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Genome-wide association study in alopecia areata implicates both innate and adaptive immunity

Abstract

Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack1,2. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P ≤ 5 × 10−7). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (Treg cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.

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Figure 1: Manhattan plot of the joint analysis of the discovery GWAS and the replication GWAS.
Figure 2: LD structure and haplotype organization of the implicated regions from GWAS.
Figure 3: ULBP3 expression and immune cell infiltration of AA hair follicles.

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Acknowledgements

We thank the many patients and their family members who participated in the National Alopecia Areata Registry from which the patient cohort was derived; S. Schwartz, D. A. Greenberg, S. E. Hodge, R. Ottman, K. Kiryluk, J. Lee, J. D. Terwilliger and R. Plenge for discussions about statistical methodology; A. Bowcock, M. Girardi, R. Clark, J. Trowsdale, R. Clynes, S. Ghosh and R. Bernstein for critical insights and perspectives on genetics, hair and immunobiology; C. Higgins, M. Kurban, M. Kiuru, H. Lam and M. Zhang for expert assistance in the laboratory; A. Martinez-Mir, M. Peacocke, A. Zlotogorski, M. Grossman, P. Schneiderman, D. Gordon and J. Ott for their critical input in the early phases of this study. We are grateful to the National Alopecia Areata Foundation (NAAF) for support of funding the initial studies, and to V. Kalabokes and her staff at NAAF for their efforts on our behalf. The patient cohort was collected and maintained by the National Alopecia Areata Registry (N01AR62279) (to M.D.). This work was supported in part by the DFG Cluster of Excellence, Inflammation at Interfaces (to R.P.) and by the National Institutes of Health grants R01AR44422 (to C.I.A. and P.K.G.), R01CA133996 and P30CA016772 (to C.I.A.) and R01AR52579 and R01AR56016 (to A.M.C.).

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Contributions

L.P. performed technical aspects in preparation of samples for genotyping, the statistical analysis and preparation of the manuscript. M.D., V.P., M.H. and D.N. participated in phenotyping, diagnosis, and access to patient samples from the National Alopecia Areata Registry. Y.S., P.S. and H.K. provided expertise in RT–PCR and immunofluorescence. K.C.M. and R.P. provided expertise in immunhistochemistry. A.L. and P.K.G. provided control samples and performed genotyping as well as insight into autoimmune diseases. W.V.C. and C.I.A. provided additional statistical analysis and control samples from a distinct cohort. C.A.B.J. performed hair follicle microdissection and provided indispensable scientific expertise on the dermal sheath. A.M.C. provided oversight and conceptual guidance to the project, input into the functional significance of candidate genes, supervision of laboratory personnel, management of collaborations, preparation of the manuscript and all reporting requirements for granting agencies.

Corresponding author

Correspondence to Angela M. Christiano.

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The authors declare no competing financial interests.

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Petukhova, L., Duvic, M., Hordinsky, M. et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 466, 113–117 (2010). https://doi.org/10.1038/nature09114

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