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Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

ABSTRACT: Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

SUBMITTER: Tziotzios C

PROVIDER: S-EPMC6408457 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

Tziotzios Christos C Petridis Christos C Dand Nick N Ainali Chrysanthi C Saklatvala Jake R JR Pullabhatla Venu V Onoufriadis Alexandros A Pramanik Rashida R Baudry David D Lee Sang Hyuck SH Wood Kristie K Liu Lu L Seegobin Seth S Michelotti Gregory A GA Lwin Su M SM Christou Evangelos A A EAA Curtis Charles J CJ de Rinaldis Emanuele E Saxena Alka A Holmes Susan S Harries Matthew M Palamaras Ioulios I Cunningham Fiona F Parkins Gregory G Kaur Manjit M Farrant Paul P McDonagh Andrew A Messenger Andrew A Jones Jennifer J Jolliffe Victoria V Ali Iaisha I Ardern-Jones Michael M Mitchell Charles C Burrows Nigel N Atkar Ravinder R Banfield Cedric C Alexandroff Anton A Champagne Caroline C Cooper Hywel L HL Vañó-Galván Sergio S Molina-Ruiz Ana Maria AM Perez Nerea Ormaechea NO Patel Girish K GK Macbeth Abby A Page Melanie M Bryden Alyson A Mowbray Megan M Wahie Shyamal S Armstrong Keith K Cooke Nicola N Goodfield Mark M Man Irene I de Berker David D Dunnill Giles G Takwale Anita A Rao Archana A Siah Tee-Wei TW Sinclair Rodney R Wade Martin S MS Dlova Ncoza C NC Setterfield Jane J Lewis Fiona F Bhargava Kapil K Kirkpatrick Niall N Estivill Xavier X Stefanato Catherine M CM Flohr Carsten C Spector Timothy T Watt Fiona M FM Smith Catherine H CH Barker Jonathan N JN Fenton David A DA Simpson Michael A MA McGrath John A JA

Nature communications 20190308 1

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four gen ...[more]

PMID: 30850646

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Project description:Human Cytomegalovirus (CMV) reactivation remains a major source of morbidity in patients after solid organ and hematopoietic stem cell transplantation (HSCT). Adoptive T cell therapy (ACT) with CMV-specific T cells is a promising therapeutic approach for HSCT recipients, but might be counteracted by CMV's immune evasion strategies. HLA-C*07:02 is less susceptible to viral immune evasion suggesting HLA-C*07:02-restricted viral epitopes as promising targets for ACT. For a better understanding of HLA-C*07:02-restricted CMV-specific T cells we used recently generated reversible HLA-C*07:02/IE-1 multimers (Streptamers) recognizing a CMV-derived Immediate-Early-1 (IE-1) epitope and analyzed phenotypic and functional T cell characteristics. Initially, we detected very high frequencies of HLA-C*07:02/IE-1 multimer+ T cells (median = 11.35%), as well as robust functional responses after stimulation with IE-1 peptide (IFN?+; median = 5.02%) in healthy individuals. However, MHC-multimer+ and IFN?-secreting T cell frequencies showed a relatively weak correlation (r2 = 0.77), which could be attributed to an unexpected contribution of CMV-epitope-independent KIR2DL2/3-binding of HLA-C*07:02/IE-1 multimers. Therefore, we developed a MHC-multimer double-staining approach against a cancer epitope-specific HLA-C*07:02 multimer to identify truly HLA-C*07:02/IE-1 epitope-specific T cells. The frequencies of these truly HLA-C*07:02/IE-1 multimer+ T cells were still high (median = 6.86%) and correlated now strongly (r2 = 0.96) with IFN?-secretion. Interestingly, HLA-C*07:02/IE-1-restricted T cells contain substantial numbers with a central memory T cell phenotype, indicating high expansion potential e.g. for ACT. In line with that, we developed a clinical enrichment protocol avoiding epitope-independent KIR-binding to make HLA-C*07:02/IE-1-restricted T cells available for ACT. Initial depletion of KIR-expressing CD8+ T cells followed by HLA-C*07:02/IE-1 Streptamer positive selection using paramagnetic labeling techniques allowed to enrich successfully HLA-C*07:02/IE-1-restricted T cells. Such specifically enriched populations of functional HLA-C*07:02/IE-1-restricted T cells with significant central memory T cell content could become a potent source for ACT.

Dataset Information

Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

Publications

Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

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