locations

Several genes and genetic variants have been implicated in rosacea through GWAS and other genetic analyses. Here are the key findings:

1. HLA-DRA and BTNL2 (Chromosome 6):
• Location: Chromosome 6p21.3 (within the major histocompatibility complex, MHC, region).
• Details: A GWAS conducted by Chang et al. (2015) identified a single nucleotide polymorphism (SNP), rs763035, located between the HLA-DRA and BTNL2 genes, strongly associated with rosacea in individuals of European ancestry. HLA-DRA is part of the human leukocyte antigen (HLA) system, which regulates immune responses, while BTNL2 is involved in immune modulation. The study found that these genes are expressed in rosacea-affected skin, particularly in inflammatory infiltrates, suggesting a role in the inflammatory processes of rosacea.
• Significance: Variants in this region are also linked to autoimmune diseases like multiple sclerosis and inflammatory bowel disease, hinting at shared inflammatory pathways.
2. HLA Alleles (Chromosome 6):
• Location: Chromosome 6p21.3 (MHC Class II region).
• Details: Specific HLA alleles, including HLA-DRB103:01*, HLA-DQB102:01*, and HLA-DQA105:01*, were significantly associated with rosacea in the same GWAS by Chang et al. (2015). These alleles are part of the MHC Class II genes, which are critical for antigen presentation and immune system activation, aligning with the inflammatory nature of rosacea.
• Significance: These findings reinforce the involvement of immune-regulating genes in rosacea susceptibility.
3. IRF4, SLC45A2, HERC2-OCA2, IL13 (Various Chromosomes):
• Location:
• IRF4: Chromosome 6p25.3
• SLC45A2: Chromosome 5p13.2
• HERC2-OCA2: Chromosome 15q13.1
• IL13: Chromosome 5q31.1
• Details: A GWAS by Aponte et al. (2018) identified seven loci associated with rosacea symptom severity. These include IRF4 (linked to skin pigmentation and inflammation), SLC45A2 (involved in melanin production), HERC2-OCA2 (related to eye and skin pigmentation), and IL13 (an immune-inflammatory cytokine). These genes suggest that both skin pigmentation and immune-inflammatory pathways contribute to rosacea.
• Significance: The association with pigmentation genes may explain the higher prevalence in fair-skinned individuals, while IL13 points to a Th2-mediated inflammatory response.
4. LRRC4, SH3PXD2A, SLC26A8 (Various Chromosomes):
• Location:
• LRRC4: Chromosome 7q31.32
• SH3PXD2A: Chromosome 10q24.33
• SLC26A8: Chromosome 6p21.31
• Details: Whole genome sequencing (WGS) and whole exome sequencing (WES) by Deng et al. (2023) in familial rosacea cases identified rare deleterious variants in these genes. LRRC4 and SH3PXD2A are involved in neural synaptic processes, while SLC26A8 relates to cell adhesion. Functional studies showed these mutations increase vasoactive neuropeptide production, linking neurogenic inflammation to rosacea.
• Significance: These findings highlight a novel neuroinflammatory component in rosacea pathogenesis.
5. GST Genes (Various Chromosomes):
• Location: Multiple chromosomes (e.g., GSTM1 and GSTT1 on 1p13.3 and 22q11.23, respectively).
• Details: Variants in glutathione S-transferase (GST) genes, which protect cells from oxidative stress, have been associated with an increased risk of rosacea. Oxidative stress may damage skin cells and trigger inflammation, contributing to disease development.
• Significance: This suggests a role for cellular protection mechanisms in rosacea susceptibility.

Broader Implications

The genetic variants identified span immune regulation (HLA genes, IL13), skin pigmentation (SLC45A2, HERC2-OCA2), inflammation (IRF4), neurogenic processes (LRRC4, SH3PXD2A), and oxidative stress response (GSTs). These findings support a multifactorial model where genetic predisposition interacts with environmental triggers (e.g., UV exposure, microbes) to manifest rosacea. The overlap with autoimmune and inflammatory diseases further suggests shared pathophysiological mechanisms.

References for Further Reading

1. Chang, A. L. S., et al. (2015). “Assessment of the Genetic Basis of Rosacea by Genome-Wide Association Study.” Journal of Investigative Dermatology, 135(6), 1548–1555.
• DOI: 10.1038/jid.2015.53
• Available on PubMed: PMID 25695604
• Key study identifying HLA-DRA and BTNL2 associations on chromosome 6.
2. Aponte, J. L., et al. (2018). “Assessment of Rosacea Symptom Severity by Genome-Wide Association Study and Expression Analysis Highlights Immuno-inflammatory and Skin Pigmentation Genes.” Human Molecular Genetics, 27(15), 2762–2772.
• DOI: 10.1093/hmg/ddy184
• Available on PubMed: PMID 29771307
• Identifies seven loci, including IRF4, SLC45A2, and IL13.
3. Deng, Z., et al. (2023). “Whole Genome Sequencing Identifies Genetic Variants Associated with Neurogenic Inflammation in Rosacea.” Nature Communications, 14(1), 3958.
• DOI: 10.1038/s41467-023-39761-2
• Available on PubMed: PMID 37402769
• Focuses on rare variants like LRRC4 and SH3PXD2A.
4. MedlinePlus Genetics: Rosacea.
• URL: https://medlineplus.gov/genetics/condition/rosacea/
• Overview of rosacea genetics, including HLA and GST involvement.

These studies provide a foundation for understanding the genetic basis of rosacea, though further research is needed to fully elucidate the mechanisms and potential therapeutic targets. The chromosomal locations and gene functions offer a starting point for exploring how genetic predisposition contributes to this complex condition.