Loricrin Gene Research Articles

Genetic Susceptibility to Astrovirus Diarrhea in Bangladeshi Infants.

Astroviral infections commonly cause acute nonbacterial gastroenteritis in children globally. However, these infections often go undiagnosed outside of research settings. There is no treatment available for astrovirus, and Astroviridae strain diversity presents a challenge to potential vaccine development. To address our hypothesis that host genetic risk factors are associated with astrovirus disease susceptibility, we performed a genome-wide association study of astrovirus infection in the first year of life from children enrolled in 2 Bangladeshi birth cohorts. We identified a novel region on chromosome 1 near the loricrin gene (LOR) associated with astrovirus diarrheal infection (rs75437404; meta-analysis P = 8.82 × 10-9; A allele odds ratio, 2.71) and on chromosome 10 near the prolactin releasing hormone receptor gene (PRLHR) (rs75935441; meta-analysis P = 1.33 × 10-8; C allele odds ratio, 4.17). The prolactin-releasing peptide has been shown to influence feeding patterns and energy balance in mice. In addition, several single-nucleotide polymorphisms in the chromosome 1 locus have previously been associated with expression of innate immune system genes PGLYRP4, S100A9, and S100A12. This study identified 2 significant host genetic regions that may influence astrovirus diarrhea susceptibility and should be considered in further studies.

The Epidermal Transcriptome Analysis of a Novel c.639_642dup LORICRIN Variant-Delineation of the Loricrin Keratoderma Pathology.

Loricrin keratoderma (LK) is a rare autosomal dominant genodermatosis caused by LORICRIN gene mutations. The pathogenesis of the disease is not yet fully understood. So far, only 10 pathogenic variants in LORICRIN have been described, with all of them but one being deletions or insertions. The significance of rare nonsense variants remains unclear. Furthermore, no data regarding the RNA expression in affected patients are available. The aim of this study is to describe the two variants in the LORICRIN gene found in two distinct families: the novel pathogenic variant c.639_642dup and a rare c.10C > T (p.Gln4Ter) of unknown significance. We also present the results of the transcriptome analysis of the lesional loricrin keratoderma epidermis of a patient with c.639_642dup. We show that in the LK lesion, the genes associated with epidermis development and keratocyte differentiation are upregulated, while genes engaged in cell adhesion, differentiation developmental processes, ion homeostasis and transport, signaling and cell communication are downregulated. In the context of the p.Gln4Ter clinical significance evaluation, we provide data indicating that LORICRIN haploinsufficiency has no skin consequences. Our results give further insight into the pathogenesis of LK, which may have therapeutic implications in the future and important significance in the context of genetic counseling.

Dermoscopic furrow ink test of the palmar lesion in loricrin keratoderma.

Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization disorders that gradually progress during childhood, resulting in difficulties to establish a diagnosis and to identify a candidate gene for sequencing. Dermoscopic examination with staining of palmoplantar skin using a whiteboard marker, so-called "furrow ink test", could be a useful tool for differentiation between furrow and ridge in understanding the morphological characteristics of PPK. One of the striking features in autosomal dominant loricrin keratoderma (LK) is diffuse PPK with honeycomb pattern. In this study, we performed dermoscopic furrow ink test in a Japanese family of LK with the most frequent mutation c.684dup, p.Ser229Valfs*107 in the loricrin gene. The severe lesion revealed that irregular circular hyperkeratoses were aggregated and normal structures of furrows and ridges were disrupted. To accurately describe the nature of this dermoscopic patterned skin surface, we suggest that the condition could be termed as "irregular cobblestone appearance" rather than "honeycomb pattern". Regular cobblestone appearance to maintain parallel furrow structure was observed in early or mild hyperkeratotic lesions. Eccrine sweat glands that open on the surface of ridges nearly disappeared, resulting in hypohidrosis.

