Liang-Dan Sun＊

1 Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230022, China; 2 Institute of Dermatology,Anhui Medical University, Hefei, Anhui 230032, China; 3 Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui 230032, China.

Abstract As a typical representative of global complex diseases, psoriasis has attracted widespread attention because of its high heritability, heterogeneity, and incidence. Environmentally induced activation of the inflammatory–immune axis in patients with psoriasis relies on genetic regulation of genomic variation. The heritability of psoriasis exceeds 80%, and research of genomic variation in psoriasis is of great significance to the interpretation of the biological pathogenesis of the disease. The development of genome-wide association studies (GWASs) has provided a powerful means for the capture of psoriasis susceptibility genes. More than 100 psoriasis susceptibility loci have been captured, enabling humans to gain a breakthrough understanding of the genetics and traits of psoriasis. With the advancement of research methods, increasingly more genetic methodologies are being used to capture the locations and types of variants outside the scope of GWAS scanning, making up for the inclinations and deficiencies of traditional GWAS capture of gene loci in a more detailed manner. This review covers several decades of research on genomic variation in psoriasis, including GWASs in psoriasis, the capture of functional gene variant types, and the translation of genomic variation into precision medicine; summarizes the research progress of genomic variation in psoriasis; and provides a theoretical reference for future genetic-based research of the mechanisms underlying psoriasis.

Keywords: psoriasis, genomic variation, functional structural variation, InDels, precision medicine

Introduction

Psoriasis is a lifelong relapsing systemic skin disease that involves both genetic and environmental aspects, and it cannot be cured.1In 2016, World Health Organization listed psoriasis as a serious global public health problem.2The prevalence of psoriasis ranges from 0.1% to 3.0% and shows an increasing trend worldwide. Psoriasis adversely affects patients’ body and emotional state, and it has a very large impact on patients’ life and mood.

Psoriasis is strongly linked to genetics. Numerous genetic epidemiological studies have shown that psoriasis is influenced by polygenic and environmental factors.3-4Genome-wide linkage studies of psoriasis pedigrees have identified at least nine distinct chromosomal loci associated with psoriasis risk (psoriasis susceptibility regions [PSORS]1 to 9), of which PSORS 1 accounts for up to 50% of genetic susceptibility to psoriasis.5However, psoriasis differs from many Mendelian diseases, which also makes it difficult to identify psoriasis susceptibility genes by linkage analysis.6With the completion of the HapMap Project and the development and maturity of high-throughput genotyping technology, genome-wide association studies (GWASs)have been carried out for any cases and controls, not just pedigrees. During the past 100 years, ＞100 psoriasis susceptibility loci have been captured in worldwide studies.7

The literatures on psoriasis genomic variation from 2009 to 2022 were searched on PubMed by searching strategy of ((psoriasis) AND (genomic variation))AND (functional structural variation) in full text, and summarized in this review.

Rise of genomic variation research

Since 2009, previous GWASs have revealed a series of susceptible genes and pathways to psoriasis, thus establishing the genetic foundation of psoriasis. In 2009, a team from the Department of Dermatology of the First Affiliated Hospital of Anhui Medical University conducted the first phase I GWAS of psoriasis samples in a Chinese population.The research team found a new susceptibility locus (LCE[rs4085613]) and confirmed 2 known susceptibility loci(MHC [rs1265181] and IL12B [rs3213094]). In 2010, this team carried out a phase II international cooperative GWAS of psoriasis, which expanded the sample size and identified six new susceptibility genes. In particular, the verification of a susceptibility gene previously reported in Europe showed genetic heterogeneity of psoriasis among different populations. In 2015, this same team used genome-wide meta-analysis to analyze seven independent psoriatic GWAS datasets,expanded the sample size, and discovered new susceptibility genes across races (Europe–China), revealing genetic heterogeneity among different races.8-9

However, susceptibility loci discovered by GWASs focusing on capturing single-nucleotide polymorphisms (SNPs)can only explain part of the heritability in psoriasis.10To more fully analyze the genetic deletions of psoriasis in the past few years, researchers have used many new methods to analyze more types of genomic structural variations(SVs), especially those that have a greater impact on protein function, such as small insertions and deletions (InDels),11copy number variation (CNV),12and protein-truncating variants.13These studies complement the lack of genetic descriptions of psoriasis in traditional GWASs and provide more evidence for precision medicine in psoriasis.

