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Original Investigation |

Thymic Stromal Lymphopoietin Variation, Filaggrin Loss of Function, and the Persistence of Atopic Dermatitis FREE

David J. Margolis, MD, PhD1,2; Brian Kim, MD2; Andrea J. Apter, MD, MSc3; Jayanta Gupta, MD, PhD1; Ole Hoffstad, MA1; Maryte Papadopoulos, MBE1; Nandita Mitra, PhD1
[+] Author Affiliations
1Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
2Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
JAMA Dermatol. 2014;150(3):254-259. doi:10.1001/jamadermatol.2013.7954.
Text Size: A A A
Published online

Importance  Atopic dermatitis (AD) is a common chronic illness of childhood.

Objective  To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD.

Design, Setting, and Participants  A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry.

Exposure  Evaluation of TSLP variation.

Main Outcomes and Measures  Self-reported outcome of whether a child’s skin had no symptoms of AD and required no medications for 6 months at 6-month intervals.

Results  We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86).

Conclusions and Relevance  The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.

Figures in this Article

Atopic dermatitis (AD) is a common chronic relapsing inflammatory disease of the skin that is seen most often in childhood.1 The development of AD has been associated with genetic polymorphisms, skin barrier dysfunction, environmental exposures, and host immune dysregulation.2,3 Conceptually, the pathophysiology of AD may be associated with a child’s sensitization to specific environmental or food allergens in association with skin barrier dysfunction, which is hypothesized to result from defects in the production of filaggrin (FLG) protein, a key constituent of the granular cell layer.3 In 2006, loss-of-function mutations in the FLG gene (OMIM 135940) were shown to be associated with AD.46 Ultimately, FLG proteolysis results in the creation of natural moisturizing factors that are part of the skin barrier. Animal models have shown that a defect in the production of FLG creates a more porous skin surface, resulting in epicutaneous sensitization to environmental allergens and activating the host immune system, thereby resulting in local inflammation, pruritus, and visible skin lesions.7

In 2010, Barnes8 and Gao et al9 reported an association between thymic stromal lymphopoietin (TSLP) and AD as well as a decreased susceptibility to an infectious inflammatory complication of AD called eczema herpeticum. Thymic stromal lymphopoietin promotes the differentiation of naive T cells into type 2 helper T cells, a cell type associated with and thought to be pathogenic in atopic diseases.10,11 Increased expression of TSLP has been strongly associated with AD as well as other allergic diseases, including asthma, allergic rhinitis, and food allergy.9,1114 Furthermore, a report by Beck et al15 revealed that individuals who developed eczema herpeticum had more severe AD as well as biomarkers consistent with increased allergic inflammation. This led to our hypothesis that genetic variations that result in increased or decreased TSLP activity could be associated with either more severe or milder skin disease.

More specifically, alterations in the activity of TSLP should directly influence the association between FLG and AD persistence. As noted, FLG mutations result in skin barrier dysfunction and are associated with an increased risk of developing AD and persistence of skin symptoms.4,16,17 Because TSLP acts to promote type 2 helper T-cell responses, it is conceivable that people with diminished TSLP expression, even in the setting of skin barrier dysfunction due to an FLG loss-of-function mutation, would be less likely to exhibit active symptoms of AD. The goal of this study was first to evaluate the association between TSLP (OMIM 607003) variation and the persistence of skin symptoms of AD and then to determine whether TSLP variation alters the known association between FLG loss-of-function mutations and the persistence of AD.

The Pediatric Eczema Elective Registry (PEER) (http://www.thepeerprogram.com) is an ongoing prospective 10-year observational registry that is part of a postmarketing commitment originally by Novartis, and now by Valeant, to the US Food and Drug Administration and the European Drug Agency. The goal of this longitudinal safety study is to determine whether there is a long-term risk of cancer associated with the use of pimecrolimus cream, 1%, in a real-world setting. To be eligible for enrollment, a child must be older than 2 years, not currently have cancer, have AD, and have used pimecrolimus cream, 1%, for at least 6 weeks (cumulative) in the previous 6 months. In most cases, the parent of the enrolled participant completes the biannual questionnaire. All individuals completed an additional written informed consent approved by the Institutional Review Board of the University of Pennsylvania and provided a saliva sample from which DNA was extracted. Participants received financial compensation.

