The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta‐analysis

Background Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient‐based case‐control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. Objectives To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross‐sectional general population questionnaire data. Also, to perform a meta‐analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. Methods Between June 2006 and May 2008, a cross‐sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18–69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta‐analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris. Results The prevalence of self‐reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74–1.89; P = 0.78). The meta‐analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81–1.35). Conclusions Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta‐analysis on published studies.     

Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis

Background Filaggrin is a key protein involved in maintaining skin barrier function and hydration. Mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and are a major predisposing factor for atopic dermatitis (AD) in individuals of European and Asian descent. It has been proposed that FLG mutations are population specific and a difference in the spectra of mutations between different ancestral groups has been described. However, it is unknown whether FLG mutations in the African population are a causative genetic factor for IV and predispose to AD, or whether other mechanisms are more prominent. Objectives The present aim was to investigate the role of FLG mutations as predisposing factors for IV or AD among individuals from Ethiopia. Methods A case series of Ethiopian patients with AD (n = 103) and IV (n = 7) together with controls (n = 103; subjects without past or present history of AD, dry skin or atopic manifestations) was collected at the outpatient dermatology clinics at ALERT Dermatology Hospital, Tikur Anbessa Hospital and Gondar University Hospital, Ethiopia. AD was diagnosed by a dermatologist using the U.K. Working Party’s diagnostic criteria. The IV diagnosis was based on clinical examination and genetic testing of the steroid sulphatase gene to exclude X‐linked recessive ichthyosis. Patients were studied with direct sequencing (n = 40) and/or allelic discrimination (n = 110). Immunohistochemical analysis was performed for filaggrin expression in the skin of patients (n = 7) and controls (n = 2). Results The Ethiopian patients and controls were genotyped for the four previously described common European FLG null mutations (R501X, 2282del4, S3247X, R2447X) and no carriers were found. In one patient with AD a novel heterozygous 2‐bp deletion, 632del2, leading to a premature stop codon was revealed by direct sequencing. No additional carrier of this deletion or other mutations was found. In addition, no difference in filaggrin expression was detected in AD or IV skin compared with healthy control skin. Conclusions Our results indicate that FLG loss‐of‐function‐variants are less common in patients with IV and AD in the Ethiopian population, suggesting that other factors may be of importance in the pathogenesis in this ethnic group.     

Filaggrin compound heterozygous patients carry mutations in trans position

More than 40 null mutations in the filaggrin (FLG) gene are described. It is therefore possible to find two different null mutations in one individual (compound heterozygosity). It has been generally perceived that homozygous and compound heterozygous individuals were genotypically comparable; however, this has not been scientifically investigated. Two different FLG null mutations in the same individual may be in trans position, meaning that each mutation locates to a different allele functionally equivalent to homozygosity, or may be in cis position, meaning that both mutations locate to the same allele functionally equivalent to heterozygosity. To experimentally investigate allelic in cis versus in trans configuration of the two most common filaggrin (FLG) mutations (R501X and 2282del4) in compound heterozygous individuals. Testing for in cis or in trans allele configuration was performed by means of allele‐specific PCR amplification and analysis of PCR products by agarose gel electrophoresis. All R501X/2282del4 compound heterozygous samples collected over a 4‐year period of routine FLG mutation testing were investigated. In total, 37 samples were tested. All thirty‐seven R501X/2282del4 compound heterozygous individuals were found to carry the two mutations in trans position. FLG null mutation compound heterozygous individuals can be considered functionally equivalent to FLG null mutation homozygosity for any of the two mutations.     

Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with atopic dermatitis

Background Recently, mutations in the filaggrin gene (FLG) have been shown to be a major predisposing factor for atopic dermatitis (AD). Objective In this study, we evaluated the influence of four prevalent mutations (R501X, 2282del4, R2447X and S3247X) in a large cohort of 462 Austrian and German AD patients and in 402 control individuals. Results We found a strong association of the FLG mutations with AD. Subgroup analysis revealed a significantly higher proportion of patients with an early age of disease onset and significantly higher median serum IgE levels among mutation carriers. Furthermore, we observed an overrepresentation of null alleles in AD patients with concomitant asthma compared with those without this co‐morbidity. Conclusion Our data confirm and extend the knowledge of the influence of FLG mutations in AD.     

Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis

Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.     

