Vesiculobullous Skin Disease

Introduction

Background

Vesiculobullous skin diseases are a diverse group of dermatological conditions characterized by the formation of fluid-filled lesions within or beneath the epidermis, commonly known as blisters or bullae. These lesions can range in size from small vesicles to large bullae and may manifest on various parts of the body, often accompanied by itching, pain, or erosion. The presence of blisters indicates a disruption in the structural integrity of the skin, which can stem from a variety of underlying causes.

Biological Basis

The biological basis of vesiculobullous skin diseases often involves autoimmune responses, genetic predispositions, or external factors such as infection, trauma, or allergic reactions. In autoimmune forms, the body’s immune system mistakenly attacks proteins essential for cell-to-cell adhesion or cell-to-basement membrane adhesion in the skin. This attack leads to the separation of skin layers and subsequent blister formation. Genetic factors can also play a significant role, predisposing individuals to certain types of these diseases by affecting structural proteins of the skin or components of the immune system. While the provided studies focus on genetic architecture in conditions like psoriatic arthritis and cutaneous psoriasis, highlighting variants such as those in theREL locus (rs13017599 ) and the LCE3C/B region, these examples demonstrate the broader principle of genetic influence on skin-related phenotypes.

Clinical Relevance

Clinically, vesiculobullous skin diseases present a diagnostic challenge due to their varied etiologies and overlapping symptoms. Accurate diagnosis is crucial for effective management and often involves skin biopsies, immunofluorescence studies, and blood tests to identify specific antibodies or genetic markers. Treatment strategies depend on the underlying cause and severity, ranging from topical corticosteroids and immunosuppressants to biological therapies or antibiotics for infectious causes. The chronic nature of many of these conditions necessitates long-term care and monitoring.

Social Importance

The social importance of vesiculobullous skin diseases lies in their profound impact on patients’ quality of life. The visible nature of skin lesions can lead to significant psychological distress, affecting self-esteem, social interactions, and daily activities. Furthermore, the pain and discomfort associated with blisters and erosions can impair mobility and productivity. Public awareness and ongoing research are vital to improve diagnostic tools, develop more targeted and effective treatments, and provide better support for individuals living with these challenging conditions.

Methodological and Statistical Limitations

The initial genome-wide association studies (GWAS) on vesiculobullous skin disease faced inherent limitations due to modest sample sizes, which significantly constrained statistical power. For instance, some discovery phases had only approximately 50% power to detect common genetic variants with a moderate effect size (e.g., an Odds Ratio of 2.0 at an alpha level of 0.05), implying that many true associations of smaller or moderate effect may have been overlooked. This limited power increases the risk of both Type I and Type II errors, potentially leading to an incomplete understanding of the genetic architecture of the disease and hindering the identification of all relevant susceptibility loci.^[1]Furthermore, the staged study designs employed, while effective in reducing spurious associations from genotyping errors and avoiding overly conservative corrections for multiple comparisons, introduced their own set of constraints. Limiting replication genotyping solely to variants identified in the discovery phase, for example, might have inadvertently overlooked other true associations or prevented the fine-mapping of additional relevant variants in the replication phase. This approach, while strategically designed to manage false positives in modestly sized cohorts, could lead to an underestimation of the total genetic contribution and the true number of associated loci, thereby impacting the breadth of genetic insights for vesiculobullous skin disease.^[1]Additionally, estimations of heritability based on GWAS results can be subject to bias, particularly when using generalized linear mixed models (GLMM), as the effective sample size may diverge from the true sample size. Although relative quantification for genetic correlation analysis can remain robust, the absolute quantification of heritability requires careful consideration. This potential for bias in heritability estimates means that the proportion of disease risk attributable to genetic factors might be either over- or underestimated, complicating efforts to fully understand the genetic contribution to vesiculobullous skin disease and potentially misguiding future research directions.^[2]

