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.     

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.     

Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis

Background. Although heterozygous filaggrin gene (FLG) mutation carriers seem to have an increased risk of atopic, irritant and allergic nickel dermatitis, it remains unclear whether the risk of contact sensitization to allergens other than nickel is also elevated in FLG mutation carriers. Objectives. We hypothesized that heterozygous FLG mutation carriers who suffer from dermatitis will have strongly reduced or even absent filaggrin levels during episodes of inflammation, potentially increasing the penetration of contact allergens, and hence the risk of becoming sensitized. Materials and methods. During 2006–2008, 3335 randomly invited 18–69‐year‐old adult Danes participated in a general health examination, filled out a questionnaire, and were genotyped for the R501X and 2282del4 mutations in FLG. Results. A logistic regression analysis restricted to individuals who reported atopic dermatitis and frequent episodes of hand eczema showed a strong association between FLG mutations and contact sensitization to allergens other than nickel (odds ratio 5.71; 95% confidence interval 1.31–24.94). In participants without dermatitis, no association was found between contact sensitization and FLG mutations. Conclusion. FLG mutation carriers with self‐reported dermatitis have an increased risk of contact sensitization to substances other than nickel, whereas FLG mutations alone may not, or may only slightly, increase the risk of sensitization.     

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.     

Clinical course of occupational irritant contact dermatitis of the hands in relation to filaggrin genotype status and atopy

Background Filaggrin loss‐of‐function mutations and atopy may alter the clinical course of irritant contact dermatitis (ICD). Objective To investigate the clinical course of patients with occupational ICD according to loss‐of‐function mutations in the filaggrin gene (FLG) and atopy. Methods In a prospective cohort study, the clinical course, use of topical corticosteroids, sick leave, recovery rate and job continuation were investigated in 459 inpatients treated for occupational ICD of the hands. Patients were genotyped for four FLG mutations, examined for atopy and followed for up to 3 years after discharge. Results Our study included 327 (71·2%) atopic individuals and 132 nonatopic individuals. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X and 2282del4 (60 atopic and eight nonatopic). Nonatopic patients with ICD responded well to therapeutic approaches, while atopy status made subjects more resistant to therapy, resulting in lower rates of recovery and job continuation and higher use of topical corticosteroids. Carriage of FLG loss‐of‐function mutations in combination with atopy worsened the course. The risk of abandoning one’s profession in this group was significantly increased when compared with ‘pure’ ICD (odds ratio 3·1) after 3 years. Conclusions Patients with atopy are a special risk population for ICD. In the presence of atopy, FLG mutations seem to be a modifier of the severity of the clinical course in ICD. Early‐stage identification of this subgroup may result in additional emphasis to these patients regarding the importance of adherence to specific therapeutic interventions.     

DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss‐of‐function variants

Background Loss‐of‐function variants within the filaggrin gene (FLG) are associated with a dysfunctional skin barrier that contributes to the development of eczema. Epigenetic modifications, such as DNA methylation, are genetic regulatory mechanisms that modulate gene expression without changing the DNA sequence. Objectives To investigate whether genetic variants and adjacent differential DNA methylation within the FLG gene synergistically act on the development of eczema. Methods A subsample (n = 245, only females aged 18 years) of the Isle of Wight birth cohort participants (n = 1456) had available information for FLG variants R501X, 2282del4 and S3247X and DNA methylation levels for 10 CpG sites within the FLG gene. Log‐binomial regression was used to estimate the risk ratios (RRs) of eczema associated with FLG variants at different methylation levels. Results The period prevalence of eczema was 15.2% at age 18 years and 9.0% of participants were carriers (heterozygous) of FLG variants. Of the 10 CpG sites spanning the genomic region of FLG, methylation levels of CpG site ‘cg07548383’ showed a significant interaction with FLG sequence variants on the risk for eczema. At 86% methylation level, filaggrin haploinsufficient individuals had a 5.48‐fold increased risk of eczema when compared to those with wild type FLG genotype (P‐value = 0.0008). Conclusions Our novel results indicated that the association between FLG loss‐of‐function variants and eczema is modulated by DNA methylation. Simultaneously assessing the joint effect of genetic and epigenetic factors within the FLG gene further highlights the importance of this genomic region for eczema manifestation.     