Messenger RNA (mRNA)-based age determination using skin-specific markers of saliva epithelial cells

BackgroundAge determination is a vital factor in biological identification in forensics. This study was carried out to determine the expression levels of three target genes (Keratin 9 (KRT9), Loricrin (LOR) and Corneodesmosin (CDSN)) in salivary epithelial cells and how they can be used in age determination using reference gene, β-actin. Thirty young adults participated in the study and were divided into three groups according to their ages (16–20, 21–25, and 26–30). Ribonucleic acid (RNA) extraction, complementary deoxyribonucleic acid (cDNA) synthesis and quantitative polymerase chain reaction (qPCR) were performed. Data analysis was done using IBM SPSS Version 26 and the comparative Ct method (2−∆∆Ct method).ResultsCDSN was detected in all the sampled age groups. Though the age group 16–20 had the highest (0.4237) expression of CDSN among the three age groups, there was no significant difference (p > 0.05) in the expression of the gene among the three age groups. The LOR gene was lowly expressed across all age groups used in the study. The expression of the gene did not significantly differ (p > 0.05) between the control and 26–30 years age group, but they were however significantly higher (F = 36.47, p ≤ 0.05) than the expression of the gene in both 16–20 and 21–25 years age groups. The KRT9 gene was expressed only in age groups 16–20 and 26–30 and the expression of the gene did not significantly (p > 0.05) differ between these age groups. Though the expression of all the target genes was low, it was observed that the LOR gene expression varied among 21–25 and 26–30 age groups; therefore, more data and further analyses are still required since this experimental approach for age determination using gene expression is still at an emerging stage.ConclusionAlthough RNA concentration was low and the expression values of the genes were low and could not be used in comparing the expression levels among the three age groups, it can be concluded that the three messenger ribonucleic acid (mRNA) markers CDSN, LOR and KRT9, as well as the ACTB reference mRNA marker analysed via the described qPCR assays, are suitable for identifying epithelial cells in saliva.

Endophenotypic Variations of Atopic Dermatitis by Age, Race, and Ethnicity

Atopic dermatitis (AD) is a heterogeneous disease with unique clinical manifestations across age groups and race/ethnicities. Characteristic molecular mechanisms, known as endotypes, including IgE level, status of epidermal barrier genes, and differential cytokine axes activation in the background of TH2 upregulation, are also implicated. In adults, the TH22, TH17, and TH1 pathways are involved, and a weakened epidermal barrier is characteristic. In contrast, pediatric patients exhibit less TH1 activation, and defects in epidermal lipid metabolism contribute to their barrier defect. European American patients are characterized by higher differential TH2/TH22 activation, lower expression of the TH1/TH17 axes, and suppression of filaggrin (FLG) and loricrin gene expressions. Asian patients have accentuated polarity of the TH22/TH17 pathways, and also exhibit epidermal barrier defects despite relative maintenance of FLG and loricrin expression. African American patients do not exhibit FLG mutations and have distinct attenuation of TH17/TH1 axes activation. Dissecting the molecular basis of AD endotypes has provided an important framework upon which targeted therapeutics are being developed. An increased understanding of these subtypes and the alteration of biomarkers that correlate with disease can ultimately push AD treatment in an era of personalized medicine.

Novel ELOVL4 mutation associated with erythrokeratodermia and spinocerebellar ataxia (SCA 34).

Erythrokeratodermia (EK) is a rare skin disorder, likely genetic and usually present from infancy.1 There is patchy symmetrical involvement over the body surface, manifested in progressive figurate plaques of hyperkeratosis and more transient areas of erythema. There is significant overlap in the clinical and genetic features of the “variabilis” and “progressiva” forms of EK. Restricted cutaneous syndromes of EK have been described associated with mutations in the connexin ( GJB3, GJB4 , and GJA1 ) and loricrin ( LOR ) genes. The majority of patients with EK, however, have no pathogenic mutations in the GJB genes or LOR .

Loricrin and skin diseases

Loricrin, as the major component of the cornified envelope, plays an important role in epidermal barrier function. The expression of loricrin gene is co-regulated by complex interactions between multiple transcription factors. Loricrin gene mutations can lead to loricrin keratoderma. Nuclear translocation of mutant loricrin can interfere with terminal differentiation of keratinocytes, and cause corresponding clinical phenotypes. In addition, the expression of loricrin is decreased in lesions of atopic dermatitis and psoriasis, which may be attributed to some cytokines. Key words: Skin diseases; Gene expression regulation; Mutation; Psoriasis; Loricrin; Skin barrier

Galactomyces fermentation filtrate prevents T helper 2-mediated reduction of filaggrin in an aryl hydrocarbon receptor-dependent manner.