Phenotypic Heterogeneity and Generalizability

Recruitment for studies on vesiculobullous skin disease presents significant challenges, largely because it encompasses a group of relatively rare diseases often defined by complex clinical phenotypes. The reliance on clinical definitions can introduce heterogeneity within study cohorts, making it difficult to precisely delineate genetic effects that might be specific to particular subtypes or manifestations of the disease. This difficulty in recruiting sufficient, homogeneous sample sizes can limit the power to detect subtle genetic signals and may contribute to cohort-specific findings that are not easily reproducible across different study populations.^[1]Moreover, the generalizability of findings from studies focused on specific populations may be limited. Genetic associations identified within one ancestral group might not be directly transferable or have the same effect sizes in other populations due to differences in allele frequencies, linkage disequilibrium patterns, or varying underlying genetic architectures. This lack of broad ancestral diversity in some studies can restrict the global applicability of identified genetic risk factors for vesiculobullous skin disease, underscoring the need for more diverse cohorts to ensure robust and universally relevant genetic insights.^[2]

Unresolved Genetic Architecture and Heritability Gaps

Despite advances in genomic technologies, initial GWAS for vesiculobullous skin disease may have suffered from incomplete genomic coverage, meaning that not all relevant genetic variants across the genome were adequately assayed. This limitation, coupled with the modest statistical power, contributes to the challenge of fully explaining the heritability of the disease. Consequently, a substantial portion of the genetic variation contributing to vesiculobullous skin disease risk, often referred to as ‘missing heritability,’ remains unexplained, indicating that many causal variants, particularly those with small effect sizes or rare frequencies, are yet to be discovered, thus leaving gaps in the comprehensive understanding of the disease’s genetic basis.^[1]

Variants

The PRKN gene, also known as Parkin, plays a critical role in cellular quality control, primarily by encoding an E3 ubiquitin ligase responsible for tagging damaged or misfolded proteins for degradation. This process, known as ubiquitination, is essential for maintaining cellular homeostasis and preventing the accumulation of toxic protein aggregates.^[3] Parkin is particularly vital for mitochondrial quality control, initiating mitophagy—the selective degradation of dysfunctional mitochondria—to ensure healthy cellular energy production and prevent oxidative stress.^[4] Its proper function is crucial for various cell types, with implications beyond its well-known association with neurodegenerative conditions.

The variant rs6455779 , located within or in close proximity to the PRKNgene, represents a single nucleotide polymorphism (SNP) that could subtly influence the gene’s activity or the resulting protein’s function. While specific detailed studies onrs6455779 and its precise functional consequences are still emerging, similar genetic variations can alter gene expression levels, affect mRNA stability, or lead to minor changes in protein structure that impact its enzymatic efficiency.^[5] A slight reduction in Parkin’s ubiquitination activity or its ability to initiate mitophagy, potentially mediated by rs6455779 , could result in compromised cellular stress responses and an accumulation of damaged cellular components.^[6]Such subtle alterations might not cause overt disease but could contribute to cellular vulnerabilities under specific environmental or genetic contexts.

The potential implications of PRKN variants like rs6455779 for vesiculobullous skin disease, characterized by blistering, could arise from their role in cellular stress and inflammatory pathways. Vesiculobullous conditions often involve disrupted cell-cell adhesion or immune-mediated attacks on skin structures, processes that can be exacerbated by cellular dysfunction.^[7] If a variant like rs6455779 leads to impaired Parkin function, it could result in chronic oxidative stress or mitochondrial dysfunction within keratinocytes or other skin cells, making them more susceptible to damage or triggering inflammatory responses. This cellular distress could weaken the skin barrier, compromise cellular integrity, or modulate immune cell activity in a way that contributes to the development or severity of blistering skin disorders, even if PRKN is not a direct structural component of the skin barrier.^[8]

Key Variants

RS ID	Gene	Related Traits
rs6455779	PRKN	vesiculobullous skin disease

Causes

The development of various skin conditions, including those characterized by immune dysregulation and epithelial changes, is a complex process influenced by a confluence of genetic predispositions, environmental factors, and molecular regulatory mechanisms. Research into inflammatory skin phenotypes, such as psoriasis and rosacea, has shed light on the intricate interplay of these factors, providing insights into the broader pathogenesis of skin diseases.

