Dataset Information

Filaggrin gene mutation c.3321delA is associated with various clinical features of atopic dermatitis in the Chinese Han population.

ABSTRACT:

Background

We confirmed that the filaggrin gene mutation c.3321delA is associated with atopic dermatitis in our previous genome wide association study of the Chinese Han population. c.3321delA is the most common filaggrin gene mutation in Chinese atopic dermatitis patients but is not present in European populations.

Objective

To investigate the genetic model for the c.3321delA mutation and to determine the correlation between c.3321delA and atopic dermatitis clinical phenotypes in the Chinese Han population.

Method

The filaggrin gene mutation c.3321delA was sequenced in 1,080 atopic dermatitis patients and 908 controls from the Chinese population. The ?2 test, ANOVA,nonparametric tests and logistic regression were used to investigate the relationship between the c.3321delA genotype and atopic dermatitis clinical phenotypes in the Chinese Han population.

Results

Analyses of the genetic model revealed that the additive model best described the c.3321delA mutation (P?=?3.09E-11, OR?=?3.43, 95%CI?=?2.38-4.96). Stratified analyses showed that the c.3321delA allele frequency distribution is significantly associated with concomitant skin xerosis (P?=?1.68E-03, OR?=?2.13,95%CI?=?1.32-3.46), palmar hyperlinearity (P?=?3.64E-17, OR?=?4.0,95%CI?=?2.86-5.70), white dermatographism (P?=?4.25E-03, OR?=?1.82,95%CI?=?1.22-2.71), food intolerance (P?=?1.51E-03, OR?=?1.76,95%CI?=?1.23-2.50) and disease severity ( P?=?9.67E-05).

Conclusion

Our study indicates that the filaggrin gene mutation c.3321delA is associated with clinical phenotypes of atopic dermatitis in the Chinese Han population, which might help us gain a better understanding on the pathogenesis of atopic dermatitis.

SUBMITTER: Meng L

PROVIDER: S-EPMC4032331 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Filaggrin gene mutation c.3321delA is associated with various clinical features of atopic dermatitis in the Chinese Han population.

Meng Li L Wang Li L Tang Huayang H Tang Xianfa X Jiang Xiaoyun X Zhao Jinhua J Gao Jing J Li Bing B Fu Xuhui X Chen Yan Y Yao Weiyi W Zhan Wenying W Wu Bo B Duan Dawei D Shen Changbing C Cheng Hui H Zuo Xianbo X Yang Sen S Sun Liangdan L Zhang Xuejun X

PloS one 20140523 5

<h4>Background</h4>We confirmed that the filaggrin gene mutation c.3321delA is associated with atopic dermatitis in our previous genome wide association study of the Chinese Han population. c.3321delA is the most common filaggrin gene mutation in Chinese atopic dermatitis patients but is not present in European populations.<h4>Objective</h4>To investigate the genetic model for the c.3321delA mutation and to determine the correlation between c.3321delA and atopic dermatitis clinical phenotypes in ...[more]

PMID: 24858702

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Project description:BackgroundFilaggrin gene (FLG) mutations have been identified as the cause of ichthyosis vulgaris (IV) and major predisposing factors for atopic dermatitis (AD). The relationship among AD, IV and FLG mutations has not been clarified yet. Mutations 3321delA and K4671X, two of the most common mutations in Chinese patients, were both statistically associated with AD in case-control studies.Materials and methodsA group of 100 family trios (a total of 300 members with one affected AD proband and both parents) were recruited and screened for three filaggrin null mutations (3222del4, 3321delA and K4671X). The subjects' manifestations of AD and IV were assessed by two experienced dermatologists and recorded in detail. The relationship of common mutations to AD were assessed using both case-control and family-based tests of association. Filaggrin expression was measured in skin of 3 subjects with K4671X heterozygote and the normal control using quantitative real-time RT-PCR and immunohistochemistry.ResultsOf 100 probands for AD, 22 were carriers for common FLG mutations and only 2 of them were from 40 none-IV family trios (5.00%), consistent with that of the healthy control group (3.99%, P>0.05). Significant statistical associations were revealed between AD and 3321delA (P<0.001, odds ratio 12.28, 95% confidence interval 3.35-44.98) as well as K4671X (P?=?0.002, odds ratio 4.53, 95% confidence interval 1.77-11.60). The family-based approach revealed that 3321delA was over-transmitted to AD offspring from parents (T:U?=?12?1, P?=?0.003) but failed to demonstrate transmission disequilibrium between K4671X and AD (T:U?=?10?8, P?=?0.815). Moreover, compared to the normal control, filaggrin expression at both mRNA and protein levels in epidermis of subjects with K4671X(heter) was not reduced.ConclusionsAD patients from none-IV family trios have low probability of carrying FLG mutations. The present family samples confirmed the susceptibility of mutation 3321delA to AD in Han Chinese. K4671X was not a pathogenic mutation.

Project description:Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10-36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10-8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring's susceptibility to a common human disease.

Dataset Information

Filaggrin gene mutation c.3321delA is associated with various clinical features of atopic dermatitis in the Chinese Han population.

Background

Objective

Method

Results

Conclusion

Publications

Filaggrin gene mutation c.3321delA is associated with various clinical features of atopic dermatitis in the Chinese Han population.

Similar Datasets

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