The aryl hydrocarbon receptor (AhR) recognizes diverse small molecules such as dioxins, tryptophan photoproducts and phytochemicals. It also plays crucial roles in epidermal homeostasis by upregulating epidermal barrier proteins. In preliminary screening, we found that Galactomyces fermentation filtrate (GFF), a cosmetic compound, was capable of activating AhR. To examine whether GFF upregulates the expression of the filaggrin and loricrin genes, FLG and LOR, in an AhR-dependent manner. The activation (cytoplasmic to nuclear translocation) of AhR was confirmed by immunofluorescence study and by upregulation of an AhR-specific marker, cytochrome P450-1A1 (CYP1A1). Gene expression levels were compared by quantitative reverse transcription PCR with or without GFF, interleukin (IL)-4 or IL-13 in normal human keratinocytes. AhR or control knockdown was carried out by transfection with AhR or control small interfering RNA. The protein expression of FLG and LOR was examined by immunohistochemistry using a three-dimensional epidermal equivalent treated with or without GFF or T helper (Th)2 cytokines. GFF induced the nuclear translocation of AhR with significant and dose-dependent upregulation of CYP1A1, FLG and LOR gene expression. The enhancing effects of GFF were abolished in AhR-knockdown keratinocytes. Th2 cytokines decreased expression of genes for FLG and LOR, and this expression was completely restored in the presence of GFF. The downregulated expression of the FLG gene with its restoration by GFF was also evident in the epidermal equivalent. GFF also upregulated the gene expression of genes encoding occludin, claudin-1 and 4, and kallikrein 5 and 7. Use of GFF is feasible to prevent the Th2-mediated reduction of FLG in an AhR-dependent fashion.

Evaluation of Gene Expression Using a Skin Tape Stripping Method

E S D A Y 848 Evaluation of Gene Expression Using a Skin Tape Stripping Method Byung Eui Kim, MD, PhD, Un Ha Lee, Peter Sang Kim, Donald Y. M. Leung, MD, PhD, FAAAAI; National Jewish Health, Denver, CO, Inje University, Paik Hospital, National Jewish Health. RATIONALE: Skin tape stripping is a non-invasive method used to evaluate epidermal protein expression. However, this technique has not been verified whether this skill is reliable to evaluate gene expression. METHODS: Skin tape stripping samples and skin punch biopsies were collected from 10 normal subjects and 10 patients with atopic dermatitis (AD). Total RNAwas isolated from the same donors for skin tape stripping samples and skin biopsies, and then real time RT-PCR was performed for filaggrin (FLG), thymic stromal lymphopoietin (TSLP) and loricrin (LOR). RESULTS: FLG gene expression was significantly decreased in lesional AD skin compared with skin from normal subjects in both tape stripping samples (P<0.05) and skin biopsies (P<0.05). LOR gene expression was also significantly decreased in lesional AD skin compared with skin from normal subjects in skin tape stripping samples (P<0.01) and skin biopsies (P<0.05). Additionally, LOR gene expression was significantly decreased (P<0.05) in nonlesional AD skin compared with normal subjects in tape stripping samples. TSLP gene expression from tape stripped samples was significantly increased in lesional AD skin compared with skin from normal subjects (P<0.05) and nonlesional AD (P<0.05). CONCLUSIONS: Using PCR data from both tape stripping samples and skin biopsies, we have found reduced filaggrin and loricrin, but increased TSLP, gene expression in AD. Skin tape stripping method may be used to examine gene expression in the skin since it is a non-invasive, and can be used for serial evaluation of the skin and protein expression. However, further study is required to validate this method.

Dominant Proportion of Staphylcoccus Aureus in the Skin of Atopic Dermatitis Patients through Metagenomic Analysis

E S D A Y 848 Evaluation of Gene Expression Using a Skin Tape Stripping Method Byung Eui Kim, MD, PhD, Un Ha Lee, Peter Sang Kim, Donald Y. M. Leung, MD, PhD, FAAAAI; National Jewish Health, Denver, CO, Inje University, Paik Hospital, National Jewish Health. RATIONALE: Skin tape stripping is a non-invasive method used to evaluate epidermal protein expression. However, this technique has not been verified whether this skill is reliable to evaluate gene expression. METHODS: Skin tape stripping samples and skin punch biopsies were collected from 10 normal subjects and 10 patients with atopic dermatitis (AD). Total RNAwas isolated from the same donors for skin tape stripping samples and skin biopsies, and then real time RT-PCR was performed for filaggrin (FLG), thymic stromal lymphopoietin (TSLP) and loricrin (LOR). RESULTS: FLG gene expression was significantly decreased in lesional AD skin compared with skin from normal subjects in both tape stripping samples (P<0.05) and skin biopsies (P<0.05). LOR gene expression was also significantly decreased in lesional AD skin compared with skin from normal subjects in skin tape stripping samples (P<0.01) and skin biopsies (P<0.05). Additionally, LOR gene expression was significantly decreased (P<0.05) in nonlesional AD skin compared with normal subjects in tape stripping samples. TSLP gene expression from tape stripped samples was significantly increased in lesional AD skin compared with skin from normal subjects (P<0.05) and nonlesional AD (P<0.05). CONCLUSIONS: Using PCR data from both tape stripping samples and skin biopsies, we have found reduced filaggrin and loricrin, but increased TSLP, gene expression in AD. Skin tape stripping method may be used to examine gene expression in the skin since it is a non-invasive, and can be used for serial evaluation of the skin and protein expression. However, further study is required to validate this method.