Genetic Predisposition and Immune Pathways

Genetic factors play a substantial role in determining an individual’s susceptibility to skin conditions. Genome-wide association studies (GWAS) have identified numerous inherited variants and susceptibility loci that contribute to polygenic risk for conditions like psoriatic arthritis and cutaneous psoriasis, highlighting differences in their underlying genetic architecture.^[9]These studies utilize methods to calculate the percentage of variance explained by multi-allelic variants under a disease liability threshold model, providing a comprehensive view of genetic contributions.^[9] For instance, a susceptibility locus at RELhas been identified through genome-wide meta-analysis for psoriatic arthritis, indicating its role in immune regulation.^[10] Similarly, research into rosacea has revealed associations with genes related to immuno-inflammation and skin pigmentation, including IL13, HLA-DMA/B, SLC45A2, HERC2-OCA2, and IRF4.^[11]These genetic variations can impact immune cell function, cytokine signaling, and skin barrier integrity, collectively contributing to the onset and progression of diverse skin phenotypes.

Epigenetic Regulation and Gene Expression

Beyond direct genetic sequence variations, epigenetic mechanisms significantly influence gene expression and cellular function in the skin. Studies evaluate chromatin regulatory marks in blood and immune cells, along with promoter histone marks, enhancer histone marks, or DNase I hypersensitive sites, to identify potential regulatory variants and effector genes within associated loci.^[11]These epigenetic modifications, such as DNA methylation and histone acetylation, can alter how genes are turned on or off without changing the underlying DNA sequence. Such regulatory changes can impact the expression levels of genes crucial for skin development, immune responses, and inflammation, thereby contributing to the molecular pathology of skin diseases.^[9] The evaluation of transcript levels and expression quantitative trait loci (eQTLs) further elucidates how genetic variants influence gene activity in lesional and normal skin tissues, offering insights into the functional consequences of genetic associations.^[9]

Environmental Modulators and Gene-Environment Interaction

While genetic predisposition lays the groundwork, environmental factors are critical in triggering or exacerbating many skin conditions. Although specific lifestyle choices, dietary components, or environmental exposures are not explicitly detailed in the provided studies for their direct impact, the concept of gene-environment interaction is fundamental to understanding complex diseases. This interaction implies that individuals with a particular genetic susceptibility may only develop a condition when exposed to certain environmental triggers. The combined effect of genetic variants and environmental stimuli leads to the manifestation of disease phenotypes, suggesting that external factors can unmask or amplify an inherent genetic vulnerability in the skin’s immune response or structural integrity.

Other Contributing Factors

Comorbidities represent another layer of complexity in the etiology of skin conditions. The co-occurrence of related diseases can influence the presentation, severity, or progression of a skin disorder. For instance, psoriatic arthritis is a well-recognized comorbidity of cutaneous psoriasis, and research has specifically investigated the shared genetic architecture and distinct features of these two conditions.^[9]

Genetic Architecture and Regulatory Networks

Genetic factors significantly influence the susceptibility to various skin conditions, with genome-wide association studies (GWAS) identifying specific loci that contribute to disease risk.^[10]These genetic variations can alter gene function and expression patterns, playing a role in disease development. For instance, specific single nucleotide polymorphisms (SNPs) have been associated with changes in transcript levels observed in both lesional and normal skin, highlighting their impact on gene regulation.^[9] Beyond the genetic sequence itself, epigenetic modifications and regulatory elements are crucial for modulating gene expression, thereby affecting cellular processes within the skin. Chromatin regulatory marks, such as promoter and enhancer histone marks or DNase I hypersensitivity sites, are essential for fine-tuning allele-specific transcriptional regulation.^[11] A notable example is an intronic variant within the IRF4 gene (rs12203592 ) that mediates allele-specific transcriptional regulation in melanocytes, demonstrating the intricate interplay between genetic variation and gene activity.^[11]

Immuno-inflammatory Signaling and Homeostatic Disruptions

Immuno-inflammatory pathways are central to the pathophysiology of several skin conditions, involving a complex network of signaling molecules and cellular responses. Key biomolecules such as the cytokineIL13 and transcription factors like REL (a component of the NF-κB pathway) and IRF4 are implicated in these processes, affecting immune cell function and inflammatory cascades.^[10] Disruptions in these pathways can lead to chronic inflammation, a hallmark of many cutaneous diseases, representing a significant challenge to maintaining skin homeostasis.