Research progress on genomic variation of psoriasis abroad

Genetic variations in the human genome include SNPs,InDels with a length of 1 to 10,000 bp, CNV, and large forms of SVs.11,14-15These genetic variations can not only change biological traits but can also be associated with complex genetic diseases. The earliest genetic study of psoriasis was a case–control study using classical major histocompatibility complex (MHC) alleles. This study revealed an association with human leukocyte antigen(HLA) class I alleles, among whichHLA-Cw6showed the strongest association.16

Linkage analysis has identified several psoriasis susceptibility loci. Multiple HLA genes are strongly associated with the risk of psoriasis, especially HLA-C＊06:02.17However, the susceptibility loci or genes found in families with psoriasis by linkage analysis are difficult to repeat or verify in sporadic cases.18

In 2005, the first GWAS of age-related macular degeneration was reported, which opened a new direction of complex disease susceptibility loci in the whole genome.Multiple GWASs of psoriasis have been carried out in European and Asian populations to date. In 2009, Nairet al.19identified seven psoriasis susceptibility loci in a European population and found an association between the inflammatory interleukin (IL)-23 and NF-κB pathway and psoriasis. In the same period, de Cidet al.20found that the LCE gene cluster was significantly associated with psoriasis in a study of genome-wide CNV in Caucasians.Destruction of the skin barrier may induce the deficiency of LCE3B and LCE3C and further aggravate psoriatic lesions.20Tsoiet al.21identified 15 new susceptibility loci of psoriasis in European individuals in 2012, and the candidate genes were widely involved in regulating T-cell function and innate host defense. Additionally, 8 susceptibility genes were identified in a European population,and the HLA-C and ERAP1 loci showed an interaction.The variation of the ERAP1 gene only affects psoriasis in individuals carrying HLA-C risk alleles.22Furthermore,polymorphisms of susceptibility genes for many immune diseases such as psoriasis and inflammatory bowel disease have also been studied. Three unreported common risk sites and 27 new genome-wide significant susceptibility sites were found, all of which provide a new genetic explanation for coexisting diseases in patients with psoriasis.23

Research progress on genomic variation of psoriasis in China

Studying genetic variations is an effective and accurate method for elucidating the pathogenesis of complex diseases. The number of patients with psoriasis in China is very high, and the disease exhibits ethnic diversity.A study of large-scale genetic variation in the Chinese population would further reveal the genetic mechanism underlying psoriasis and provide a basis for more accurate treatment of patients with psoriasis in China. In 2014,Tanget al.24conducted a comprehensive exome sequencing and subsequent validation of the encoded SNV in a large sample of tens of thousands of Chinese populations. In this study, two independent low-frequency missense SNVs were found in IL23R and GJB2, and five common missense SNVs related to psoriasis were found in LCE3D, ERAP1, CARD14, and ZNF816A. Rare missense SNVs in FUT2 and TARBP1 were also observed in this study. In 2015, Zuoet al.25conducted the first full exome association study in a case–control cohort of a Chinese population. In that study, 16 SNPs were found in 15 new genes/loci related to psoriasis. Four known susceptibility loci also showed a significant correlation with psoriasis. These susceptibility variants identified in this study together account for 1.9% of the heritability of psoriasis. Sixteen SNPs on 5q33.3 were recently found to be significantly associated with psoriasis in a Chinese population using least absolute shrinkage and selection operator-based regression analysis. The most statistically significant associations were found in the ADRA1B gene. Four independently related SNPs (rs72808152,rs57791007, rs185289, and rs72810112) that were found in the ADRA1B gene explained 46.5% of the phenotypic variation of psoriasis.26In 2022, Chenet al.27identified ten new psoriasis susceptibility loci in the Chinese population through genome-wide meta-analysis.In 2022, Zhanget al.28verified 19 previously reported genes by genome-wide association analysis, and found 6 psoriasis-related loci by meta-analysis.

