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.     

Filaggrin polymorphism P478S, IgE level, and atopic phenotypes

Background Whether environmental exposures may modulate the effect of the skin barrier gene on atopic dermatitis (AD) remains to be elucidated. Objectives To determine whether filaggrin (FLG) variants can serve as a predictor for atopic disorders in Chinese individuals and if allergen exposures may modify the effect of FLG variants on AD by total IgE levels. Methods In total, 116 children aged 2–5 years with AD and 212 control subjects were analysed for the FLG variants using DNA sequencing. Multiple logistic regression models were performed to estimate the association among FLG polymorphisms and atopic phenotypes. Serum total IgE level, standing for the degree of allergen exposures, was later stratified to determine the effects of FLG polymorphisms on AD. Results A significant difference in genotype frequency was found among AD cases and controls in FLG P478S polymorphism. FLG P478S GG genotype significantly increased the risk of AD [odds ratio (OR) 4·60, 95% confidence interval (CI) 1·88–11·24]. In addition, among subjects with AD, GG genotypes also significantly increased the risk of developing asthma (OR 4·68, 95% CI 1·37–16·03). Further, a similar result was obtained for allergic rhinitis (OR 3·23, 95% CI 1·01–10·30). Interestingly, the P478S GG genotype was significantly related to AD (OR 5·67, 95% CI 1·93–16·60) in children with IgE level ≥ 100 kU L^?1. However, the association was not evident when IgE level was < 100 kU L^?1. Conclusions Our results suggest that the FLG P478S polymorphism may confer susceptibility to the development of AD among Chinese individuals and may be modified by IgE levels.     

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.     

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.     

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.     

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.     

Association between filaggrin null mutations and concomitant atopic dermatitis and contact allergy

Background. The phenotypic traits of people with the filaggrin mutation (FLG) genotype and atopic dermatitis (AD) are still under elucidation, and the association with concomitant AD and contact allergy (CA) has not previously been examined. Aim. To assess FLG status in a subset of patients with AD and a minimum of one positive patch‐test reaction. Methods. In total, 430 people from a hospital population and 3335 people from the general population were tested for FLG mutations by DNA hybridization to paramagnetic polystyrene beads and analysis on a multiplex analysis system. All of the individuals in the hospital population had a minimum of one CA. AD was diagnosed according to the UK Working Party Criteria, (questions‐only version). Individuals from the hospital population who had both AD and CA were considered as cases, and comparison of mutation carrier frequency was estimated (χ² test) against individuals without AD but with CA from the hospital population, individuals from the general population, and individuals with AD from the general population. Results. The mutation frequency in patients with AD and CA in the hospital population was significantly less than that of people with AD from the general population (OR = 0.54; 95% CI 0.30–0.98). No difference in mutation frequency was found between individuals with and without AD in the hospital population (OR = 1.40; 95% CI 0.70–2.79), or between individuals with AD and CA in the hospital population and in the overall general population (OR = 1.29; 95% CI 0.76–2.20). Conclusions. The spectrum of observable traits characteristic for the FLG mutation genotype in patients with AD is at present not defined. Our results indicate that the subset of patients with both AD and CA represent a phenotype of AD that is not associated with FLG mutations.     

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.     

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 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.     

Polymorphisms in human histamine receptor H4 gene are associated with atopic dermatitis

Background Atopic dermatitis (AD) is a chronic skin disease affecting more than 15% of children and 2% of adults. A strong connection between genetic factors and AD has been described for a long time. Histamine receptor H4 (HRH4) has been shown to be related to different kinds of allergic and autoimmune disorders. However, an association between HRH4 and AD has not yet been reported. Objectives To examine a possible association between HRH4 and AD. Methods Genomic DNA from 301 patients with AD and 313 healthy controls was extracted and three exons of HRH4 were sequenced. Results We found three new single nucleotide polymorphisms (SNPs) in HRH4 which were significantly associated with AD: ss142022671 [odds ratio (OR) 1·87, 95% confidence interval (CI) 1·24–2·81; P = 0·002], ss142022677 (OR 4·40, 95% CI 2·42–8·00; P = 1·5 × 10^?7) and ss142022679 (OR 4·26, 95% CI 2·38–7·61; P = 1·3 × 10^?7). The SNPs ss142022677 and ss142022679 were found to be in strong linkage disequilibrium (D’ = 0·98; r² = 0·92). Two‐SNP haplotype analysis (ss142022677 and ss142022679) showed that the major AA haplotype was protective against AD (OR 0·22, 95% CI 0·12–0·40; P = 3·1 × 10^?8) and the minor TT haplotype was significantly associated with AD (OR 4·13, 95% CI 2·27–7·54; P = 6·6 × 10^?7). In addition, in a three‐SNP haplotype analysis (ss142022671, ss142022677 and ss142022679), the major TAA haplotype was protective against AD (OR 0·46, 95% CI 0·31–0·69; P = 0·0001), while the complementary ATT haplotype was found to be significantly associated with AD (OR 3·81, 95% CI 2·03–7·14; P = 8·3 × 10^?6). Conclusions Polymorphisms of ss142022671, ss142022677 and ss142022679 in HRH4 are associated with AD.     