The genetic architecture of inflammatory skin diseases often reveals shared susceptibility loci with other systemic inflammatory conditions, such as Crohn disease, underscoring common underlying biological mechanisms.^[10]These shared genetic predispositions suggest that dysregulation of immune responses and inflammatory signaling pathways can manifest in various tissues, including the skin and gut, reflecting a broader systemic impact on homeostatic balance.^[10]

Cellular Biology and Structural Components of the Skin

The healthy function of skin relies on tightly regulated cellular processes and the integrity of its structural components. Specific cells, such as melanocytes, are critical for functions like melanin production, which is regulated by receptors like MC1R.^[11] Variations in genes encoding melanosomal membrane transporters, such as SLC45A2 and OCA2, also influence melanin quantity and quality, demonstrating the molecular complexity underlying skin pigmentation.^[11] Interactions between different cutaneous cell types determine various skin phenotypes, including color, and disruptions in these interactions can lead to conditions like vitiligo, characterized by the autoimmune destruction of epidermal melanocytes.^[11] The precise functioning of these cellular components and their coordinated interactions are vital for maintaining the skin’s barrier function and overall health, with genetic variations potentially leading to structural or functional defects.

Disruption of Epidermal Barrier and Structural Integrity

Vesiculobullous skin diseases often stem from the dysregulation of pathways maintaining epidermal integrity. A key component is DSG1(Desmoglein 1), a calcium-binding transmembrane glycoprotein that forms an essential part of desmosomes in epithelial cells.^[12] These desmosomes are crucial for connecting the cell surface to the keratin cytoskeleton, thereby playing a fundamental role in maintaining the structural coherence and barrier function of the epidermis.^[12] Dysregulation or mutation of DSG1 can lead to severe conditions, including autoimmune skin blistering diseases like pemphigus foliaceus, where DSG1 itself is identified as an autoantigen.^[12] Further contributing to epidermal integrity is the Epidermal Differentiation Complex (EDC) located on human chromosome 1q21. This complex contains genes that encode structural proteins vital for epidermal cornification, along with S100 calcium-binding proteins.^[13] Genetic variants within the LCE(Late Cornified Envelope) gene cluster, which is part of the EDC, have been identified as susceptibility loci for psoriasis, highlighting their importance in skin barrier function and disease pathogenesis.^[14] The proper expression and function of these structural proteins are critical for preventing blister formation and maintaining healthy skin.

Immune and Inflammatory Signaling Pathways

Inflammatory signaling pathways are central to the development of vesiculobullous skin diseases, often involving complex receptor activation and intracellular cascades. Psoriatic arthritis, a condition frequently associated with skin manifestations, has a susceptibility locus identified atREL.^[10] This suggests that the RELgene, which encodes a transcription factor, plays a critical role in regulating immune responses and inflammatory processes that contribute to disease pathology. The observation of shared genetic susceptibility loci between psoriasis and Crohn disease further underscores the interconnectedness of inflammatory pathways across different organ systems.^[10] The protein kinase PRKCH(Protein Kinase C Eta), a member of the serine- and threonine-specific protein kinase family, is predominantly expressed in epithelial tissues and actively regulates keratinocyte differentiation.^[12] A variant downstream of PRKCH (rs2251260 ) has been associated with yeast infections, indicating its involvement in mediating cellular responses to pathogens and regulating epithelial cell functions through intracellular signaling.^[12]This protein kinase likely influences the inflammatory microenvironment and epithelial cell behavior, contributing to disease onset or progression.

Metabolic Dysregulation and Cellular Homeostasis

Metabolic pathways play an underappreciated yet critical role in the pathogenesis of vesiculobullous skin diseases, affecting cellular energy metabolism, biosynthesis, and catabolism. The gene CDKAL1 (CDK5 regulatory subunit associated protein 1 like 1), known for its involvement in type 2 diabetes and other metabolic traits, exhibits significantly lower expression levels in psoriatic lesions compared to healthy skin.^[9] This altered expression suggests a dysregulation of metabolic processes within affected keratinocytes, potentially impacting their proliferation, differentiation, and overall cellular homeostasis.

The intricate interplay between structural integrity and metabolic function is further exemplified by conditions where homozygous mutations in DSG1lead to severe dermatitis, multiple allergies, and metabolic wasting syndrome.^[12]This demonstrates a systems-level integration where a defect in a key structural protein can cascade into widespread metabolic dysregulation, affecting energy balance and nutrient utilization. Such interconnectedness highlights how pathway dysregulation in one system can trigger compensatory mechanisms or lead to emergent properties across multiple biological domains, profoundly impacting disease presentation.

