Alopecia areata (AA) is a chronic, non-scarring, immune-mediated skin disease that affects approximately 0.5–2% of the global population. The etiology of AA is complex and involves genetic and environmental factors, with significant advancements in genetic research occurring. In addition to well-known genes such as PTPN22, CTLA4, and IL2, which have been widely supported as being associated with AA, an increasing number of specific gene-related loci have been discovered through advances in genetic research.
Genetic research is crucial for understanding the etiology and treatment of alopecia areata (AA). Many studies have shown that AA may result from the abnormal expression and interaction of multiple genes [1][2][4,5] which are involved in biological processes such as the immune system and hair follicle growth and development. Thus, genetic testing can help assess patients’ susceptibility and predict and diagnose the disease. For instance, central centrifugal cicatricial alopecia (CCCA) is a prevalent alopecia disorder that predominantly affects women of African and African descent. It has been established that mutations in PADI3 are implicated in CCCA. If patients exhibit these mutations during genetic testing, they may have an increased predisposition to CCCA or be at risk of developing the condition [3][6]. Furthermore, AA-based genetic research can facilitate the development of new treatments. Indeed, recent breakthroughs in genetic research have led to the application of JAK inhibitors in the treatment of AA.
Location | Gene | Associated Function | Connection to Other Diseases * | Reference |
---|---|---|---|---|
Chromosome 1 | FASLG | Activation-induced cell death (AICD) of T cells | Not defined | [13][42] |
PTPN22 | Regulating CBL function in the T-cell receptor signaling pathway | T1D, RA, SLE, GD | [14][15][16][43,44,45] | |
CLCNKA | Salt reabsorption in the kidney and potassium recycling in the inner ear | Bartter syndrome, type 4b | [17][46] | |
CLCNKB | Renal salt reabsorption | Not defined | [17][46] | |
CPT2 | Oxidization of long-chain fatty acids in the mitochondria | Carnitine palmitoyltransferase II deficiency, infantile | [17][46] | |
PINK1 | Protection of cells from stress-induced mitochondrial dysfunction | PD | [17][46] | |
SUCO | Collagen biosynthetic process | Mesial temporal lobe epilepsy | [17][46] | |
USH2A | Development and homeostasis of the inner ear and retina | Deafness | [17][46] | |
MASP2 | Coagulation cascade | Not defined | [18][47] | |
CD2 | Immune recognition | Not defined | [19][48] | |
MIR34A | Tumor suppressor | Not defined | [20][49] | |
Chromosome 2 | CTLA4 | Co-stimulation | T1D, RA, CeD, MS, SLE, GD | [2][10][16][18][21][5[,3922,45,47],50,51] |
ICOS | Co-stimulation | T1D, MS | [2][10][21][5,39,50] | |
ACOXL/ BCL2L11 |
Apoptosis, autophagy regulation | T1D, IgA nephropathy, primary sclerosing cholangitis | [2][5] | |
IL36A | Inflammatory response | Allergic contact dermatitis, AD, acne, hidradenitis suppurativa | [23][52] | |
ALS2 | A guanine nucleotide exchange factor for the small GTPase RAB5 | ALS | [17][46] | |
CYP27A1 | Drug metabolism and synthesis of cholesterol, steroids, and other lipids | CTX, Cholestanol storage disease | [17][46] | |
IRS1 | Encoding a protein that is phosphorylated by insulin receptor tyrosine kinase | DM | [17][46] | |
COL4A4 | The structural component of basement membranes | Thin basement membrane disease | [17][46] | |
TPO | Thyroid gland function | Congenital hypothyroidism | [17][46] | |