Short-Term Effect of Airborne Formaldehyde on Skin Barrier Function in Atopic Dermatitis

E S D A Y 848 Evaluation of Gene Expression Using a Skin Tape Stripping Method Byung Eui Kim, MD, PhD, Un Ha Lee, Peter Sang Kim, Donald Y. M. Leung, MD, PhD, FAAAAI; National Jewish Health, Denver, CO, Inje University, Paik Hospital, National Jewish Health. RATIONALE: Skin tape stripping is a non-invasive method used to evaluate epidermal protein expression. However, this technique has not been verified whether this skill is reliable to evaluate gene expression. METHODS: Skin tape stripping samples and skin punch biopsies were collected from 10 normal subjects and 10 patients with atopic dermatitis (AD). Total RNAwas isolated from the same donors for skin tape stripping samples and skin biopsies, and then real time RT-PCR was performed for filaggrin (FLG), thymic stromal lymphopoietin (TSLP) and loricrin (LOR). RESULTS: FLG gene expression was significantly decreased in lesional AD skin compared with skin from normal subjects in both tape stripping samples (P<0.05) and skin biopsies (P<0.05). LOR gene expression was also significantly decreased in lesional AD skin compared with skin from normal subjects in skin tape stripping samples (P<0.01) and skin biopsies (P<0.05). Additionally, LOR gene expression was significantly decreased (P<0.05) in nonlesional AD skin compared with normal subjects in tape stripping samples. TSLP gene expression from tape stripped samples was significantly increased in lesional AD skin compared with skin from normal subjects (P<0.05) and nonlesional AD (P<0.05). CONCLUSIONS: Using PCR data from both tape stripping samples and skin biopsies, we have found reduced filaggrin and loricrin, but increased TSLP, gene expression in AD. Skin tape stripping method may be used to examine gene expression in the skin since it is a non-invasive, and can be used for serial evaluation of the skin and protein expression. However, further study is required to validate this method.

Progressive Symmetric Erythrokeratoderma. First case reported in the Dominican Republic

Progressive symmetric erythrokeratoderma (PSEK) is an autosomal dominant genodermatosis with incomplete penetrance and variable expressivity. It belongs to the group of erythrokeratodermas where it can be differentiated from erythrokeratoderma variabilis in the absence of migratory erythematous lesions and in a greater incidence of palmoplantar keratoderma. Molecular basis of PSEK has not yet been established although there are reports of mutations in the loricrin gene. We report a 13-year-old boy with symmetrically distributed hyperkeratotic plaques over the dorsum of the hands and the extensor aspect of the forearms, elbows and knees. As far as we are aware, we report the first case of PSEK in the Dominican Republic.

Mutation analysis for GJB2 and LOR genes in two patients with Vohwinkel syndrome

To assess the association between matrix metalloproteinase-3 (MM-3) gene polymorphisms and subtypes of ischemic stroke (IS) in northern Han Chinese population. A total of 289 patients with acute IS (within 3 days after the onset, including 185 with large artery atherosclerosis (LAA) and 104 for small artery occlusion (SAO)) and 175 matched healthy controls were recruited for this case-control study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or sequenc-based typing (SBT) was carried out to analyze 3 SNPs of the MMP-3 gene. An incomplete linkage disequilibrium (LD) block was constructed with the 3 SNPs, and the distribution of genotypes of the 3 SNPs differed between the LAA group and controls in a dominant model: Carriers of 5A allele (5A5A+5A6A) of the rs3025058 locus were 1.72 times more susceptible to LAA stroke compared with carriers of 6A6A alleles (P=0.017, OR=1.72, 95% CI: 1.10-2.69), carriers of G alleles (GG+AG) of the rs522616 locus were 0.52 times more susceptible to LAA stroke compared with carriers of AA alleles (P=0.005, OR=0.52, 95% CI: 0.33-0.82), whilst carriers of A allele of the rs679620 locus were 1.55 times more susceptible to LAA stroke compared with carriers of GG alleles (P=0.042, OR=1.55, 95% CI: 1.01-2.37). However, no significant difference has been found between particular genotypes of such SNPs between SAO patients and controls (P> 0.05). Furthermore, 5A-A-A and 6A-A-A haplotypes were significantly more common in LAA group than the controls (P< 0.05), whilst 6A-G-G haplotype has been the opposite (P< 0.01). Our study has demonstrated that serum MMP-3 level is significantly increased at acute stage of LAA as well as SAO type strokes. There may be an association of rs3025058, rs522616 and rs679620 of MMP-3 gene with susceptibility to LAA stoke in northern Han Chinese population.

