Filaggrin Gene Mutations in African Americans with Both Ichthyosis Vulgaris and Atopic Dermatitis

Atopic dermatitis (AD) and ichthyosis vulgaris (IV) are two common disorders of epidermal homeostasis resulting in dry skin. The profilaggrin gene, located on chromosome 1q22, encodes a keratin filament aggregating protein (filaggrin) that is essential to forming the epidermal barrier and maintaining hydration. Null mutations in filaggrin have been found to underlie IV and are common in patients with AD, but the minority of African Americans with AD or IV show these mutations in filaggrin. We have selectively studied African Americans with both AD and IV to maximize the possibility of finding filaggrin null mutations in this population. DNA was collected using buccal swabs from 18 African American children with both AD and IV and 17 African American controls without either of these diseases. Purified genomic DNA was amplified using polymerase chain reaction from three regions of the filaggrin gene, exon 3, including R501X, 2282del4, E2554X, R2447X, 1249insG, R826X, 2767insT, and E2422X. Of the African American children with both AD and IV, 22.2% were heterozygous for filaggrin null mutations. Out of the control group, one carried a null mutation and was later discovered to have a history of asthma. Null mutations found in this population included R501X (n = 1), 2282del4 (n = 2), and R826X (n = 2, including the control patient). Our data demonstrate a prevalence of filaggrin mutations in the African American population that exceeds previously published data, although the overall prevalence is still lower than in other populations. It is likely that factors other than known FLG mutations are involved in African American patients.     

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.     

Lack of association between filaggrin gene mutations and onset of psoriasis in childhood

Background Atopic dermatitis (AD; OMIM#603165) and psoriasis (OMIM#177900) are two common inflammatory skin disorders. Both are genetically complex, multifactorial and do not follow a Mendelian pattern of inheritance. Both diseases share several genetic susceptibility loci such as the epidermal differentiation complex (EDC) on chromosome 1q21. Within the EDC, mutations in the filaggrin (FLG) gene are strongly associated with AD whereas no association has been replicated with psoriasis. However, reduced levels of filaggrin have been reported in psoriatic skin. Further, filaggrin deficiency was shown to be a modifying factor for the phenotype in another epidermal skin disorder, X‐linked recessive ichthyosis. Altogether, this raises the question if FLG mutations may modify the disease course in other epidermal skin diseases such as psoriasis. Psoriasis is a highly heterogeneous disease and so far genetic studies have not taken the distinct sub‐phenotype childhood onset into account. Objective To determine if FLG mutations modify the onset of psoriasis. Materials and methods A total of 241 children with onset of psoriasis below 15 years of age and 314 healthy controls were identified at the Dermatology clinic, Karolinska University Hospital and diagnosed by the same dermatologist (JL). Blood samples were taken and medical history was recorded. FLG was genotyped in all patients and controls using allelic discrimination (n = 555) and sequencing (n = 20). Results and conclusions No association between FLG mutations and early onset of psoriasis was demonstrated (P = 0.57) and no novel mutations were detected, indicating that FLG loss‐of‐function variants do not have a strong effect on the onset of psoriasis in childhood.     

Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations

Pachyonychia congenita (PC), a rare autosomal‐dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss‐of‐function mutations in the filaggrin (FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X‐linked ichthyosis and alopecia areata. We report a parent–child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC.     

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.     

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.     

Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis

Background Loss‐of‐function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients’ susceptibility to recurrent skin infection. Objectives To investigate the association between FLG‐null mutations and the risk of recurrent skin infection among a series of patients with AD in Singapore. Methods This study included 228 Singaporean Chinese patients with AD with at least 1 year of follow‐up at the time of recruitment between January 2008 and December 2009 at the National Skin Centre in Singapore. Each patient had their medical records reviewed for history of skin infection in the preceding year and was genotyped for 22 FLG‐null mutations. Results Compared with those without the FLG‐null mutations, patients with AD who had FLG mutation(s) had approximately a seven times increased risk of more than four episodes of skin infection requiring antibiotics in the past year (odds ratio 6·74; 95% confidence interval 2·29–19·79). This risk was much greater in those with mild or moderate disease, and was present in both users and nonusers of oral steroids. Conclusion This study highlights a novel association between FLG‐null mutations and an increased susceptibility to recurrent bacterial skin infection among patients with AD.     

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.     

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.     

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.     

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.     

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.     

Impact of filaggrin mutations on Raman spectra and biophysical properties of the stratum corneum in mild to moderate atopic dermatitis

Background Atopic dermatitis (AD) is associated with null mutations in the filaggrin (FLG) gene. Objective To assess the impact of FLG null mutations on biophysical properties and the molecular composition of the stratum corneum (SC) in healthy individuals and AD patients. Methods A total of 196 French adults, including 97 with a history of mild to moderate AD, were genotyped for the three major European FLG mutations. Components of the natural moisturizing factor (NMF), lipids and water content in the SC were determined using Raman spectroscopy. In addition, trans‐epidermal water loss, capacitance and pH of the SC were measured. Results Stratum corneum concentrations of total NMF, water, ornithine and urocanic acid (UCA) were significantly lower in AD patients than in healthy controls. Null mutations of FLG were detected in 4% of controls and 10% of AD patients. FLG mutations were associated with increased SC levels of lactate, reduced concentrations of most other NMF components and higher disease severity in AD patients. In AD patients without FLG mutations, the content of NMF constituents decreased with increasing disease severity. The concomittant presence of low concentrations of histidine, alanine and either glycine or pyrrolidone‐5‐carboxylic acid (PCA) in the SC was associated with FLG mutations with 92% specificity. Conclusions Our findings suggest a low prevalence of FLG mutations in mild AD and support an important role for filaggrin in determining the physicochemical parameters of the SC. The combined measurement of several filaggrin breakdown products in the SC may be useful to specifically predict the presence of FLG 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.     

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.     

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.     

Intragenic Copy Number Variation in the Filaggrin Gene in Ethiopian Patients with Atopic Dermatitis

Genetic variants in filaggrin (FLG) involving truncating mutations or intragenic copy number variation are strongly associated with the risk of developing atopic dermatitis (AD) in European and Asian populations. Few loss‐of‐function mutations have been identified in Africans, although an association between FLG copy number variation and AD severity in a small African American cohort has been proposed. We studied the association between FLG copy number and AD in 132 Ethiopians and found no association between AD severity and FLG copy number, suggesting that other, still unidentified genetic factors are of more importance in predisposing Ethiopians to AD.     

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.