Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
Study Design
- 研究类型
- Observational Study
- 样本量
- 4332
- 干预措施
- Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
- 对照组
- Placebo
- 效应方向
- Positive
- 偏倚风险
- Low
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 attack. 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 <or= 5 x 10(-7)). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (T(reg) 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.
Full Text
Figures
Figure 1
Manhattan plot displaying genome-wide association results for alopecia areata across 1,054 cases and 3,278 controls, with 139 SNPs reaching significance (P <= 5 x 10^-7). Several genomic loci implicated in both innate and adaptive immunity exceed the genome-wide significance threshold.
chart
Figure 2
Regional association plot or gene-level analysis from the alopecia areata GWAS, highlighting specific immune-related loci associated with hair follicle immune privilege collapse. The identified risk variants cluster in regions encoding HLA, cytokine, and T-cell regulatory genes.
chart
Figure 3
Summary of genetic associations between alopecia areata and immune-related genomic regions, supporting the involvement of both innate killer cell activity and adaptive T-cell responses in disease pathogenesis.
chartTables
Table 1
| Region | Gene | Function | Strongest association ( | Maximum odds ratio | Involved in other autoimmune disease |
|---|---|---|---|---|---|
| 2q33.2 | Co-stimulatory family | 3.55 × 10−13 | 1.44 | T1D, RA, CeD, MS, SLE, GD | |
| Co-stimulatory family | 4.33 × 10−8 | 1.32 | |||
| 4q27 | T-, B- and NK-cell proliferation | 4.27 × 10−8 | 1.34 | T1D, RA, CeD, PS | |
| 6q25.1 | NKG2D activating ligand | 4.49 × 10−19 | 1.65 | None | |
| NKG2D activating ligand | 4.43 × 10−17 | 1.52 | None | ||
| 9q31.1 | Premature hair greying | 3.60 × 10−7 | 1.33 | None | |
| 10p15.1 | T-cell proliferation | 1.74 × 10−12 | 1.41 | T1D, MS, GD, GV | |
| 11q13 | Antioxidant enzyme | 4.14 × 10−7 | 1.33 | MS | |
| 12q13 | Treg transcription factor | 3.21 × 10−8 | 1.34 | T1D, SLE | |
| Epidermal growth factor receptor | 1.27 × 10−7 | 1.34 | T1D, SLE | ||
| 6p21.32 | NKG2D activating ligand | 1.19 × 10−7 | 1.44 | T1D, RA, CeD, UC, PS, SLE | |
| (HLA) | Haematopoietic differentiation | 1.03 × 10−8 | 1.61 | T1D, RA, MS | |
| Unknown | 1.45 × 10−16 | 2.36 | T1D, RA, PS, GV | ||
| Co-stimulatory family | 2.11 × 10−26 | 2.70 | T1D, RA, UC, CD, SLE, MS, GV | ||
| Antigen presentation | 2.93 × 10−31 | 2.62 | T1D, RA, CeD, MS, GV | ||
| Antigen presentation | 3.60 × 10−17 | 2.15 | T1D, RA, CeD, MS, SLE, PS, CD, UC, GD | ||
| Antigen presentation | 1.38 × 10−35 | 5.43 | T1D, RA | ||
| Antigen presentation | 1.73 × 10−13 | 1.60 | RA |
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