China is a multiethnic country, and ethnic diversity has a certain impact on the genetic mechanism of psoriasis. Analysis of the genetic variation of psoriasis has been performed not only in the Chinese Han population but also in other nationalities or regions of China. SNP rs495337 in the zinc finger protein 313 coding gene and SNP rs20541 in the IL-13 coding gene were found to be associated with psoriasis in the Chinese Uygur population.29The Affiliated Hospital of Guangdong Medical College team found that SNP rs3804099 located in TLR2 was significantly associated with psoriasis vulgaris in the population of southern China.30Yaoet al.31found that SNP rs6704688 in the CASP8 family was significantly correlated with psoriasis vulgaris in the Northeast Han population of China. Changet al.32found that the HCR gene, SNP n.7＊A, SNP n.9＊C, and Cw＊0602 were the major susceptibility markers for patients with psoriasis in Taiwan, China. In addition,studies in the Chinese population have shown that SNPs located in genes such as IL-6R, miR-146a, and GJB2 are significantly associated with psoriasis.33-35By analyzing the genetic data of patients with psoriasis, schizophrenia, and control individuals, Yinet al.36found that the common susceptibility variation correlation of schizophrenia and psoriasis risk in a Chinese population was estimated to be 21%. Additionally, HLA regions shared the most significant risk effects. Studies on SNVs and SNPs have further refined the gene localization and improved the cognition of susceptible sites, thus providing a more accurate research target for the treatment of psoriasis, especially in Chinese patients.

InDels are the second most common genetic biomarker after SNPs. During the past decade, millions of InDels have been found in individual human genomes. The genetic variation caused by InDels is huge. Many InDels map to functionally important loci in human genes and can affect genetic diseases.37Zhenet al.11comprehensively screened the exon sequence data of 1,326 genes in 32,043 Chinese Han individuals and identified 29 unreported InDels among 25 susceptibility genes related to psoriasis. The study identified 12 common, 9 low-frequency, and 8 rare InDels, which explained about 1.29% of psoriasis heritability. These unreported susceptibility genes are involved in many aspects of psoriasis, such as immunity and keratinocyte differentiation. These findings further enrich our understanding of the pathogenesis of psoriasis and other complex genetic diseases.11Recently, on the basis of SVs,Zhenet al.12further used fine-mapping analysis, genetic interaction analysis, and RNA expression analysis to show that esv3608550 and esv3608542 were independently associated with psoriasis, and a new independent SNP(rs9378188) was found at 6q21.33.

Genomic SVs are usually described as long sequence changes and positional relationship changes in the genome. There are many types of SVs in the genome,including insertion or deletion of long fragments exceeding 50 bp, tandem repetition, chromosome inversion,sequence translocation within or between chromosomes,CNVs, and more complex chimeric variations.38

SVs can affect the stability of the genome as well as the expression and regulation of related genes, finally determining the phenotype of a species. Statistical data indicate that ＞20,000 SVs exist in each human genome,which may lead to ＞1,000 diseases, including autism, neurodegenerative conditions, schizophrenia, and cancer.39The impact of SVs is greater than that of SNVs/SNPs or InDels.

There is an important association between SV and psoriasis. Zhenet al.12scanned 5 independent cohorts of 45,386 subjects from a Chinese Han population on a large scale to study the relationship between SVs and psoriasis. In total, 4,535 SVs were obtained; among these, 2 new deletions were found in 6q21.33 (MHC), a new Alu insertion was found in 5q33.3 (IL12B), and a previously reported deletion was verified in 1q21.1.2 (LCE). Based on genetic interaction analysis and RNA expression analysis,the association between the two deletions of 6q21.33 and psoriasis might be related to its effect on the expression of HLA-C. This study systematically explained the genetic susceptibility mechanism and genetic etiology of psoriasis, constructed the most complete SV map of psoriasis to date, provided evidence that SV was independently related to psoriasis and proposed its possible mechanism of action, and offered new ideas and directions for a more comprehensive and refined genomics study related to psoriasis.