The POU domain transcription factors Oct-6 and Oct-11 negatively regulate loricrin gene expression in keratinocytes: association with AP-1 and Sp1/Sp3

Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific regulatory mechanisms for activation and suppression of loricrin gene transcription in differentiated keratinocytes. Here, we identified a regulatory element in the proximal promoter region of the loricrin gene involved in suppression of its expression in keratinocytes. A database search indicated that this sequence contained a POU transcription factor binding motif. Electrophoretic mobility shift assay revealed that Oct-1, Oct-6, and Oct-11 actually bind to the motif. Constructs with point mutations in the POU-binding motif showed increased reporter activity, indicating that the POU factors negatively regulate loricrin gene transcription. Cotransfection experiments suggested that Oct-6 and Oct-11 suppress loricrin gene transcription in a cooperative manner with AP-1 and Sp1. Furthermore, in vitro experiments indicated that the Oct-6 and Oct-11 can physically associate with both AP-1 factors and Sp1/Sp3. These findings indicate that Oct-6 and Oct-11 contribute to the regulation of loricrin gene transcription via interaction with AP-1 factors and Sp1/Sp3.

GATA‐3 regulates differentiation‐specific loricrin gene expression in keratinocytes

Loricrin is a major component of the epidermal cornified cell envelope and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific regulatory mechanisms for activation of loricrin gene transcription in differentiated keratinocytes. Here, we identified a positive regulatory element in the proximal promoter region of the loricrin gene involved in activation of its expression in differentiated keratinocytes. A database search indicated that this sequence contained a GATA-3 binding motif. Constructs with point mutations in the GATA-3 binding motif showed decreased reporter activity, indicating that GATA-3 positively regulates loricrin gene transcription. Western blotting analysis indicated that GATA-3 is more abundant in differentiated than in undifferentiated keratinocytes. Cotransfection experiments indicated that GATA-3 activates transcription of the loricrin gene in a cooperative manner with c-Fos and Sp1. These findings indicate that GATA-3 contributes to keratinocyte differentiation-specific activation of loricrin gene transcription via interaction with c-Fos and Sp1.

Collodion baby and loricrin keratoderma: a case report and mutation analysis

Hereditary palmoplantar keratodermas (PPK) comprise a clinically and genetically heterogeneous group of genodermatoses, which share the characteristic of impaired epidermal differentiation, resulting in prominent palmoplantar hyperkeratosis. Molecular genetic analyses have helped characterize the underlying genetic defects in an increasing number of hereditary PPKs over the past two decades, and thus a pathophysiological classificaiton seems more reasonable. Today PPK can be classified based on defects in keratins, loricrin, desmosomes, connexins and cathepsins. In this report, we describe a 22-year-old man who had been born a collodion baby, and later developed diffuse PPK with pseudoainhum and generalized ichthyosis. His mother and grandmother had similar characteristics. Direct sequencing of genomic DNA identified a frameshift insertion mutation (730insG) in the loricrin gene. This family had the typical presentation of loricrin keratoderma. It also indicates that collodion baby may be the first presentation in patients with loricrin keratoderma.

Evidence for the absence of mutations at GJB3, GJB4 and LOR in progressive symmetrical erythrokeratodermia

Progressive symmetrical erythrokeratodermia (PSEK) is a rare inherited cornification disorder characterized by symmetrical erythematous hyperkeratotic plaques. The genetic basis for PSEK is not clear. PSEK shares many clinical features with erythrokeratodermia variabilis (EKV), which is associated with mutations in genes coding for gap junction beta (GJB) 3 and 4. A mutation in the loricrin gene (LOR) was found in patients with PSEK, who were members of a family with Vohwinkel syndrome. It would therefore be of interest to determine if PSEK is also caused by mutations in these genes. To examine the mutation status of GJB3, GJB4 and LOR in patients with PSEK and in control subjects. Genomic DNA samples from 25 patients with PSEK and 56 healthy controls were examined by sequencing analysis of the coding sequences of GJB3, GJB4 and LOR. There were no mutations found in any of these three genes. PSEK is a disorder distinct from EKV, and the true pathogenesis of PSEK remains unknown.

