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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Cooper, G. S., Bynum, M. L. & Somers, E. C. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J. Autoimmun. 33, 197–207 (2009)
Safavi, K. H., Muller, S. A., Suman, V. J., Moshell, A. N. & Melton, L. J. III. Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin. Proc. 70, 628–633 (1995)
Jelinek, J. E. Sudden whitening of the hair. Bull. N. Y. Acad. Med. 48, 1003–1013 (1972)
Gilhar, A., Paus, R. & Kalish, R. S. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J. Clin. Invest. 117, 2019–2027 (2007)
Gilhar, A. et al. Transfer of alopecia areata in the human scalp graft/Prkdc(scid) (SCID) mouse system is characterized by a TH1 response. Clin. Immunol. 106, 181–187 (2003)
Gilhar, A., Shalaginov, R., Assy, B., Serafimovich, S. & Kalish, R. S. Alopecia areata is a T-lymphocyte mediated autoimmune disease: lesional human T-lymphocytes transfer alopecia areata to human skin grafts on SCID mice. J. Investig. Dermatol. Symp. Proc. 4, 207–210 (1999)
Ito, T., Meyer, K. C., Ito, N. & Paus, R. Immune privilege and the skin. Curr. Dir. Autoimmun. 10, 27–52 (2008)
McDonagh, A. J. & Tazi-Ahnini, R. Epidemiology and genetics of alopecia areata. Clin. Exp. Dermatol. 27, 405–409 (2002)
Van der Steen, P. et al. The genetic risk for alopecia areata in first degree relatives of severely affected patients. An estimate. Acta Derm. Venereol. 72, 373–375 (1992)
Jackow, C. et al. Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J. Am. Acad. Dermatol. 38, 418–425 (1998)
Martinez-Mir, A. et al. Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am. J. Hum. Genet. 80, 316–328 (2007)
Radosavljevic, M. et al. A cluster of ten novel MHC class I related genes on human chromosome 6q24.2–q25.3. Genomics 79, 114–123 (2002)
Eagle, R. A. & Trowsdale, J. Promiscuity and the single receptor: NKG2D. Nature Rev. Immunol. 7, 737–744 (2007)
Eagle, R. A., Traherne, A. J., Hair, J. R., Jafferji, I. & Trowsdale, J. ULBP6/RAET1L is an additional human NKG2D ligand. Eur. J. Immunol. 39, 3207–3216, (2009)
Caillat-Zucman, S. How NKG2D ligands trigger autoimmunity? Hum. Immunol. 67, 204–207 (2006)
Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002)
Strid, J. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nature Immunol. 9, 146–154 (2008)
Borchers, M. T. et al. Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease. J. Clin. Invest. 119, 636–649 (2009)
Ito, T. et al. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J. Invest. Dermatol. 128, 1196–1206 (2008)
Zhang, Q., Li, J., Deavers, M., Abbruzzese, J. L. & Ho, L. The subcellular localization of syntaxin 17 varies among different cell types and is altered in some malignant cells. J. Histochem. Cytochem. 53, 1371–1382 (2005)
Rosengren Pielberg, G. et al. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nature Genet. 40, 1004–1009 (2008)
Akar, A. et al. Antioxidant enzymes and lipid peroxidation in the scalp of patients with alopecia areata. J. Dermatol. Sci. 29, 85–90 (2002)
Holley, J. E., Newcombe, J., Winyard, P. G. & Gutowski, N. J. Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes. Mult. Scler. 13, 955–961 (2007)
Gerard, A. C., Many, M. C., Daumerie, C., Knoops, B. & Colin, I. M. Peroxiredoxin 5 expression in the human thyroid gland. Thyroid 15, 205–209 (2005)
Wang, M. X. et al. Expression and regulation of peroxiredoxin 5 in human osteoarthritis. FEBS Lett. 531, 359–362 (2002)
Karasawa, R., Ozaki, S., Nishioka, K. & Kato, T. Autoantibodies to peroxiredoxin I and IV in patients with systemic autoimmune diseases. Microbiol. Immunol. 49, 57–65 (2005)
Pan, F. et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325, 1142–1146 (2009)
Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008)
Monteleone, G., Pallone, F. & Macdonald, T. T. Interleukin-21 as a new therapeutic target for immune-mediated diseases. Trends Pharmacol. Sci. 30, 441–447 (2009)
Gregersen, P. K. & Olsson, L. M. Recent advances in the genetics of autoimmune disease. Annu. Rev. Immunol. 27, 363–391 (2009)
Duvic, M., Norris, D., Christiano, A., Hordinsky, M. & Price, V. Alopecia areata registry: an overview. J. Investig. Dermatol. Symp. Proc. 8, 219–221 (2003)
Mitchell, M. K., Gregersen, P. K., Johnson, S., Parsons, R. & Vlahov, D. The New York Cancer Project: rationale, organization, design, and baseline characteristics. J. Urban Health 81, 301–310 (2004)
Plenge, R. M. et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007)
Hunter, D. J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nature Genet. 39, 870–874 (2007)
Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nature Genet. 39, 645–649 (2007)
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007)
Tian, C. et al. European population genetic substructure: further definition of ancestry informative markers for distinguishing among diverse european ethnic groups. Mol. Med. 15, 371–383, (2009)
Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005)
Bazzi, H. et al. Desmoglein 4 is expressed in highly differentiated keratinocytes and trichocytes in human epidermis and hair follicle. Differentiation 74, 129–140 (2006)
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.).
The authors declare no competing financial interests.
About this article
Cite this article
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
The ZNF76 rs10947540 polymorphism associated with systemic lupus erythematosus risk in Chinese populations
Scientific Reports (2021)
Human Cell (2021)
Clinical and Experimental Medicine (2021)
Der Hautarzt (2021)
Seminars in Immunopathology (2021)