Abstract
Atopic dermatitis (AD) is a common illness that most commonly originates in childhood, but can be seen in all ages. Filaggrin (FLG) loss of function variants have been associated with the onset and severity of atopic dermatitis and are the most common genetic association with AD. Previous studies have shown variability in the frequency of FLG variants. We have recently demonstrated that previous FLG genotyping methods were inadequate for proper genotyping. In this concise report, we show that genotyping using a popular older informatics program is problematic. In fact, publications that used the older program likely do not properly capture all FLG variants.
References
Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P et al (2006) Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy 61(8):969–987
Charman CR, Williams HC (2002) Epidemiology. In: Bieber T, Leung DYM (eds) Atopic dermatitis. Marcel Dekker, Inc., New York, pp 21–42
Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL et al (2014) Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. [Review]. J Am Acad Dermatol 70(2):338–351
Leung DY, Bieber T (2003) Atopic dermatitis. [Review] [100 refs]. Lancet 361(9352):151–160
Ober C, Yao TC (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 242(11):10–30
Brown SJ, McLean WH (2012) One remarkable molecule: filaggrin. J Investig Dermatol 132(3 Pt 2):751–762
Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE et al (2012) The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol 130(4):912–917
Margolis DJ, Hoffstad O, Bilker W (2007) Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology 214(4):289–295
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. [see comment]. Nat Genet 38(4):441–446
Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H et al (2007) Filaggrin null mutations are associated with increased asthma severity in children and young adults. J Allergy Clin Immunol 120(1):64–68
Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands A, McLean WH et al (2009) 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. Br J Dermatol 161(4):884–889
Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands A, Wilson IJ et al (2008) Filaggrin mutations and childhood atopic eczema: a population-based case–control study. J Allergy Clin Immunol 121:940–946
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291
Margolis DJ, Gupta J, Apter AJ, Hoffstad O, Papadopoulos M, Rebbeck TR et al (2014) Exome sequencing of filaggrin and related genes in African–American children with atopic dermatitis. J Investig Dermatol 134(8):2272–2274
Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM et al (2007) Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 39(5):650–654
Wong X, Denil S, Foo JN, Chen H, Tay ASL, Haines RL et al (2018) Array-based sequencing of filaggrin gene for comprehensive detection of disease-associated variants. J Allergy Clin Immunol 141(2):814–816
Thaswer-Esmail F, Jakasa I, Todd G, Wen Y, Brown SJ, Krobach K et al (2014) South African amaXhosa patient with atopic dermatitis have decreased levels of filaggrin breakdown products but no loss-of-function mutations in filaggrin. J Allergy Clin Immunol 133(1):280–282
Winge MCG, Bilcha KD, Lieden A, Shibeshi D, Sandilands A, Wahlgren CF et al (2011) Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis. Br J Dermatol 165(5):1074–1080
Pigors M, Common JEA, Wong X, Malik S, Scott CA, Tabarra N et al (2018) Exome sequencing and rare variant analysis reveals multiple filaggrin mutations in Bangladeshi families with Atopic Eczema and additional risk genes. J Investig Dermatol 138(12):2674–2677
Taylan F, Nilsson D, Asad S, Lieden A, Wahlgren CF, Winge MC et al (2015) Whole-exome sequencing of Ethiopian patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 136(2):507–509 (e19)
Margolis DJ, Mitra N, Gochnauer H, Wubbenhorst B, D’Andrea K, Kraya A et al (2018) Uncommon filaggrin variants are associated with persistent atopic dermatitis in African Americans. J Investig Dermatol 138(7):1501–1506
Chang J, Mitra N, Hoffstad O, Margolis DJ (2017) Association of filaggrin loss of function and thymic stromal lymphopoietin variation with treatment use in pediatric atopic dermatitis. JAMA Dermatol 153(3):275–281
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43(5):491–498
Poplin R, Ruano-Rubio V, DePristo MA, Fennell TJ, Carneiro MO, Van der Auwera GA et al (2018) Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv. https://doi.org/10.1101/201178
Mandelker D, Schmidt RJ, Ankala A, McDonald Gibson K, Bowser M, Sharma H et al (2016) Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing. Genet Med 18(12):1282–1289
Hasan MS, Wu X, Zhang L (2015) Performance evaluation of indel calling tools using real short-read data. Hum Genom 9:20
Eaaswarkhanth M, Xu D, Flanagan C, Rzhetskaya M, Hayes MG, Blekhman R et al (2016) Atopic dermatitis susceptibility variants in filaggrin Hitchhike hornerin selective sweep. Genome Biol Evol 8(10):3240–3255
Thyssen JP, Bikle DD, Elias PM (2014) Evidence that loss-of-function filaggrin gene mutations evolved in northern Europeans to favor intracutaneous vitamin D3 production. Evol Biol 41(3):388–396
Acknowledgements
This study was funded by support from the NIH NIAMS R01-AR069062. The sponsor did not have a role in the design of the study, in the collection, analysis or interpretation of the data, the preparation of this report or in the decision to submit this report for publication. None of the authors have a financial conflict of interest with respect to this investigation.
Funding
This study was funded by R01-AR060962 from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
David Margolis had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. David Margolis receives research funding as the principal investigator via the Trustees of the University of Pennsylvania (R01-AR060962, R01-AR070873, and R01-DK116199) and from the NIH and Valeant Pharmaceuticals (PEER study) and Sunovion Pharmaceuticals. Only funding from R01-AR060962 of was used for this study. He has consulting activities primarily as a member of data monitoring boards or scientific advisory boards with Leo, Johnson and Johnson, Pfizer, Sanofi, Kerecis, and Cell Constructs. None of these activities are associated with the outcomes of this study. Authors Mitra, Wubbenhorst and Nathanson received research funding from R01-AR060962 and report no other authors report conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Margolis, D.J., Mitra, N., Wubbenhorst, B. et al. Filaggrin sequencing and bioinformatics tools. Arch Dermatol Res 312, 155–158 (2020). https://doi.org/10.1007/s00403-019-01956-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-019-01956-3