Ichthyosis vulgaris: the filaggrin mutation disease

Ichthyosis vulgaris is caused by loss‐of‐function mutations in the filaggrin gene (FLG) and is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. According to the published studies presented in this review article, FLG mutations are observed in approximately 7·7% of Europeans and 3·0% of Asians, but appear to be infrequent in darker‐skinned populations. This clinical review article provides an overview of ichthyosis vulgaris epidemiology, related disorders and pathomechanisms. Not only does ichthyosis vulgaris possess a wide clinical spectrum, recent studies suggest that carriers of FLG mutations may have a generally altered risk of developing common diseases, even beyond atopic disorders. Mechanistic studies have shown increased penetration of allergens and chemicals in filaggrin‐deficient skin, and epidemiological studies have found higher levels of hand eczema, irritant contact dermatitis, nickel sensitization and serum vitamin D levels. When relevant, individuals should be informed about an increased risk of developing dermatitis when repeatedly or continuously exposed to nickel or irritants. Moreover, with our current knowledge, individuals with ichthyosis vulgaris should be protected against neonatal exposure to cats to prevent atopic dermatitis and should abstain from smoking to prevent asthma. Finally, they should be advised against excessive exposure to factors that decrease skin barrier functions and increase the risk of atopic dermatitis.     

Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling

Background Filaggrin gene (FLG) loss‐of‐function mutations have been shown to represent the strongest so far known genetic risk factor for atopic dermatitis (AD). Whereas the barrier characteristics in FLG mutation carriers under baseline conditions have been investigated, there are only limited data on the permeability barrier function in filaggrin‐AD under compromised conditions. Aim We investigated: (i) stratum corneum (SC) integrity/cohesion; (ii) barrier recovery after controlled mechanical and irritant‐induced barrier abrogation; and (iii) the lipid composition of the non‐lesional and lesional skin of AD patients harbouring the European R501X, 2282del4, 3702delG, R2447X or S3247X FLG variants. Methods Thirty‐seven AD patients (14 FLG mutation carriers and 23 non‐carriers) and 20 healthy controls participated in the study. Stratum corneum integrity/cohesion was assessed by measurement of transepidermal water loss (TEWL) and amount of removed protein following sequential tape stripping. Barrier recovery was monitored by repeated measurements of TEWL and erythema up to 96 h after barrier abrogation. Samples for lipid analysis were obtained from non‐lesional and lesional skin using the cyanoacrylate method. Results Tape stripping revealed distinct genotype‐related impairment of the SC integrity/cohesion. No differences in the rate of barrier recovery among the groups were found. The SC lipid analysis revealed significant differences regarding the percentage amount of cholesterol, ceramide/cholesterol ratio and triglycerides in the uninvolved skin as well as the amounts of free fatty acids, CER[EOH] and triglycerides in the skin lesions of the AD FLG mutation carriers. Conclusions Our results provide evidence for discernible FLG‐related barrier integrity phenotypes in atopic eczema.     

Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age

Background Filaggrin loss‐of‐function (FLG) mutations are associated with eczema and skin barrier impairment, but it is unclear whether skin barrier impairment precedes phenotypic eczema in FLG mutation carriers. Objectives To study the association between FLG mutations, skin barrier impairment and clinical eczema at 3 months of age. Methods A total of 88 infants were examined for eczema. Disease severity was determined by the SCORAD eczema severity score. Transepidermal water loss (TEWL) was measured on unaffected forearm skin. Venous blood samples were screened for the four most common FLG mutations found in the U.K. white population (R501X, 2282del4, R2447X and S3247X). Median SCORAD and TEWL measurements in children with and without eczema and FLG mutations were compared. Results Thirty‐three per cent (29/88) of children had clinical eczema. Median SCORAD was 10·6 (range 3·5–31·0). TEWL (g m^?2 h^?1) was higher in children with eczema compared with unaffected infants (median TEWL 14·24 vs. 11·24, P < 0·001). Higher TEWL was associated with more severe disease (r = 0·59, P < 0·001, median TEWL, SCORAD < 15, 13·1 vs. 29·6, SCORAD ≥ 15, P = 0·029). Clinically dry skin was associated with higher TEWL, even in the absence of eczema (median TEWL 17·55 vs. 11·08, P = 0·008). Seventeen per cent (15/88) of children carried at least one FLG mutation. FLG mutation carriers were significantly more likely to have clinically dry skin, even in the absence of eczema [odds ratio (OR) 8·50, 95% confidence interval (CI) 1·09–66·58, P = 0·042]. FLG mutation carriers were also more likely to have eczema by 3 months of age (OR 4·26, 95% CI 1·34–13·57, P = 0·014). FLG mutations were significantly associated with higher median TEWL (all children, FLG‘yes’ 21·59 vs. FLG‘no’ 11·24, P < 0·001), even without clinical eczema (FLG‘yes’ 15·99 vs. FLG‘no’ 10·82, P = 0·01). Conclusions By the age of 3 months, FLG mutations are associated with an eczema phenotype, dry skin and TEWL. The observation that TEWL is elevated in unaffected FLG mutation carriers suggests that skin barrier impairment precedes clinical eczema.     

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.     

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.     

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.     

Eczema severity in preadolescent children and its relation to sex,filaggrin mutations,asthma, rhinitis,aggravating factors and topical treatment: a report from the BAMSE birth cohort

Background Filaggrin (FLG) mutations are major genetic determinants for eczema, but their role in eczema severity needs further investigation. Children with eczema are at higher risk of having asthma and rhinitis but it is not known if this risk is associated with the severity of eczema. Objectives To investigate eczema severity in relation to sex, FLG mutations, asthma, rhinitis and topical treatment among preadolescent children in a population‐based cohort. Methods Parental questionnaires were used to obtain data on symptoms of eczema, asthma, and rhinitis among 3301 preadolescent children. Eczema severity was evaluated based on sleep disturbance, extent of disease and total time with eczema the previous year. Genotyping was performed in 1854 individuals for three common FLG mutations (R501X, R2447X and 2282del4). Results Eczema was more prevalent among girls (14·5%) than boys (9·4%). FLG mutations were detected in 13·1% of children with mild eczema and 12·5% with moderate‐to‐severe eczema. Of children with moderate‐to‐severe eczema, 45·1% had rhinitis and 22·0% had asthma compared with 32·7% and 13·8% of children with mild eczema, respectively. Children with moderate‐to‐severe eczema used moisturizers and topical glucocorticoids more frequently than children with mild eczema. Boys used moisturizers less frequently than girls. Conclusions More preadolescent girls than boys had eczema. FLG mutations did not influence eczema severity in our population‐based cohort. Prevalence of rhinitis and asthma was associated with eczema severity, with the highest prevalence among boys with moderate‐to‐severe eczema.     

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.     