Association between atopic dermatitis and obesity in adulthood

Background Obesity in early childhood is associated with increased risk for and severity of atopic dermatitis (AD). Objective  To determine whether obesity in adulthood is associated with risk of AD. Methods This was a retrospective case–control study of 2090 adults using questionnaire, height and weight, and skin‐prick testing between January 1994 and December 2003. Results  Obesity in adults was associated with increased AD [multinomial logistic regression: adjusted odds ratio (aOR) 1·43, 95% confidence interval (CI) 1·08–1·89; P = 0·01], but not nonatopic dermatitis (aOR 0·59, 95% CI 0·21–1·68; P = 0·32). Obesity was also associated with increased atopic asthma (aOR 1·98, 95% CI 1·47–2·66, P < 0·0001), but not associated with nonatopic asthma (P = 0·20), atopic or nonatopic rhinoconjunctivitis (P = 0·08 and 0·31, respectively), food allergies (P = 0·67 and 0·35, respectively) or atopy (P = 0·40). The association between obesity and AD remained significant even when controlling for history of asthma, rhinoconjunctivitis and food allergies (aOR 1·40, 95% CI 1·05–1·86; P = 0·02) or in subset analyses of subjects with AD alone (aOR 1·96, 95% CI 1·02–3·75; P = 0·04) and with comorbid asthma, rhinoconjunctivitis and/or food allergies (aOR 1·40, 95% CI 1·03–1·91; P = 0·03). Conclusion Obesity in adulthood is associated with AD. Further studies are warranted to determine if weight loss may prevent or mitigate AD in adults.     

Maternal employment and atopic dermatitis in children: a prospective cohort study

Background Considering the early onset of atopic dermatitis (AD), which most often arises in the first year of life, risk factors occurring very early in life must be considered. Little is known about the effects of maternal occupational exposure on the development of atopic disorders in children. Objectives The aim of this study was to evaluate associations between maternal employment and childhood AD. Methods We used multistage stratified systematic sampling to recruit 24 200 mother–newborn pairs from the Taiwan national birth register. Information on maternal occupation categories, work stress, working time, shift work and potential confounders during pregnancy was gathered by questionnaires after birth. At 3 years of age, information on the development of AD was assessed by home interviews. Multiple logistic regression analysis was performed to estimate the association of maternal employment and AD. Results Overall, 11 962 out of 19 381 mothers (61·7%) worked during pregnancy. The children of mothers who worked during pregnancy had an increased risk of AD compared with those whose mothers did not work [odds ratio (OR) 1·38, 95% confidence interval (CI) 1·25–1·53]. The children of mothers with a professional or technical occupation had a higher risk of AD (OR 1·64, 95% CI 1·44–1·87). The risk of AD was found to increase with maternal work stress during pregnancy in a dose–response manner (P_trend < 0·01). The mothers of children with AD had a longer working time than those without AD (P < 0·0001). However, no significant association between AD and maternal shift work was found. Conclusions Working in professional or technical occupations increased the risk of childhood AD in addition to work stress during pregnancy.     

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.     

Interactions between FLG mutations and allergens in atopic dermatitis

Filaggrin gene (FLG) mutations and sensitization in patients with atopic dermatitis (AD) have been well documented. However, whether an interaction exists between these mutations and specific sensitization in AD patients is still unknown. The aim of the study was to explore the interaction between FLG mutations and specific sensitization in AD patients. A total of 249 AD outpatients were recruited in the current study. Skin prick tests were conducted to assess the patient??s sensitization to specific allergens. FLG mutations were analyzed through comprehensive sequencing. Logistic regression analyses were conducted to determine the interactions between FLG mutations and sensitization present. The mean age of the patients was 3.5?years, and the mean age of onset of AD was 9.6?months. The mean SCORAD of the patients was 25.8. Fourteen types of mutations were identified in the FLG of 64 patients. A total of 24 (9.6?%) and 29 (11.6?%) cases were mutated with 3321delA and K4671X, respectively. Sensitization to at least one type of allergen was detected in 118 patients (47.4?%). Logistic regression analyses showed that FLG mutations presented an interaction with sensitization to peanut and did not interact with the other detected allergens among AD patients. Sensitization to peanut allergens would have an interaction with the mutation of K4671X and the combined mutations in FLG in patients with atopic dermatitis. However, sensitization to the other common allergens might not interact with FLG mutations in the development 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.     