HOXD13 | Morphogenesis in all multicellular organisms | Synpolydactyly | [17][46] | |
Chromosome 3 | CHRNB2 | Regulation of synaptic vesicle exocytosis | AD | [17][46] |
COLQ | Encoding the subunit of a collagen-like molecule | Congenital myasthenic syndrome | [17][46] | |
TLR9 | Pathogen recognition and activation of innate immunity | Not defined | [24][53] | |
Chromosome 4 | IL-21 | Th17 and NK cell proliferation | T1D, RA, CeD, PS | [2][10][21][5,39,50] |
IL-2 | T and B cell proliferation | T1D, RA, CeD, PS | [2][10][21][5,39,50] | |
Cxcl9 | Chemoattractant for lymphocytes | RA, T1D, PS, SLE | [2][5] | |
Cxcl10 | Chemokine: monocyte, NK and, T cell stimulation | RA, T1D, PS, SLE | [2][5] | |
Cxcl11 | Chemokine: chemotaxis of activated T cells | RA, T1D, PS, SLE | [2][5] | |
TLR1 | Pathogen recognition and activation of innate immunity | Not defined | [18][21][47,50] | |
EGF | Growth, proliferation, and differentiation of numerous cell types | Not defined | [25][54] | |
Chromosome 5 | IL-13/IL-4 | Th2 differentiation | Not defined | [2][21][5,50] |
IL12B | Mediation of long-term protection to an intracellular pathogen | MS | [26][55] | |
IL7R | V(D)J recombination during lymphocyte development | PIDDs | [17][46] | |
IL31RA | Type I cytokine receptor family | Not defined | [27][56] | |
VCAN | Tissue morphogenesis and maintenance | Retinitis pigmentosa | [17][46] | |
Chromosome 6 | NOTCH4 | T cell differentiation | T1D, RA, MS | [2][5] |
C6orf10 | Unknown function in vivo | T1D, RA, PS, GV | [2][21][5,50] | |
BTNL2 | Co-stimulation | T1D, RA, UC, CD, SLE, MS | [2][21][5,50] | |
HLA-DRA | Antigen presentation (MHC II) | T1D, RA, CeD, MS, GV | [2][21][5,50] | |
HLA-DRB1*04 | Antigen presentation (MHC II) | Not defined | [28][57] | |
HLA-DRB1*16 | Antigen presentation (MHC II) | Not defined | [28][57] | |
HLA-DRB1*11 | Antigen presentation (MHC II) | Not defined | [28][57] | |
HLA-DQA1 | Antigen presentation (MHC II) | T1D, RA, UC, CD, SLE, MS, CeD, GD | [2][21][5,50] | |
HLA-DQA2 | Antigen presentation (MHC II) | T1D, RA | [2][21][5,50] | |
HLA-DQB2 | Antigen presentation (MHC II) | RA | [2][21][5,50] | |
HLA-DOB | Antigen presentation (MHC II) | SLE | [2][5] | |
HLA-A | Antigen presentation (MHC I) | T1D, MS, PS, GD | [21][50] | |
HLA-B*13 | Antigen presentation (MHC I) | Not defined | [29][58] | |
KLRK1 | NK and T cell activation (NKG2D) | T1D, RA, MS, CD, CeD, SLE | [2][5] | |
MICA | NKG2D Activating ligand | T1D, RA, UC, CeD, PS, SLE | [2][21][5,50] | |
ULBP6 | NKG2D Activating ligand | Not defined | [2][21][5,50] | |
ULBP3 | NKG2D Activating ligand | Not defined | [2][21][5,50] | |
TNFA | Proinflammatory cytokine | RA, MS, IBD, SLE | [2][5] | |
PPP1R18 | Targeting the enzyme to different cellular locations | Not defined | [11][40] | |
TNXB | Localizing to the major histocompatibility complex (MHC) class III | Not defined | [11][40] | |
POLH | A member of the Y family of specialized DNA polymerases | XP, variant type | [17][46] | |
COL9A1 | Assembly of type IX collagen molecules | Not defined | [17][46] | |
Chromosome 7 | IL-6 | Inflammatory cytokine | T1D, RA, CeD | [2][5] |
SLC26A4 | No known | Enlarged vestibular aqueduct, Pendred’s syndrome | [17][46] | |
EGFR | Protein kinase superfamily | Lung cancer, severe form of coronavirus disease 2019 (COVID-19) |
[25][54] | |
Chromosome 8 | LPL | Encodes lipoprotein lipase | Hyperlipoproteinemia, type I | [17][46] |
