Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

Abstract

Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, TGFß/Tregs and JAK kinase signaling, and support the causal role of aberrant immune processes in AA.

Alopecia Areata. Current situation and perspectives

“…1,2 One example is alopecia areata (AA) (OMIM 104000), which is c h a r a c t e r i z e d b y n o n -s c a r r i n g hair loss. 3 It has a variable and unpredictable evolution in each patient 4 and is classified into the following three groups according to severity and the areas where hair loss is observed: 1) alopecia areata in patches (AA), considered the most common form and identified by round or oval patches on the head (90% of cases) or in different parts of the body; 2) alopecia totalis (AT), in which there is a complete or almost complete absence of hair on the scalp; and 3) alopecia universalis (AU), established as the most severe and differentiated from the previous two because the total loss of hair is observed all over the body in addition to the face and scalp.…”

Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata

“…Two decades of experimental research using animal models of AA and genome-wide association studies both in mice and humans have elucidated key factors in AA pathogenesis (3,4). An important therapeutic insight was the discovery that blockade of common signaling pathways downstream of cytokine receptors, in particular JAK/STAT, could reverse AA in mice (5).…”

Alopecia areata. Actualidad y perspectivas

“…1,2 Ejemplo de ello es la alopecia areata (AA) (OMIM 104000), caracterizada por la pérdida de pelo, no cicatricial, 3 c o n u n a e v o l u c i ó n v a r i a b l e e impredecible en cada paciente, 4 la cual está clasificada en tres grupos de acuerdo con la gravedad y con las regiones en donde se observa la ausencia de pelo: 1) alopecia areata en parche (AA), considerada la forma más común e identificada por la presencia de parches redondos u ovalados en la cabeza (90% de los casos) o en diferentes regiones del cuerpo; 2) alopecia total (AT), en la cual existe una ausencia total o casi total de pelo en el cuero cabelludo; y 3) alopecia universal (AU), establecida como la más grave y diferenciada de las dos anteriores porque la pérdida total de pelo es observada en todo el cuerpo, que incluye la cara y el cuero cabelludo.…”