Recently, findings on FLG associations with AD in the PEER were published.16 In light of the findings from Gao et al,9 we extended our study of PEER participants to evaluate the 14 tag single-nucleotide polymorphisms (SNPs) selected by Gao et al in TSLP using a custom SNP chip (Illumina GoldenGate; Illumina). Tag SNPs are believed to represent a region of a candidate gene, thereby making it possible to investigate a gene without evaluating every known polymorphism of that gene. The FLG mutations were assessed via an assay (TaqMan; Life Technologies Corp) and were evaluated for the presence or absence of any FLG null mutation.16 The call rate for all assays exceeded 90% unless otherwise noted. Ancestry was determined using a panel of previously described ancestral informative markers and was estimated using clustering techniques.16,1820 Genetically derived ancestry was highly correlated with self-reported race (ie, white: European ancestry, and African American: African ancestry) in this cohort.16

We investigated the self-reported outcome of whether a child’s skin was AD symptom free for 6 months while not requiring the use of topical medication (eg, corticosteroids or calcineurin inhibitors). The symptom-based question was, “During the last 6 months, would you say your child’s skin disease has shown: complete disease control, good disease control, limited disease control, or uncontrolled disease control.” To be symptom free the child had to have complete disease control for the preceding 6-month period. Our evaluation of symptoms was primarily based on pruritus and skin breakdown and may not include other symptoms or signs of AD, such as lichenification, pityriasis alba, xerosis, and keratosis pilaris. Because individuals in this study were monitored longitudinally and surveyed every 6 months, this outcome was reported on more than 1 occasion. We assessed the statistical association between the repeated measures of the binary outcome and each SNP, assuming an additive genetic model within a mixed-effects framework called a generalized linear latent and mixed model (GLLAMM). Because our outcome was binary, the logistic link function was used with a binomial family with an adaptive quadrature. The GLLAMM model has both random-effects and fixed-effects terms, allowing for subject-specific regression coefficients or subject-specific estimates of the association of a risk factor and the outcome. In other words, the GLLAMM models can be more useful if relationships between an outcome and an individual are more important than inferences about the population.21,22 The decision to correct or not correct for multiplicity is a complex and complicated issue. There is no universal solution because the decision to adjust a P value depends on the study design and hypothesis. The primary question in our study was the confirmation of previously described SNPs by Gao et al9 with respect to a new outcome (ie, persistence of AD) and a prespecified hypothesis; therefore, we did not correct for multiple testing.23 All SNP association tests were conducted separately within the 2 subgroups on the basis of race—white and African American. In addition, a pooled analysis that combined whites and African Americans (with adjustment for principal components derived from ancestry informative markers),24 as well as stratified analyses based on FLG and asthma status, were conducted. Finally, a meta-analysis was performed to combine SNP association results across races. The meta-analysis was implemented and heterogeneity was assessed using available software.25 All analyses were conducted using Stata, version 12.1 (StataCorp).

Samples for DNA genotyping were available from as many as 796 children enrolled in PEER. A description of PEER participants who provided DNA and those who did not showed that no clinically important differences exist.26 With respect to our present study cohort, 51.9% were girls (n = 413), 46.1% were African American (n = 367), the mean (SD) age at PEER enrollment was 7.1 (3.7) years, and participants were monitored for 5.7 (1.4) years or approximately 4799 person-years. At the time of enrollment, 3.2% of the children had complete disease control, 43.9% noted good disease control, 42.2% reported limited disease control, and 10.7% experienced uncontrolled disease.

Table 1 presents the unadjusted association of TSLP tagging SNPs with the persistence of AD over time by race. One SNP, rs10213865, was not evaluated further because the genotyping call rate was less than 90% and thus was considered inadequate. The rs1898671 SNP was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45); rs764916 also attained statistical significance in whites (P = .031). However, the ORs were in opposite directions within the white and African American subgroups, and the SNP was not significant in the pooled analysis (white and African Americans analyzed as a single group) with adjustment for covariates.

Table Graphic Jump LocationTable 1.  Association of TSLP SNPs With Outcomea

The Figure shows the frequency of reporting that an individual’s AD was not persistent based on their age in categories at the time of reporting and stratified by the presence or absence of variation in rs1898671. As expected, persistence of AD symptoms decreased as the PEER population became older, but within each age category, those with the rs1898671 variation were less likely to have persistent AD. The results of further analysis of rs1898671 after adjustment for multiple covariates are presented in Table 2. Similar P values were noted for the pooled approach and the meta-analysis approach (P = .03 for both). The results presented in Table 2 for the combined population are from the pooled approach. Rs1898671 was the only SNP that was statistically significant after appropriate adjustments based on sex, ancestry, presence of an FLG mutation, and age at onset of AD in the combined population (OR, 1.55; 95% CI, 1.01-2.30). The results from the adjusted subgroup analyses were almost identical with those of the unadjusted analyses. There were FLG loss-of-function mutations in 69 individuals with the rs1898671 variation. The association between the TSLP rs1898671 variation and the persistence of AD in the presence (n = 134) or absence (n = 598) of an FLG loss-of-function mutation is presented separately for these 2 subgroups in Table 2. The strength of the association was influenced by the absence (ie, FLG wild type) or presence of an FLG loss-of-function mutation (OR, 1.52; 95% CI, 1.01-2.29 and 4.92; 2.04-11.86, respectively, for the subgroups of children without or with an FLG mutation). In the PEER cohort, rs1898671 was not associated with the risk of asthma.