Ichthyosis vulgaris: novel FLG mutations in the German population and high presence of CD1a+ cells in the epidermis of the atopic subgroup

Background  Ichthyosis vulgaris (IV) is a genetic disorder with a prevalence of 1 : 250–1000 caused by filaggrin ( FLG ) mutations, which also predispose to atopic diseases.
Objectives  To study the genotype/phenotype relationship in IV and to analyse whether the suggested skin barrier defect is associated with differences of epidermal dendritic cells.
Patients/methods  We evaluated a cohort of 26 German patients with IV, established an IV severity score and analysed epidermal ultrastructure, histology, filaggrin and CD1a antigens. Mutations were screened by restriction enzyme analysis. Particular sequencing techniques allowed the complete FLG analysis to reveal novel mutations.
Results  The combined null allele frequency of R501X and 2282del4 was 67·3%. Patients also showed the mutations S3247X and R2447X as well as five novel FLG mutations: 424del17 and 621del4 (profilaggrin S100 domain), 2974delGA (repeat 2), R3766X (repeat 10₁) and E4265X (repeat 10₂). Their combined allele frequency in controls was < 0·7%. No mutation was found in one IV patient, all in all ∼27% were heterozygous, and the majority (∼69%) showed two null alleles. The IV severity score and ultrastructure showed a significant correlation with genotypes. Interestingly, CD1a cell counts showed a significant difference between nonatopic and atopic IV patients both with eczema and without eczema.
Conclusions  We confirm that the mutations R501X and 2282del4 represent the most frequent genetic cause in German IV patients. The novel mutations are probably population and family specific. The observed differences of CD1a cells support the hypothesis that there is a barrier defect that predisposes to atopic manifestations, possibly independent of atopic eczema.     

寻常型鱼鳞病一家系Filaggrin基因突变检测

目的探讨一家系寻常型鱼鳞病(ichthyosis vulgaris,IV)丝聚合蛋白(filaggrin,FLG)基因的突变。方法提取IV患者及其家庭成员和100例健康对照者基因组DNA,采用PCR及直接测序法,对FLG基因已报道的13个突变位点(3321delA,441delA,1249insG,E1795X,S3296X,R501X,2282del4,R2447X,S2889X,7945delA,3702delG,Q2417X,R4307X)进行测序。结果三代7位成员中4例IV患者同时检测到FLG(441delA)基因突变。结论患者FLG(441delA)基因突变可能导致其发病。     

Usefulness of a global clinical ichthyosis vulgaris scoring system for predicting common FLG null mutations in an adult caucasian population

Background Loss of function FLG alleles were first identified as causative of ichthyosis vulgaris (IV) and were subsequently found to be major predisposing factors for atopic dermatitis (AD) and atopic disorders. Objectives To identify independent factors associated with the clinical IV phenotype in adult caucasian patients with AD and to assess the performance of a global clinical severity score of IV in predicting common FLG null mutations. Patients and methods This was a prospective study conducted from January 2007 to June 2008. Adult patients attending the department of dermatology with a diagnosis of AD with or without IV were eligible to participate. For each patient, five clinical signs of IV were scored from 0 to 3 – diffuse xerosis, hyperlinearity of palms, scales on legs, scalp desquamation and keratosis pilaris – and a global IV clinical severity score was derived (0–15). Age of onset of AD, SCORAD (SCORing of Atopic Dermatitis), family and personal history for other signs of atopy, and total immunoglobulin E were recorded. Genotyping was performed for R501X and 2282del4. Univariate and multivariate analysis for factors associated with AD or AD + IV were conducted. Results In univariate analysis, family history of atopy, global clinical severity scoring and 2282del4 FLG mutation were positively correlated with the AD + IV phenotype. Using multivariate analysis, SCORAD for AD (OR 0·94, P = 0·01) and global clinical severity scoring for AD + IV (OR 2·62, P < 0·0001) were found to be independent factors. Conclusions The 2282del4 FLG mutation was confirmed as a good marker of early‐onset disease. Moreover, our global clinical severity score yielded a good negative predictive value of common caucasian null FLG mutations.     

Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children

Background Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined. Objectives This study investigated the genotype–phenotype association between detailed skin phenotype and FLG genotype data in a population‐based cohort of children. Methods Children (n = 792) aged 7–9 years were examined by a dermatologist. Features of ichthyosis vulgaris, atopic eczema and xerosis were recorded and eczema severity graded using the Three Item Severity score. Each child was genotyped for the six most prevalent FLG null mutations (R501X, 2282del4, R2447X, S3247X, 3702delG, 3673delC). Fisher’s exact test was used to compare genotype frequencies in phenotype groups; logistic regression analysis was used to estimate odds ratios and penetrance of the FLG null genotype and a permutation test performed to investigate eczema severity in different genotype groups. Results Ten children in this cohort had ichthyosis vulgaris, of whom five had mild–moderate eczema. The penetrance of FLG null mutations with respect to flexural eczema was 55·6% in individuals with two mutations, 16·3% in individuals with one mutation and 14·2% in wild‐type individuals. Summating skin features known to be associated with FLG null mutations (ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema) showed a penetrance of 100% in children with two FLG mutations, 87·8% in children with one FLG mutation and 46·5% in wild‐type individuals (P < 0·0001, Fisher exact test). FLG null mutations were associated with more severe eczema (P = 0·0042) but the mean difference was only 1–2 points in severity score. Three distinct patterns of palmar hyperlinearity were observed and these are reported for the first time. Conclusions Filaggrin haploinsufficiency appears to be highly penetrant when all relevant skin features are included in the analysis. FLG null mutations are associated with more severe eczema, but the effect size is small in a population setting.     

Combined occurrence of filaggrin mutations and IL-10 or IL-13 polymorphisms predisposes to atopic dermatitis

Background: Although filaggrin mutations are presently believed to play a key role in the development of atopic dermatitis (AD), obviously also immunological factors involved in acquired immune response are important for the development of allergic inflammation. Objective: To assess the frequency of FLG mutations and the polymorphisms 590 C/T in the IL‐4 gene, ‐1082A/G in the IL‐10 gene and ‐1055C/T in the IL‐13 gene in patients with AD and their correlations between severity of AD and asthma. Methods: R501X and 2282del4 FLG mutations and IL‐4, IL‐10 and IL‐13 polymorphisms were assayed in 163 patients with AD of Polish origin. Results: In the Polish patients with AD, the prevalence of FLG mutations was higher in patients with AD than in the controls and 2282del4 FLG mutation was more frequent than R501X, and it was associated with a 6‐fold higher risk for AD development (P < 0.001; OR: 5.76), moderate or severe disease course, early onset of asthma and palmar hyperlinearity. Significant interactions between the 2282del4 FLG mutation and the CT genotype for IL‐13 or GG genotype for IL‐10 and a higher risk for developing AD were demonstrated. Conclusion: FLG mutation, alone and in combination with certain IL‐10 or IL‐13 polymorphisms, enhances the risk for the development of AD in the Polish population.     

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study

Summary Background Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. Objectives To investigate the association between FLG null mutations and hand eczema. Methods A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. Results Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2·98; 95% confidence interval (CI) 1·27–7·01], but not in subjects without atopic dermatitis (OR 0·82; 95% CI 0·41–1·67). Conclusions FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.     

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations

Background  Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD. Objectives  To investigate further the spectrum of FLG‐null mutations in Chinese patients and to compare it with that in other populations. Methods  We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate‐to‐severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results  In total, 22 FLG‐null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher’s exact test; P = 5·3 × 10^?9; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher’s exact test; P = 9·0 × 10^?15; OR 5·8), keratosis pilaris (Fisher’s exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063). Conclusions  This study emphasizes the wider genetic landscape of FLG‐null mutations in Asia that is slowly emerging.     

Impact of atopic dermatitis and loss‐of‐function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis

Background Atopic dermatitis (AD) and loss‐of‐function mutations in the filaggrin gene (FLG) are both associated with chronic irritant contact dermatitis (ICD). As FLG mutations also are a major risk factor for AD, it is not clear whether FLG mutations are an independent risk factor for ICD or whether the risk is mediated by AD. Objectives To investigate the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls (vocational school apprentices). Methods A total of 634 patients and 393 controls were genotyped for R501X, 2282del4, R2447X and S3247X. Current or past flexural eczema was used as an indicator of AD. Results FLG mutations were found in 15·9% of the patients with ICD and 8·3% of the controls, with a crude odds ratio (OR) of 2·09 [95% confidence interval (CI) 1·33–3·28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1·62 (95% CI 1·01–2·58). Subjects with AD were at approximately three times higher risk of developing ICD than controls (OR 2·89; 95% CI 2·09–3·99). There was no evidence of an interaction between these two risk factors. Conclusions Our results indicate that both FLG mutations and AD increase the risk of ICD. Individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD.     

Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: a case-control study

Background  Polymorphisms in the filaggrin (FLG) gene, which result in loss of filaggrin production, may alter the skin barrier and are a well-known predisposing factor for atopic dermatitis.
Objectives  As a compromised skin barrier and atopic dermatitis are risk factors for chronic irritant contact dermatitis (CICD), our objective was to determine whether polymorphisms in the FLG gene contribute towards susceptibility to occupational CICD.
Methods  In a case–control study, the FLG polymorphisms R501X and 2282del4 were determined in 296 patients with CICD. Two hundred and seventeen apprentices in vocational training for high-risk occupations for CICD were chosen as controls. Data on skin diseases and conditions were collected by dermatologists from patients and by means of questionnaires from controls.
Results  Heterozygotes for R501X and 2282del4, FLG null alleles, were more frequent among patients with CICD (12·5%) compared with controls (6·9%), resulting in an odds ratio of 1·91 (95% confidence interval 1·02–3·59). Among patients who were carriers of a FLG null allele, we found a higher lifetime prevalence of flexural eczema (62% vs. 46%; P  = 0·04) and a higher atopy score (13 vs. 10 points; P  = 0·05) compared with noncarriers. In the apprentice group, signs of dermatitis before the start of the vocational training were four times more prevalent in carriers (43%) than in noncarriers (10%; P  < 0·001).
Conclusions  Our study shows that FLG null alleles are associated with increased susceptibility to CICD; whether or not the FLG null allele is an independent risk factor needs further study.     

Genotype–phenotype associations in filaggrin loss‐of‐function mutation carriers

Background. Loss‐of‐function mutations in the filaggrin gene (FLG) have been reported to be associated with specific phenotypic characteristics such as hyperlinearity and keratosis pilaris. Objectives. To study phenotypic features in patients with occupational irritant contact eczema of the hands in relation to FLG loss‐of‐function mutations. Materials and methods. In a prospective cohort study, genotype was determined for 459 study subjects for four FLG null alleles, and investigated for selected history, clinical and laboratory features. Results. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X, and/or 2282del4. Flexural eczema, xerosis cutis, pityriasis alba, dirty neck, pulpitis sicca, hyperlinear palms, keratosis pilaris and family history of eczema were positively associated with FLG mutations (p < 0.05). Although we observed a statistically significant correlation with higher serum IgE in FLG mutation carriers, allergic rhinoconjunctivitis and allergic asthma were not over‐represented in this group. Conclusion. This study shows further genotype–phenotype correlations in patients with occupational irritant contact eczema and FLG mutation carrier status. These features may help to identify those with FLG mutations on a specific phenotype basis.     

Mutations analysis in filaggrin gene in northern China patients with atopic dermatitis

Background Recently, we have reported filaggrin mutations (FLG) of atopic dermatitis in southern China. However, there have been few detailed reports of FLG mutations of patients with AD in northern China by now. Objectives The present aim was to establish the mutation spectrum of FLG gene in AD patients in northern China. Methods A total of 339 cases met Hanifin and Rajka diagnostic criteria of AD were recruited. A comprehensive sequencing of the entire FLG coding region in these patients was conducted. All detected FLG null mutations were screened in a cohort of 301 normal controls. Results Seven novel mutations (478insA, Q1070X, 4026delT, Q1712X, Q2397X, 7145del4 and 8001del4) and eleven reported mutations (3222del4, 3321delA, 4271delAA, S1515X, Q1790X, 5757del4, 6834del5, Q2417X, E2422X, 7945delA and K4671X) in AD were identified. Mutations 3321delA and K4671X were two of the most common mutations in AD. FLG null mutations were present in 26.0% of AD patients. FLG null alleles (compound genotypes) were significantly higher in AD (P < 0.001) than in the controls. The compound genotypes for all FLG variants were significantly associated with IV (P < 0.001) and palmar hyperlinearity (P < 0.001). The common mutation, K4671X, was significantly associated with AD‐coexistent allergic rhinitis (P = 0.005). Conclusions Our study increases the total number of FLG mutations. We clearly demonstrated that FLG loss‐of‐function mutations were significantly associated with AD in northern China. The FLG null mutations in the Chinese population differed not only from that in the European population but also from that in sub‐populations of Asians outside of the Chinese mainland.     