Filaggrin null mutations and association with contact allergy and allergic contact dermatitis: results from a tertiary dermatology clinic

Background: Filaggrin null (FLG) mutations lead to skin barrier disruption with a reduced resistance towards exogenous agents and also influence the course of disease in atopic dermatitis.
Objectives: To examine the association between FLG mutations and contact allergy, polysensitization, hand eczema at first appearance of disease, occurrence, and course of dermatitis.
Methods: A venous blood sample from 430 individuals was genotyped for FLG mutations R501X and 2282del4 with polymerase chain reaction followed by typing through hybridization to paramagnetic polystyrene beads and analysis on a BioPlex 200. All individuals had a minimum of one positive patch test reaction.
Results: In all, 3.5% were 2282del4 heterozygote and 5.1% were R501X heterozygote. An odds ratio (OR) of 1.49 [95% confidence interval (CI) 0.74–3.00] was found for nickel allergy, OR 0.84 (95% CI 0.41–1.74) for polysensitization, OR 0.78 (95% CI 0.25–2.43) for dermatitis, OR 0.96 (95% CI 0.48–1.92) for hand eczema at debut, OR 1.25 (95% CI 0.99–1.57) for duration of disease, and OR 0.76 (95% CI 0.59–0.97) for age at onset.
Conclusions: No association between nickel allergy, polysensitization, hand eczema at first appearance or occurrence of dermatitis, and FLG mutations was found. However, patients with FLG mutations had an earlier age of onset compared with the wild‐type genotype and a trend towards longer duration of disease.     

IL1A‐889 C/T gene polymorphism in irritant contact dermatitis

Background Upon skin contact to irritants, interleukin‐1 alpha (IL‐1α) is released in the stratum corneum as a primary step of skin inflammation. Variations in the IL‐1A gene have been shown to alter the expression of IL‐1α. This may influence the susceptibility to skin inflammation and the development of irritant contact dermatitis (ICD). Objective To determine effects of an IL1A‐889 C/T polymorphism in view of susceptibility to develop irritant contact dermatitis. Methods In a case–control study, 478 Caucasian patients with occupational ICD of the hands were genotyped for an IL1A‐889 C/T polymorphism. Results were compared to 393 apprentices from the same high risk occupations (controls). Results Trends of a protective effect of the C→T transition at position IL1A‐889 were seen (OR = 0.81; 95% CI: 0.65–1.00). The genotype distribution for IL1A‐889 was 52.2% wild type (C/C), 39.2% heterozygous (C/T) and 8.6% homozygous for variant allele (T/T) in patients and 46.0%, 42.7% and 11.4% in controls. Subgroup analysis, which took into account atopy status and exposure, did not reveal a significant effect of this polymorphism for an aberrant risk to acquire for ICD. Conclusion Our study indicates a possible protective effect of the IL1A‐889 C/T polymorphism regarding the development of ICD.     

Probiotics in pregnant women to prevent allergic disease: a randomized,double‐blind trial

Background Previous reports have suggested that certain probiotics given to mothers and children at risk of atopy halves the incidence of atopic dermatitis (AD) at 2 years of age. Objectives To examine if probiotics given to pregnant women in a nonselected population could prevent atopic sensitization or allergic diseases during the child’s first 2 years. Methods In a randomized, double‐blind trial of children from a nonselected maternal population (ClinicalTrials.gov identifier: NCT00159523), women received probiotic milk or placebo from 36 weeks of gestation to 3 months postnatally during breastfeeding. The probiotic milk contained Lactobacillus rhamnosus GG, L. acidophilus La‐5 and Bifidobacterium animalis subsp. lactis Bb‐12. Children with an itchy rash for more than 4 weeks were assessed for AD. At 2 years of age, all children were assessed for atopic sensitization, AD, asthma and allergic rhinoconjunctivitis. The intention‐to‐treat (ITT) analysis was enabled by multiple imputations. Results Four hundred and fifteen pregnant women were computer randomized. At 2 years, 138 and 140 children in the probiotic and the placebo groups, respectively, were assessed. In the ITT analysis, the odds ratio (OR) for the cumulative incidence of AD was 0·51 in the probiotic group compared with the placebo [95% confidence interval (CI) 0·30–0·87; P = 0·013]. There were no significant effects on asthma (OR 0·68, 95% CI 0·26–1·80; P = 0·437) or atopic sensitization (OR 1·52, 95% CI 0·74–3·14; P = 0·254). Conclusions Probiotics given to nonselected mothers reduced the cumulative incidence of AD, but had no effect on atopic sensitization.