Place holder to copy figure label and caption
Figure.
Age by Category and the Absence of Symptoms

The child’s age at the time a survey was received is presented. The individuals were monitored over time and provided more than 1 survey. TSLP is thymic stromal lymphopoietin.

Graphic Jump Location
Table Graphic Jump LocationTable 2.  Association of rs1898671 With Outcomea

Thymic stromal lymphopoietin has been shown11,14 to be a master initiator of allergic inflammation. Although FLG protein contributes to the skin barrier, TSLP expression occurs after antigen sensitization through a disrupted skin barrier and subsequently promotes the immune responses that result in inflammation that leads to AD.4,11,14 Recently, small interfering RNA–mediated knockdown of FLG expression was shown27 to induce TSLP expression in epidermal keratinocytes. Gao et al9 had evaluated TSLP variation as a risk factor for developing AD and for the diagnosis of eczema herpeticum among individuals with AD and noted that rs1898671 was associated with a decreased risk of eczema herpeticum. We found that this variant was also associated with decreased likelihood of having persistent AD (ie, more likely to report an AD symptom–free state not requiring topical medication). Taken together, these findings can be explained by the presence of a genetic variant (or variants) resulting in diminished TSLP protein activity that is protective in terms of development of cutaneous inflammation and allergy.11,28This hypothesis is further substantiated by the effect of rs1898671 on FLG loss-of-function mutations. Individuals who have the FLG loss-of-function mutation are more likely to have persistent AD16; however, within the subcohort of individuals with that mutation, those who also had an rs1898671 variant were nearly 5 times less likely to have persistent AD compared with those without the variant. Furthermore, previous findings3 have shown that persons with increased TSLP activity are more prone to asthma. However, in our AD cohort, the rs1898671 variant (eg, less active TSLP) did not confer any additional risk for asthma.

The FLG loss-of-function mutations are most commonly found in individuals of European and Asian ancestry vs those of African ancestry.4 The FLG mutations assayed in the present study are most commonly noted in people of European ancestry and are rarely seen in those of African ancestry.4,16 For example, in a previous study16 of this cohort, 27% of whites carried an FLG loss-of-function mutation (minor allele frequency, 0.16) compared with only 5.7% of African Americans (minor allele frequency, 0.03). As a result, many studies have focused solely on individuals of European ancestry to diminish concerns about population stratification, which is a form of bias that can result when genetic variation is associated with ancestry.24 In the present study, differing rates of carriage of rs1898671 occurred based on ancestry but not to the extreme noted for FLG. In addition, our ultimate question was based on the interaction between TSLP and FLG. We therefore have presented results from a pooled analysis as well as from analyses carried out separately in whites and African Americans.

As is true of all studies, there are limitations to the interpretation of our results. First, children enrolled in the PEER must have received at least 6 weeks (cumulative) of pimecrolimus, 1%, cream in the 6 months prior to entry into PEER. Most children, however, do not continue with this therapy while in PEER.29 Pimecrolimus, 1%, cream is approved for use in individuals with mild to moderate AD. It is therefore possible that the results of our study will not generalize to everyone with AD. However, rs1898671 was identified in a cohort of individuals with AD.9 The primary interest of that investigation was to study eczema herpeticum, so it is likely that those individuals may have had more severe AD. However, an important contribution of our study is the potential confirmation of the interplay between barrier dysfunction and immune activation, and it is likely that this observation is generalizable. In addition, we tested the 4 most common European FLG mutations. These FLG mutations have been found rarely in people of African ancestry. It is possible that mutations also exist in other barrier proteins.3032 Interactions between these yet-to-be-identified mutations and the TSLP variation described in our study could potentially influence the outcome in a different manner than that described in the present study. This concern, however, can be addressed only as additional mutations are found. Because all children enrolled in PEER had to have used pimecrolimus, 1%, cream before entry into the study, it may be possible that the rs1898671 variation interacts with pimecrolimus therapy, resulting in an improved outcome. However, by the third year of enrollment, more than 45% of PEER participants were no longer using pimecrolimus, so we believe that this explanation is unlikely.29