Expansion of research on genomic variation in psoriasis

As analyses of genomic variation become more widely used in many diseases, researchers are beginning to realize that most of the changes found by genomic variation alone cannot fully explain the risk of disease. Because the pathogenesis of psoriasis involves more than genetic and immune factors,40it cannot be analyzed by a single method. Follow-up studies on genomic variation need to expand to new methods and research areas, such as high-throughput sequencing, epigenomics, genotype filling, structural genomics, functional genomics, comparative studies, and other methods to capture rare pathogenic variations. Using combinations of these new methods, findings regarding pathogenicity variations will complement the research results of genomic variation and thus more accurately reveal the complex pathogenesis of diseases.

Epigenomics

The field of epigeneticmodification at the genome level is known as epigenomics. Epigenomics adds a new perspective to the understanding of genomes: not only do sequences contain genetic information, but their modifications can also record it.

The methylated H3K4 level changes significantly in patients who respond to biological drugs, suggesting that H3K27 and H3K4 methylation may contribute to patients’ response to biological drugs and serve as an indicator in psoriasis.41However, it cannot be concluded that DNA methylation directly increases or decreases the expression of related genes because the expression of these genes is regulated by a complex network including DNA methylation, miRNA, histone modification, and transcription factor binding.

When she began to weep and to say, Dearest sweetheart, I freed you in the horrible wild wood, and from an iron stove, he jumped up and said, You are right

Functional genomics

Functional genomics refers to the science of organically linking the genome sequence with gene function (including gene network) and phenotype at the system level by using various omics techniques based on genome sequence information, finally revealing the functions of biological systems at different levels in nature.Functional genomics uses isolated genes of unknown function as a starting point. For example, activation of NF-KB signaling triggers A20 ubiquitination, which prevents subsequent NF-KB activation of TNFAIP3 gene polymorphisms associated with susceptibility to multiple autoimmune diseases.

In-depth analysis of genomic variation data of psoriasis

With the continuous innovation of sequencing technology,a large amount of information about psoriasis genomic variation has been excavated from the first to third generations. However, how to make full use of these data and apply the genome results to clinical practice remains challenging.

Bioinformatics analysis of genes has allowed researchers to predict key epigenetic differentially expressed genes through integrated bioinformatics analysis, and S100A9 was identified as a new biomarker of psoriasis.42

Spatio-temporal gene expression profile analysis,including both mRNA-level and protein-level expression profile analysis, combined with expression profile analysis revealed the association between psoriasis and the IL-23 and NF-κ B pathway.43

Other analyses include gene function prediction, functional prediction using bioinformatics, and structural prediction of gene function. Genome-wide pathway analysis allows the integration of these genetic and biological aspects to test functional genes associated with complex traits.

Clinical transformation of genomic variation in psoriasis

A possible disease mechanism is commonly obtained on the basis of genetics and then verified by a series of in vitro experiments. However, only a few such results can be applied to clinical practice. More efforts are needed to achieve smooth flow from basic research to diagnosis and treatment and finally to clinical applications. The following aspects reflect the close relationship between psoriasis genomic variation and clinical applications.

Disease risk prediction

Through predictive genetic examination, the application of genomic medicine in diagnosis and prevention has begun. A computational program to predict the development of psoriatic arthritis (PsA) in patients with psoriasis has been introduced. Researchers have identified genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis and evaluated the performance of PsA risk prediction models.44The findings suggest that the potential genetic differences among psoriatic subtypes can be used for risk assessment of individual subtypes.

Drug development

As early as 20 years ago, Zhanget al.45began to explore the pathogenesis of psoriasis and found that IL-15 was a psoriasis susceptibility gene and was highly expressed in patients with psoriasis vulgaris. IL-15 stimulates T cells to produce IL-17, which stimulates the excessive proliferation of keratinocytes that results in the formation of thick scales in patients with psoriasis.45Based on this study,foreign pharmaceutical companies have successfully developed biological agents aimed at IL-17 targets, and these agents have shown very good therapeutic effects in the clinical setting. In 2009, we performed a GWAS and became the first team worldwide to discover the psoriasis susceptibility gene LCE; we also and found 6 new psoriasis susceptibility genes. Repeated study of the gene loci has shown that IL-12 and IL-23 are psoriasis susceptibility genes, and corresponding biological agents have since been developed. Half of the susceptibility genes for psoriasis were discovered by team from the Department of Dermatology of the First Affiliated Hospital of Anhui Medical University,and eventually used as drug targets to develop biological agents. At present, the most common clinical biological agents in China can be classified according to their targets: TNF-α (enalapril, infliximab,and adalimumab), IL-12/23 (Ulsinumab, Gusecciumab),and IL-17 (Treasurer Chiumab, etchizumab).46