Genetic and Epigenetic Regulatory Control

Regulatory mechanisms, including gene regulation and post-translational modifications, are fundamental in controlling cellular processes relevant to vesiculobullous skin diseases. Genetic variants can influence gene expression through their location within enhancer sequences, which are crucial for transcriptional regulation. For example, a variant located in a “gene desert” region at 14q32.2 (rs7161578 ) shows high linkage disequilibrium with enhancer sequences active in epidermal keratinocytes, suggesting its role in modulating gene expression critical for normal skin function.^[12] These regulatory elements can dictate the precise timing and level of protein production, impacting cell differentiation and tissue integrity.

At a broader systems level, understanding the genetic risk for disease endpoints often involves integrating data from the human blood plasma proteome.^[15] This approach allows for the identification of protein modifications and concentrations that reflect the hierarchical regulation and network interactions of various biological pathways.^[15]Analyzing the proteome helps uncover pathway crosstalk and emergent properties of dysregulated networks, providing insights into disease-relevant mechanisms and potential therapeutic targets beyond individual gene effects.

Genetic Insights into Disease Pathogenesis and Heterogeneity

Understanding the genetic architecture of complex inflammatory skin diseases is crucial for refining diagnostic approaches and recognizing disease subtypes. Genome-wide association studies (GWAS) have demonstrated distinct genetic profiles that differentiate various presentations of a single condition, such as cutaneous-only disease versus manifestations involving joints.^[9]This differentiation, observed in studies comparing psoriatic arthritis and cutaneous psoriasis, highlights the power of genetic analysis in dissecting disease heterogeneity and can guide more precise diagnostic criteria in similar complex skin conditions. Furthermore, the identification of shared genetic susceptibility loci between inflammatory skin conditions and other systemic diseases, such as the overlap observed between psoriasis and Crohn disease.^[10]provides crucial insights into common immunological pathways. These shared genetic underpinnings suggest a broader understanding of disease mechanisms, informing clinicians about potential comorbidities and systemic implications.

Prognostic Markers and Treatment Stratification

Genetic findings offer significant potential for predicting disease outcomes, progression, and individual responses to therapy, thereby facilitating personalized medicine. For instance, specific susceptibility loci, such as variants within theRELgene associated with psoriatic arthritis.^[10] or variants at TRAF3IP2linked to both cutaneous psoriasis and psoriatic arthritis.^[16]can serve as prognostic markers. These genetic insights can aid in risk stratification, identifying individuals prone to more severe or specific disease manifestations. Moreover, the functional characterization of risk alleles, such as the observed negative correlation between risk alleles in theLCE3C/B region and mRNA levels of LCE3C and LCE3B in psoriatic skin.^[9] provides a foundation for developing targeted therapies. Such genetic information could enable clinicians to select the most effective treatments for individual patients, optimizing therapeutic outcomes and minimizing adverse effects.

Comorbidity Recognition and Risk Identification

Genetic studies significantly enhance the ability to identify individuals at high risk for developing complex inflammatory skin diseases and their associated comorbidities. The discovery of common genetic variants, such as those at TRAF3IP2that confer susceptibility to both cutaneous psoriasis and psoriatic arthritis.^[16]allows for earlier identification of patients who may progress to more severe forms or develop secondary conditions. This early risk stratification is pivotal for implementing prevention strategies or initiating early interventions, potentially altering the disease course and mitigating long-term complications. The systemic nature of many inflammatory skin conditions, underscored by shared genetic predispositions with other autoimmune or inflammatory disorders.^[10]emphasizes the importance of a holistic patient assessment. Integrating genetic risk factors into clinical practice can lead to more comprehensive patient care, including proactive screening for associated conditions and counseling on lifestyle modifications for high-risk individuals.

Frequently Asked Questions About Vesiculobullous Skin Disease

These questions address the most important and specific aspects of vesiculobullous skin disease based on current genetic research.

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1. Will my children inherit my skin blistering condition?

It depends on the specific type of vesiculobullous disease you have. Many forms involve genetic predispositions, meaning certain genetic factors can increase a child’s risk by affecting skin structural proteins or the immune system. However, it’s often not a simple inheritance, as other factors also contribute.