We chose to not correct our P values for multiple comparisons. This was based on the notion that our study was guided by a hypothesis established from previously published data.9 Our hypothesis was that diminished TSLP activity would lead to less persistent AD even in the setting of an FLG loss-of-function mutation. Our initial interest in diminished protein activity parallels the assumptions used by those who originally investigated FLG.4Because TSLP is a master inducer of inflammation, diminishing the function of the TSLP protein should diminish the inflammatory component of AD.10,11 This hypothesis is consistent with the observation by Gao et al9 with respect to eczema herpeticum and is also consistent with our observations (eg, diminished inflammation resulting from diminished TSLP activity resulted in fewer cases of eczema herpeticum and less persistent AD, respectively).10,11,15 A more pertinent statistical observation would be the probability that 2 independent studies evaluating 14 SNPs achieved the same statistical results. The probability of finding this observation is P = .009.

Because rs1898671 is a tag SNP of the TSLP gene, further investigations, including fine-mapping and functional investigations of the TSLP protein, are needed to determine the causal variant with respect to the persistence of AD. We also did not evaluate whether rs1898671 is associated with the onset of AD. As with many illnesses, agents that cause a disease or affect its severity and persistence are often not the same. Furthermore, we did not study TSLP protein levels in our participants. It is, however, noteworthy that rs1898671 has now been validated in at least 2 different cohorts by different investigators (Gao et al9 and us). Based on our evaluation of the persistence of AD, inhibition or diminution of the effect of TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that could be tested in clinical trials.

Accepted for Publication: August 29, 2013.

Corresponding Author: David J. Margolis, MD, PhD, 901 Blockley Hall, Departments of Dermatology and Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 423 Guardian Dr, Philadelphia, PA 19104 (margo@upenn.edu).

Published Online: January 8, 2014. doi:10.1001/jamadermatol.2013.7954.

Author Contributions: Dr Margolis and Mr Hoffstad had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Margolis, Apter, Mitra.

Acquisition of data: Margolis, Hoffstad, Papadopoulos.

Analysis and interpretation of data: Margolis, Kim, Apter, Gupta, Mitra.

Drafting of the manuscript: Margolis, Apter, Gupta, Mitra.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Margolis, Gupta, Hoffstad, Mitra.

Obtained funding: Margolis.

Administrative, technical, or material support: Kim, Papadopoulos.

Study supervision: Margolis, Mitra.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by grant R01-AR0056755 from the National Institute of Arthritis Musculoskeletal and Skin Diseases. The PEER study is funded by a grant from Valeant Pharmaceuticals.

Role of the Sponsor: The National Institute of Arthritis Musculoskeletal and Skin Diseases and Valeant Pharmaceuticals had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This study was presented as an oral abstract at the International Investigative Dermatology Meeting; May 8, 2013; Edinburgh, Scotland.

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Fallon  PG, Sasaki  T, Sandilands  A,  et al.  A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41(5):602-608.
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Figures

Place holder to copy figure label and caption
Figure.
Age by Category and the Absence of Symptoms

The child’s age at the time a survey was received is presented. The individuals were monitored over time and provided more than 1 survey. TSLP is thymic stromal lymphopoietin.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Association of TSLP SNPs With Outcomea
Table Graphic Jump LocationTable 2.  Association of rs1898671 With Outcomea

References

Leung  DY, Bieber  T.  Atopic dermatitis. Lancet. 2003;361(9352):151-160.
PubMed   |  Link to Article
Abramovits  W.  Atopic dermatitis. J Am Acad Dermatol. 2005;53(1)(suppl 1):S86-S93.
PubMed   |  Link to Article
Kabashima  K.  New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci. 2013;70(1):3-11.
PubMed   |  Link to Article
Brown  SJ, McLean  WH.  One remarkable molecule: filaggrin. J Invest Dermatol. 2012;132(3, pt 2):751-762.
PubMed   |  Link to Article
Smith  FJ, Irvine  AD, Terron-Kwiatkowski  A,  et al.  Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337-342.
PubMed   |  Link to Article
Irvine  AD, McLean  WH, Leung  DY.  Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315-1327.
PubMed   |  Link to Article
Fallon  PG, Sasaki  T, Sandilands  A,  et al.  A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41(5):602-608.
PubMed   |  Link to Article
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