Chromosome 9 | STX17 | No known inflammatory role. It is involved in premature hair greying | Not defined | [2][21][5,50] |
GNE | Initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc) | Inclusion body myopathy 2 | [17][46] | |
Chromosome 10 | IL-2RA | T-cell proliferation | T1D, MS, GD, GV | [2][16][21][5,45,50] |
TWNK | mtDNA replication | Ataxia | [17][46] | |
DKK1 | Embryonic development | Not defined | [30][59] | |
TCF7L2 | Wnt signaling pathway | DM | [31][60] | |
Chromosome 11 | PRDX5 | Antioxidant enzyme with roles in inflammation | MS | [2][21][5,50] |
IL-18 | Proinflammatory cytokine that augments natural killer cell activity and stimulates IFNγ production in T-helper type I cells | RA, SLE | [2][32][5,61] | |
GARP (LRRC32) | Treg differentiation and activity | IBD, Allergies | [2][5] | |
SLC22A12 | Regulation of urate levels in blood | Renal hypouricemia | [17][46] | |
TYR | Encoding tyrosinase | Oculocutaneous albinism | [17][46] | |
Chromosome 12 | IL-26 | T cell differentiation | MS | [2][5] |
IFNG | Regulation of immune responses | SLE | [2][5] | |
KRT82 | A member of the keratin gene family | Not defined | [12][41] | |
CD27 | T cell immunity and regulating B-cell activation | Not defined | [33][62] | |
WNT10B | Implicated in oncogenesis and in several developmental processes | Oligodontia | [17][46] | |
Chromosome 13 | MIR17HG | Cell survival, proliferation, differentiation, and angiogenesis | Not defined | [34][63] |
Chromosome 15 | IL16 | The modulator of T cell activation and an inhibitor of HIV replication | Not defined | [35][64] |
CHAC1 | Promotion neuronal differentiation | Not defined | [36][65] | |
Chromosome 16 | SOCS1 | STAT inhibitor, regulator of IFN-γ response | T1D, CeD | [2][5] |
FUS | Regulation of gene expression, maintenance of genomic integrity, and mRNA/microRNA processing | ALS | [17][46] | |
Chromosome 17 | CCL13 | Chemotactic activity for monocytes, lymphocytes, basophils, and eosinophils | Not defined | [37][66] |
Chromosome 18 | PTPN2 | Phosphatase involved in cell signaling | T1D, CeD | [2][5] |
Chromosome 19 | CD70 | Enhances T helper and cytotoxic T cell activation | Not defined | [33][62] |
NPHS1 | Ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine | Finnish congenital nephrotic syndrome | [17][46] | |
Chromosome 20 | PIGT | Glycosylphosphatidylinositol (GPI)-anchor biosynthesis | Multiple congenital anomalies-hypotonia- seizures syndrome 3 | [17][46] |
RTEL1 | Encodes a DNA helicase | Dyskeratosis congenita | [17][46] | |
Chromosome 21 | AIRE | Autoimmune regulator, selection of auto-reactive cells | APECED, T1D, GV, HT | [2][5] |
COL6A2 | Encodes one of the three α chains of type VI collagen | Muscular dystrophy | [17][46] | |
Chromosome 22 | CELSR1 | Cell adhesion and receptor-ligand interactions | Neural tube defects | [17][46] |
IL17RA | Inducer of the maturation of CD34-positive hematopoietic precursors into neutrophils. | RA | [27][56] | |
Chromosome X | Cxcr3 | Chemokine receptor | RA, T1D, PS, SLE | [2][5] |
MAMLD1 | Transcriptional co-activator | 46XY disorder of sex development | [17][46] | |
TLR7 | Pathogen recognition and activation of innate immunity. | [24][53] | ||
Chromosome MT | MT-ND1 | Mitochondrial electron transport | AD, PD | [17][46] |
Disease | Genes | Reference |
---|---|---|
Type 1 Diabetes | PTPN22, CTLA4, ACOXL/BCL2L11, IL-21, IL-2, Cxcl9, Cxcl10, Cxcl11, NOTCH4, C6orf10, BTNL2, HLA-DRA, HLA-DQA1, HLA-DQA2, HLA-A, KLRK1, MICA, IL-6, IL-2RA, SOCS1, PTPN2, Cxcr3 | [2][21][5,50] |