Activation of Vascular Endothelial Growth Factor Receptor 2 in a Cellular Model of Loricrin Keratoderma

Loricrin is a major constituent of the epidermal cornified cell envelope. Recently, heterozygous loricrin gene mutations have been identified in two dominantly inherited skin diseases, Vohwinkel syndrome with ichthyosis and progressive symmetric erythrokeratoderma, collectively termed loricrin keratoderma. We generated stable HaCaT cell lines that express wild-type (WT) loricrin and a mutant form found in Vohwinkel syndrome with ichthyosis, using an ecdysone-inducible promoter system. The cells expressing the mutant loricrin grew more rapidly than those expressing WT loricrin after induction for 5 days. Confocal immunofluorescence microscopy revealed that phospho-Akt occurred in the nucleolus where the mutant loricrin was also located. The level of activity of Akt kinase was about nine times higher in cells with the mutant than in those with WT loricrin. ERK1/2, the epidermal growth factor receptor, vascular endothelial growth factor (VEGF) receptor 2 and Stat3 were all phosphorylated in cells with the mutant loricrin. The docking proteins, Gab1 and c-Cbl, were also tyrosine-phosphorylated in these cells. Furthermore, chromatin immunoprecipitation assays showed that Stat3 protein bound to the VEGF promoter in cells with the mutant. Thus, this study suggests that VEGF release and the subsequent activation of VEGF receptor 2 link loricrin gene mutations to rapid cell proliferation in a cellular model of loricrin keratoderma.

Association of Skin Barrier Genes within the PSORS4 Locus Is Enriched in Singaporean Chinese with Early-Onset Psoriasis

Psoriasis (OMIM#177900) is a common polygenic skin disorder affecting approximately 2% of the northern European population and 0.1% of the Han Chinese. Psoriasis patients suffer from chronic skin inflammation, manifested by erythematous scaly lesions. PSORS1-PSORS9 have been confirmed as psoriasis susceptibility loci in independent genetic studies on predominantly Caucasian populations, with psoriasis susceptibility loci (PSORS1, PSORS9) and additional loci at 9q33-34 and 2p22.3-11.2 reported in Han Chinese patients. In this study, we show the association of PSORS4 with psoriasis in Singaporean Chinese. Dense genotyping of single-nucleotide polymorphism-tagging candidate genes within the epidermal differentiation complex revealed significant association in the proximity of the involucrin gene (IVL); the strongest association was seen in early-onset psoriasis patients (P=0.0014). A follow-up genome-wide association screen localized the psoriasis susceptibility region to approximately 360 kb along chromosome 1 in the vicinity of IVL, small proline-rich region (SPRR) and proline-rich region 9 (PRR9) genes. The study of interactions between the causative variant(s) in this locus will provide insights into a possible role for epidermal barrier formation in the pathogenesis of psoriasis.

Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families

A susceptibility locus for psoriasis, PSORS4, has been mapped to chromosome 1q21 in the region of the epidermal differentiation complex. The region has been refined to a 115 kb interval around the loricrin (LOR) gene. However, no evidence of association between polymorphisms in the LOR gene and psoriasis has been found. Therefore, we have analysed association to three candidate gene clusters of the region, the S100, small proline-rich protein (SPRR) and PGLYRP (peptidoglycan recognition protein) genes, which all contain functionally interesting psoriasis candidate genes. In previous studies, the SPRR and S100 genes have shown altered expression in psoriasis. Also polymorphisms in the PGLYRP genes have shown to be associated with psoriasis. We genotyped altogether 29 single nucleotide polymorphisms (SNPs) in 255 Finnish psoriasis families and analysed association with psoriasis using transmission disequilibrium test. A five-SNP haplotype of PGLYRP SNPs associated significantly with psoriasis. There was also suggestive evidence of association to SPRR gene locus in Finnish families. To confirm the putative associations, selected SNPs were genotyped also in a family collection of Swedish and Irish patients. The families supported association to the two gene regions, but there was also evidence of allelic heterogeneity.