Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors - 05/01/22

Doi : 10.1016/j.jaci.2021.05.034

Christopher H. Arehart, BS ^a, Michelle Daya, PhD ^a, Monica Campbell, MS ^a, Meher Preethi Boorgula, MS ^a, Nicholas Rafaels, MS ^a, Sameer Chavan, MS ^a, Gloria David, PhD ^b, Jon Hanifin, MD ^c, Mark K. Slifka, PhD ^c, Richard L. Gallo, MD, PhD ^d, Tissa Hata, MD ^d, Lynda C. Schneider, MD ^e, Amy S. Paller, MD ^f,^g, Peck Y. Ong, MD ^h,ⁱ, Jonathan M. Spergel, MD ^j, Emma Guttman-Yassky, MD, PhD ^k, Donald Y.M. Leung, MD, PhD ^l, Lisa A. Beck, MD ^m, Christopher R. Gignoux, MS, PhD ^a, Rasika A. Mathias, ScD ^n,^{∗
These authors contributed equally to this work and are equally senior authors.}, Kathleen C. Barnes, PhD ^a,^⁎^{∗
These authors contributed equally to this work and are equally senior authors.}
^a Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
^b Rho, Inc, Durham, NC
^c Department of Dermatology, Oregon Health and Science University, Portland, Ore
^d Department of Dermatology, University of California San Diego, San Diego, Calif
^e Division of Immunology, Boston Children’s Hospital, Boston, Mass
^f Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill
^g Department of Pediatrics (Dermatology), Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Ill
^h Division of Clinical Immunology and Allergy, Children’s Hospital Los Angeles, Los Angeles, Calif
ⁱ Keck School of Medicine, University of Southern California, Los Angeles, Calif
^j Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pa
^k Icahn School of Medicine at Mount Sinai, New York, NY
^l Division of Allergy and Immunology, Department of Pediatrics, National Jewish Health, Denver, Colo
^m Department of Dermatology, Medicine and Pathology, University of Rochester Medical Center, Rochester, NY
ⁿ Department of Medicine, Johns Hopkins University Department of Medicine, Baltimore, Md

^∗Corresponding author: Kathleen C. Barnes, PhD, University of Colorado Anschutz Medical Campus, 13001 E. 17^th Place, Room 5330A, Mail Stop F563, Aurora, CO 80045.University of Colorado Anschutz Medical Campus13001 E. 17^th PlaceRoom 5330AMail Stop F563AuroraCO80045

Abstract

Background

While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.

Objectives

This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.

Methods

AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.

Results

Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRS_AD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRS_AD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRS_AD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRS_AD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).

Conclusions

This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

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Key words : Atopic dermatitis, polygenic risk score, atopic march, allergic disease, genetic architecture, filaggrin, disease prediction, genetic predisposition

Abbreviations used : AD, AUC, EASI, EDC, GRS, GWAS, LD, LOF, OR, P+T, PRS, RL

Plan

Methods

External AD GWAS

External atopic phenotype GWASs

Common factor GWAS_AD+

PRS validation data from ADRN

PRS model derivation and selection

Contribution of FLG mutations to the PRS_AD++

AD severity correlations with PRS_AD, PRS_AD+, and PRS_AD++

Results

PRS Model Selection

PRS_AD, PRS_AD+, and PRS_AD++

PRS correlates with AD severity

FLG mutations and the PRSs

Discussion

Funding for this work was provided by the National Institutes of Health/National Institute of Allergy and Infectious Disease (grant U19 AI117673), the Atopic Dermatitis Research Network, and the Oregon National Primate Research Center (grant 8P51 OD011092 [to M.K.S.]).

Disclosure of potential conflict of interest: R.L. Gallo is a board member of MatriSys and Bioscience; has received a consulting fee from Sente; has pending grants through Novan and Regeneron; and has stock in Sente and MatriSys. L.C. Schneider is an investigator for Regeneron and DBV Technologies; a consultant for Amagma, Alladapt, and Ukko; and has grants from Genentech and Pfizer. A.S. Paller has been a consultant for AbbVie, Boehringer Ingelheim, Dermira, Eli Lilly, Forte, Galderma, LEO Pharma, Novartis, Pfizer, Regeneron, and Sanofi Genzyme; and an investigator for AbbVie, Eli Lilly, Incyte, LEO Pharma, Novartis, and Regeneron. L.A. Beck is a consultant for AbbVie, Allakos, AstraZeneca, Benevolent AIBio, Incyte, Janssen, Leo Pharma, Lilly, Naos Bioderma, Novartis, Pfizer, Principia Biopharma, Rapt Therapeutics, Regeneron, Sanofi/Genzyme, Sanofi-Aventis, UCB, and Vimalan; is an investigator for AbbVie, AstraZeneca, Kiniksa, Leo Pharma, Pfizer, Regeneron, and Sanofi; and has stock in Medtronics, Moderna, and Gilead. C. R. Gignoux has stock in 23andMe. K.C. Barnes receives royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 149 - N° 1

P. 145-155 - janvier 2022 Retour au numéro

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Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors - 05/01/22

Abstract

Background

Objectives

Methods

Results

Conclusions

Plan

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