Rheumatoid Arthritis | PTPN22, CTLA4, IL-21, IL-2, Cxcl9, Cxcl10, Cxcl11, NOTCH4, C6orf10, BTNL2, HLA-DRA, HLA-DQA1, HLA-DQA2, HLA-DQB2, KLRK1, MICA, TNFA, IL-6, IL-18, IL17RA, Cxcr3 | [2][21][5,50] |
Systemic Lupus Erythematous | PTPN22, CTLA4, Cxcl9, Cxcl10, Cxcl11, BTNL2, HLA-DQA1, HLA-DOB, KLRK1, MICA, TNFA, IL-18, IFNG, Cxcr3 | [2][5[21],50] |
Graves’ Disease | PTPN22, CTLA4, HLA-DQA1, HLA-A, IL-2RA, | [2][21][5,50] |
Parkinson’s Disease | PINK1, MT-ND1 | [2][17][5,46] |
Celiac Disease | CTLA4, IL-21, IL-2, HLA-DRA, HLA-DQA1, KLRK1, MICA, IL-6, SOCS1, PTPN2 | [2][21][5,50] |
Ulcerative Colitis | BTNL2, HLA-DQA1, MICA, | [2][5] |
Multiple Sclerosis | CTLA4, ICOS, IL12B, NOTCH4, BTNL2, HLA-DRA, HLA-DQA1, HLA-A, KLRK1, TNFA, IL-2RA, PRDX5, IL-26 | [2][21][26][5,50,55] |
Amyotrophic Lateral Sclerosis | ALS2, FUS | [2][17][5,46] |
Generalized Vitiligo | C6orf10, HLA-DRA, IL-2RA, AIRE | [2][5] |
Inflammatory Bowel Disease | TNFA, GARP (LRRC32) | [2][5] |
Atopic Dermatitis | HLA-DQB1, HLA-DRB1, HLA-DQA1, IL-4, IL-13, IL-17, IL-23R | [38][39][40][67,68,69] |
Study | Population | Gene | SNP | Finding | Reference |
---|---|---|---|---|---|
2022, Alghamdi | Not defined | IL17RA | rs879575 | Not associated with AA susceptibility among Jordanian patients | [27][56] |
IL31RA | rs161704 | ||||
2021, Gil-Quiñones | Not defined | PTPN22 | rs2476601 | T allele is a risk factor for developing AA | [16][45] |
2021, Conteduca | Italian | ICOS | rs4404254 rs4675379 |
Carrying the 3’ UTR alleles was more frequently observed in AA patients | [43][72] |
2021, Ismail | Egyptian | CTLA4 | rs231775 | Significantly higher in AA patients | [22][51] |
2020, Abd El-Raheem | Egyptian | TNFα promoter region |
rs1800629 | No association with AA | [44][73] |
2020, Eitan | Jordanian | IL16 exon region | rs11073001 | The A-allele was distributed more frequently | [35][64] |
IL16 promoter region | rs17875491 | A difference was found between the patients and the controls | |||
2019, Lei | Not defined | PTPN22 | rs2476601 | Significantly correlated with AA. The C-allele and CC-genotype carriers at this locus have a lower risk of AA. | [45][74] |
2019, Al-Eitan |
Jordanian | TNFα | rs1800629 | Significantly associated with AA in the heterozygous and rare homozygous genotypes | [42][71] |
2018, Sumeyya |
Turkish | IL 18 | rs1946518 | Distribution of CC + CA genotypes and frequency of -607/allele C were higher in AA | [32][61] |
rs187238 | Distribution of GG genotype and frequency of -137/allele G were higher in AA | ||||
2015, Kalkan | Turkish | MnSOD | Ala-9Val | No association with AA | [46][75] |
GPx1 Pro 198 Leu | No association with AA | ||||
2015, Kim | Korean | TAP1 promoter region |
rs2071480 | Association with AA | [47][76] |
2015, Salinas-Santander | Mexican | PTPN22 | C1858T | T allele as a genetic risk factor for patchy AA | [15][44] |
2014, Conteduca | Not defined | FOXP3 | rs2294020 | Reduced relative gene expression in AA patients | [48][77] |
ICOSLG | rs378299 | ||||
2014, Kim | Korean | IL18 | rs187238 rs549908 |
Associated with the development of AA | [49][78] |
2014, Seok | Korean | TLR1 missense region | rs4833095 | Significantly associated with the development of AA | [50][79] |
TLR1 promoter region |
rs5743557 | Weakly associated with the development of AA | |||
2014, Seok | Korean | HSPA1B | rs6457452 | Weakly related to the age of onset of AA | [51][80] |
rs2763979 | Weakly related to AA | ||||
2012, Forstbauer |
European | SPATA5 intronic region |
rs304650 | Significant association with AA | [9][38] |