A 7‐step consultation plan for health care workers and hairdressers

Background: Skin diseases are among the most common occupational disor‐ders in health care workers and hairdressers. Optimal prevention methods make it possible for more individuals to remain active in their profession. We devised a 7‐step consultation plan which was employed in a standard fashion and then evaluated. Patients and Methods: 264 employes were evaluated in the Education and Support Center of the German Accident Prevention and Insurance Association in the Health and Welfare Services (BGW schu.ber.z Berlin) from 2003 to 2005 in a standardized manner. Included were detailed history, physical examination, skin physiology measurements (transepidermal water loss, corneometry, sebumetry) and then making a diagnosis and therapeutic recommendations. Results: Within the study group of 264 employes the most frequent diagnosis were toxic‐irritant hand eczema (28.4%), allergic contact eczema (19.7%), atopic eczema (15.5%) and irritant contact eczema with atopic diathesis (13.6%). The frequency of contact sensitivity was high in the study group (80.7%). The skin physiological parameters were not remarkably altered and did not differ between individuals with an atopic diathesis versus without an atopic diathesis. Conclusion: This standardized protocol for a “7‐step consultation plan”when applied in a standardized manner offers quality‐controlled but also individually‐adapted support considering dermatological, educational and occupational aspects. Skin physiology parameters did not provide any further information indicating the need of the development of novel techniques to measure skin barrier function.     

Tiled array‐based sequencing identifies enrichment of loss‐of‐function variants in the highly homologous filaggrin gene in African‐American children with severe atopic dermatitis

Filaggrin (FLG) loss‐of‐function (LOF) variants are a major risk factor for the common inflammatory skin disease, atopic dermatitis (AD) and are often population‐specific. African‐American (AA) children are disproportionately affected with AD, often later developing asthma and/or allergic rhinitis and comprise an atopy health disparity group for which the role of FLG LOF is not well known. Discovery of FLG LOF using exome sequencing is challenging given the known difficulties for accurate short‐read alignment to FLG's high homology repeat variation. Here, we employed an array‐based sequencing approach to tile across each FLG repeat and discover FLG LOF in a well‐characterized cohort of AA children with moderate‐to‐severe AD. Five FLG LOF were identified in 23% of our cohort. Two novel FLG LOF singletons, c.488delG and p.S3101*, were discovered as well as p.R501*, p.R826* and p.S3316* previously reported for AD. p.S3316* (rs149484917) is likely an African ancestral FLG LOF, reported in African individuals in ExAC (Exome Aggregation Consortium), Exome Variant Server (ESP), and 4 African 1000G population databases (ESN, MSL, ASW, and ACB). The proportion of FLG LOF (11.5%) among the total FLG alleles in our cohort was significantly higher in comparisons with FLG LOF reported for African individuals in ExAC (2.5%; P = 4.3 × 10^?4) and ESP (1.7%; P = 3.5 × 10^?5) suggesting a disease‐enrichment effect for FLG LOF. Our results demonstrate the utility of array‐based sequencing in discovering FLG LOF, including novel and population‐specific, which are of higher prevalence in our AA severe AD group than previously reported.     

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.     

FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics

Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C‐terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C‐terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype–phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.     

Novel and recurrent mutations in the filaggrin gene in Chinese patients with ichthyosis vulgaris

Background Ichthyosis vulgaris (IV) is a common inherited skin disorder, and the filament aggregating protein (filaggrin) is a key protein involved in skin barrier function. Mutations in the filaggrin gene (FLG) have recently been identified as the cause of IV. However, there have been no reports of FLG mutations in mainland Chinese families with IV. Objectives To identify FLG mutations in Chinese patients with IV. Methods Eleven unrelated Chinese families with IV were examined for FLG mutations with denaturing high‐performance liquid chromatography prescreening and sequencing. SNaPShot was employed to obtain a high‐throughput screening for the identified mutations. Results Three mutations – one novel mutation (Q1256X) and two known mutations (3321delA and E2422X) – were identified in these families. The novel mutation, Q1256X, found in a Chinese family with IV, was located in filaggrin repeat 3. Mutation 3321delA, previously found in Japanese patients, was present in eight Chinese families with IV. Mutation E2422X, previously found in a Dutch patient of Chinese origin, was present in two Chinese families with IV. Neither of the null mutations, Q1256X and E2422X, were found in 100 unrelated control cases from the Chinese population; however, the mutation ratio for 3321delA was 3% in these controls. Conclusions Our study suggests that each population may have a unique and prevalent set of FLG mutations.