Drug clinical guidance

The team from the Department of Dermatology of the First Affiliated Hospital of Anhui Medical University analyzed the efficacy of methotrexate in patients with different genotypes based on susceptibility genes found by GWASs, such as TNIP1, LCE3D, and HLA-Cw6. The results showed that the TT genotype with the rs10036748 locus of the TNIP1 gene could improve the efficacy of methotrexate in the treatment of psoriasis from 45% to 70%. Cyclosporine and abamectin are the other 2 main systemic drugs used for the treatment of psoriasis. One study detected a polymorphism of the apolipoprotein E gene, and a second study showed that a variation at position 460 in the vascular endothelial growth factor gene was significantly associated with resistance to acitretin in patients with psoriasis.47

Prediction of adverse drug reactions

Pharmacogenetics is the study of whether and how genetic mutations affect a patient’s response to drugs,including identification of predictors of efficacy and toxicity. Methotrexate treatment in patients with and without arthropathic psoriasis showed dizziness in 9.4% and 0.9% of patients, gastrointestinal symptoms in 25.0%and 12.1%, and hepatotoxicity in 26.6% and 15.0%,respectively. Methotrexate can inhibit the secretion of folic acid; therefore, patients should be supplemented with folic acid. Additionally, the gene MTHFR reportedly contains an SNP associated with increased hepatotoxicity. MTHFR is essential for thymidine synthesis and is necessary for cell proliferation. Interestingly, the same SNP is associated with a higher risk of adverse reactions in patients with rheumatoid arthritis treated with methotrexate.48

Genomic variation and precision medicine

The term “genome” was first proposed in 1920 and includes both genes and noncoding DNA; that is, it is the completed DNA sequence in a set of chromosomes of an organism. The Human Genome Project, a worldwide collaborative biological endeavor, was officially launched in 1990. Genomics research is closely related to precision medicine. Since Obama put forward the “Precision Medicine Initiative” in his State of the Union Address,precision medicine has been receiving increasingly more attention. Using gene sequencing to find the pathogenic basis of disease represents a new way of thinking. In addition to gene sequencing, the development of genomics is also an important technology and includes fields such as metabolomics, transcriptomics, and proteomics. In the case of psoriasis, genomic variation studies have revealed many disease susceptibility genes, thus helping to speed up the development of new therapeutic approaches and methods.The current research can provide a basis for dermatologists to make a prenatal diagnosis, for example. However,because some patients with psoriasis have a family history,genetic diagnosis is of great help in treatment of the disease. The team from the Department of Dermatology of the First Affiliated Hospital of Anhui Medical University has found ＞80 susceptibility genes and finally found that 14 occupy a certain position, providing a large number of prediction indicators with quite high accuracy. For example, through exome sequencing, the team found that there are also coding variants in susceptibility genes, and some of these coding variants (eg, IL-23) have been developed into a new preparation for the treatment of psoriasis. In fact, this may allow us to describe a patient’s psoriasis as,for example, psoriasis associated with the CARD14 gene.Although the symptoms are similar, the underlying triggers may be different. Patients with psoriasis caused by specific mutations may be more likely to benefit from specific treatments. Genomic variation research will certainly play an important role in developing individual treatments of psoriasis and precise immunotherapy.

Study limitations are as follows: this review summarizes the main development of the genomic variation research of psoriasis at home and abroad, but because there are many studies in this field and the research methods are changing with each passing day, it is impossible to search all the related literatures. The purpose of this article is to provide a reference basis and make a certain contribution to promoting the research process in this field.