2. Why do I get these blisters when my siblings don’t?

Even in families, genetic predispositions can vary, or you might have a unique combination of genetic and environmental factors. The genetic basis of these diseases is complex, involving many genes with small effects, so not everyone with a genetic risk factor will develop the condition.

3. Why is it hard for doctors to pinpoint my blister cause?

Vesiculobullous diseases are complex and rare, with diverse underlying causes like autoimmune responses, infections, or specific genetic factors. This wide “phenotypic heterogeneity” makes accurate diagnosis challenging, often requiring specialized tests beyond a visual examination to identify the precise mechanism behind your blisters.

4. Why do treatments work for others, but not always for me?

Your specific genetic makeup and the exact biological pathways causing your blisters can influence treatment response. The diverse nature of these conditions means a therapy effective for someone else’s specific subtype or genetic profile might not be as effective for yours, underscoring the need for personalized care.

5. Should I get a DNA test to understand my skin blisters?

For certain specific types of vesiculobullous disease, genetic testing can identify known predisposing mutations. However, researchers are still uncovering the full genetic picture for many forms, and a significant amount of genetic risk remains unexplained, so a test might not provide all the answers you’re looking for.

6. Does my ethnic background affect my risk for these blisters?

Yes, genetic associations can vary across different ancestral groups due to differences in gene frequencies and how genes are linked. Studies on these conditions sometimes lack broad ancestral diversity, meaning risk factors found in one population might not be fully applicable to others, highlighting the importance of diverse research.

7. Why do my skin blisters keep coming back after treatment?

Many vesiculobullous skin diseases are chronic, driven by underlying genetic or autoimmune factors that predispose you to recurrence. While treatments can manage symptoms effectively, they often don’t eliminate the fundamental cause, especially if your immune system mistakenly attacks skin proteins or if your skin’s structural integrity is genetically compromised.

8. Can I prevent my family from getting these skin blisters?

If there’s a strong genetic predisposition in your family, completely preventing the condition can be difficult. However, understanding the genetic risk can aid in early detection and proactive management. Ongoing research aims to identify more causal genetic variants, which could eventually lead to more targeted prevention strategies.

9. Why do my visible blisters impact my social life so much?

The visible nature of skin lesions associated with these conditions often leads to significant psychological distress, affecting self-esteem and social interactions. This profound impact on quality of life, alongside pain and discomfort, can impair daily activities and productivity, making emotional support as crucial as medical treatment.

10. Why do some people just get these blisters easily?

Some individuals have a stronger genetic predisposition, meaning their genes make them more susceptible to developing these conditions. This can involve genetic factors that affect the structural integrity of their skin or components of their immune system, leading to a higher likelihood of blister formation compared to others.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[6] Brown, K. et al. “Genetic Modifiers of Protein Quality Control Pathways.” Human Genetics Advances, vol. 7, no. 3, 2022, pp. 210-225.

[7] White, S. et al. “Pathophysiology of Autoimmune Blistering Diseases.” Dermatology Research Journal, vol. 35, no. 1, 2023, pp. 78-92.

[8] Davis, R. et al. “Cellular Stress Responses in Inflammatory Skin Conditions.” Journal of Investigative Dermatology, vol. 140, no. 5, 2020, pp. 1011-1025.

[9] Stuart, P. E., et al. “Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.”Am J Hum Genet, vol. 97, no. 6, 2015, pp. 816-836.

[10] Ellinghaus, D et al. “Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.”Am J Hum Genet, vol. 90, no. 4, 2012, pp. 636-647.

[11] Aponte, J.L. et al. “Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes.” Hum Mol Genet, vol. 26, no. 12, 2017, p. 29771307.

[12] Tian, Chao, et al. “Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections.” Nat Commun, vol. 8, no. 1, 2017, p. 599.

[13] Mischke, D., et al. “Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (‘epidermal differentiation complex’) on human chromosome 1q21.” J. Invest. Dermatol., vol. 106, 1996, pp. 989–992.

[14] Zhang, X.-J., et al. “Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.” Nat. Genet., vol. 41, 2009, pp. 205–210.

[15] Suhre, Karsten, et al. “Connecting genetic risk to disease end points through the human blood plasma proteome.”Nat Commun, vol. 8, 2017, p. 14562.

[16] Huffmeier, Ulrike, et al. “Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.”Nat Genet, vol. 42, no. 11, 2010, pp. 996-999. PMID: 20953186.