Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural ...history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10−8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10−11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10−27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the “eczema plus early wheeze” and “eczema plus asthma” phenotypes.
Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated ...with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL−1 ) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients ( P = 3.0 × 10−6 ; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study ( P = 5.4 × 10−5 ; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant ( P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.
Background Filaggrin is a key protein involved in skin barrier function. Filaggrin ( FLG ) null mutations are important genetic predisposing factors for atopic disease. Objective To study the role of ...FLG null alleles in the clinical phenotype in children and young adults with asthma. Methods FLG mutations R501X and 2282del4 were assayed in 874 subjects 3 to 22 years old with asthma from Tayside. Lung function and disease severity were also studied. Results The filaggrin mutations were significantly associated with greater disease severity for asthma. Independent of eczema, mean FEV1 /forced vital capacity of FLG wild-type individuals differed from those carrying either FLG null allele (0.89 vs 0.86; P = .012). Individuals bearing FLG null alleles were more likely to be prescribed increased medication (χ2 = 10.3; P = .001), with the homozygote null individuals having an odds ratio of 6.68 (95% CI, 1.7-27.0; P = .008) for being prescribed long-acting β-agonists in addition to inhaled steroids. FLG null alleles were also associated with increased rescue medication use ( P = .004). Individuals with asthma and with FLG null alleles were more likely to have eczema, and individuals with eczema tended to have more severe asthma; however, the association of FLG null alleles with all markers of asthma disease severity was similar in children with and without eczema. Conclusion FLG mutations are associated not only with eczema-associated asthma susceptibility but also with asthma severity independent of eczema status. Clinical implications FLG status influences controller and reliever medication requirements in children and young adults with asthma.
Background Null mutations within the filaggrin gene (FLG) are associated with moderate-to-severe atopic eczema; their role in mild-to-moderate eczema in the general population is unknown. Objective ...We sought to investigate the significance of 5 common FLG null mutations in childhood atopic eczema in an unselected population cohort. Methods Eight hundred eleven English children aged 7 to 9 years were screened for FLG mutations. Eczema cases were defined by using United Kingdom diagnostic criteria and skin examination. Asthma and seasonal rhinitis cases were defined by parental questionnaire. Association between phenotype and genotype was investigated using Fisher exact test and logistic regression analysis. Results The 12-month period prevalence of atopic eczema was 24.2% (95% CI, 21.2% to 27.2%), with 96% (115/120) of cases having mild-to-moderate disease. The combined null genotype (carriage of ≥1 FLG mutations) was significantly associated with atopic eczema ( P = 1.2 × 10−4 ). The odds ratio (OR) for individuals carrying 2 null mutations was 26.9 (95% CI, 3.3-217.1), but heterozygote carriers showed no significant increase in risk (OR, 1.2; 95% CI, 0.7-1.9). Eight of 190 eczema cases (4.2%) carried 2 FLG null mutations and thus might be attributed to filaggrin deficiency. Asthma in the context of eczema showed significant association with the FLG null mutations ( P = 7.1 × 10−4 ). There was no association of FLG with asthma independent of eczema ( P = .15) and no association with seasonal rhinitis ( P = .66). Conclusion FLG null mutations are significantly associated with mild-to-moderate atopic eczema in childhood, with a recessive pattern of inheritance.
Abstract Background Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is widely used as an intravenous anesthetic agent and has also been shown to possess anti-inflammatory ...effects, but its effects on high-mobility group box-1(HMGB1) have not been well defined. In the present study, we investigated the effects of ketamine on HMGB1 in lipopolysaccharide (LPS)-induced Raw264.7 cells and in a mouse model of cecal ligation and puncture-induced sepsis. Materials and methods Raw264.7 cells were incubated with or without 1 μg/mL LPS in the presence or absence of ketamine, mitogen-activated protein kinases (MAPKs) inhibitor, or small interfering RNA (siRNA). The protein and expression levels of inflammatory mediators, such as HMGB1, nitric oxide (NO), and heme oxygenase-1(HO-1), were measured using enzyme-linked immunosorbent assays, Western blot analysis, and real-time polymerase chain reaction. The effect of ketamine on nuclear factor erythroid 2-related factor 2 (Nrf2) and MAPKs activation was evaluated using enzyme-linked immunosorbent assays and Western blot analysis. Results In vitro , ketamine inhibits HMGB1 and NO release and induces HO-1 expression in a concentration-dependent manner, whereas HO-1 siRNA antagonizes the inhibition of HMGB1 and NO. The effect of ketamine is inhibited by the p38 MAPK inhibitor SB203580 and Nrf2 siRNA, indicating that ketamine induces HO-1 via p38 MAPK and Nrf2. In vivo , ketamine increases survival and decreases serum and lung HMGB1 levels in cecal ligation and puncture-induced sepsis. Conclusions Ketamine inhibits LPS-induced HMGB1 release through HO-1 induction, and these effects may be mediated by blockade of p38 MAPK and Nrf2 signaling pathways.
Background Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK5) and the serine protease kallikrein-related peptidase 7 gene (KLK7) appear to confer ...risk to eczema in some cohorts, but these findings have not been widely replicated. These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG) , the strongest identified genetic risk factor for eczema to date. Objectives We sought to clarify the individual risk of eczema conferred by the SPINK5 polymorphism rs2303067 (Glu420Lys) and a previously described insertion in the 3′ untranslated region of KLK7 and to examine potential epistatic effects between these variants and FLG mutations. Methods Initially, we examined the effects of these polymorphisms and FLG in 486 unrelated patients from a German family-based study, an additional 287 German patients, and 418 unrelated Irish/English patients with eczema (n for 3 genes studied = 1191 vs 4544 control subjects). We then additionally studied the SPINK5 polymorphism and FLG mutations in 1583 patients with eczema from the Avon Longitudinal Study of Parents and Children cohort (sample size for 2 genes studied = 2774 vs 10,607 control subjects). Results No association was seen with the SPINK5 or KLK7 variants in the case-control analysis; however, a weaker effect was observed for the SPINK5 variant with maternal transmission in the family-based study. No interactions were seen between the polymorphisms in KLK7 , SPINK5 , and FLG. Conclusion The SPINK5 420LysSer mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor. The KLK7 insertion appears to confer no risk of eczema. We found no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations.
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