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population

Background It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine‐rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in ‘bypassing’ of the filaggrin proteins. Objectives To investigate the association between FLG null mutations and (nickel) contact sensitization. Methods A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. Results The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73–18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17–38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. Conclusions This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.     

Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis‐associated IV

Background Ichthyosis vulgaris (IV; OMIM 146700) is a very common inherited skin disorder. Loss‐of‐function mutations in the filaggrin gene (FLG) have been identified as the cause of IV. In a previous study, we found that the percentage of FLG null mutations was lower in IV associated with atopic dermatitis (AD) than in IV not associated with AD (isolated IV). We speculated that some clinical manifestations of IV in patients with AD are not induced by FLG mutations. Objectives In order to clarify this issue, we collected 21 IV pedigrees, 33 patients with sporadic isolated IV and 116 patients with AD‐associated IV to analyse FLG mutation frequency and filaggrin expression in isolated IV and AD‐associated IV. Methods A comprehensive sequencing of the FLG gene in all patients was performed using an overlapping polymerase chain reaction (PCR) strategy. We also studied the immunohistochemistry of profilaggrin/filaggrin protein expression in the skin and measured the mRNA expression using real‐time PCR in seven patients, including one patient with IV harbouring the mutation c.3321delA, two patients with AD‐associated IV harbouring c.3321delA and c.6834del5, and four patients with AD‐associated IV without FLG mutations. Results The percentage of mutations in the FLG gene was 74% and 43% in patients with isolated IV and patients with AD‐associated IV, respectively. Immunohistochemical staining revealed that profilaggrin/filaggrin peptides were remarkably reduced in the epidermis of all the patients. All the patients with either AD or IV showed lower FLG mRNA expression compared with the normal control. Conclusions These results indicate that factors other than FLG gene mutations can downregulate profilaggrin/filaggrin expression, leading to the ichthyosiform phenotype in the context of AD.     

Filaggrin null alleles are not associated with psoriasis

Psoriasis is a common skin disease with an etiology consistent with a multifactorial trait. Several psoriasis susceptibility loci are known, a number of which are also implicated in a predisposition to atopic dermatitis (AD), including the epidermal differentiation complex on chromosome 1q21. It has recently been shown in several replicate studies that prevalent null alleles for the filaggrin gene (FLG) on 1q21 are an important genetic factor in AD. Here, we examined the role of these FLG variants in psoriasis using case:control association studies comparing Irish and UK psoriasis cohorts (combined n=691) to ethnically matched populations (combined n=2117). No association was present for the two common European FLG mutations R501X and 2282del4 (combined chi2 P=0.989). In addition, the 3' end of the FLG open-reading frame was sequenced in a number of patients with differing types of psoriasis (plaque, guttate, palmoplantar, and late-onset), which excluded the possibility of a gain-of-function frameshift mutation such as those found in loricrin or certain keratin genes. These data suggest that FLG mutations are unlikely to be involved in genetic susceptibility to psoriasis and implies that there may be within-locus heterogeneity in chromosomal regions involved in both AD and psoriasis.     

Loss-of-function variants of the filaggrin gene are associated with atopic eczema and associated phenotypes in Swedish families

Recent studies have identified 2 loss-of-function variants, R501X and 2282del4, in the filaggrin gene as predisposing factors in the development of eczema. In this study, representing the first analysis of the variants in a Swedish population, we analysed transmission in 406 multiplex eczema families with mainly adult patients. In accordance with previous studies we found association between the filaggrin gene variants and atopic eczema (p=9.5 x 10(-8)). The highest odds ratio for the combined allele, 4.73 (1.98-11.29), p=3.6 x 10(-8), was found for the subgroup with a severe eczema phenotype, and association was also found with raised allergen-specific IgE, allergic asthma and allergic rhinoconjunctivitis occurring in the context of eczema. Our results support an important role for the filaggrin gene variants R501X and 2282del4 in the development and severity of atopic eczema and indicate a possible role for the subsequent progression into eczema-associated phenotypes.