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Abstract Alopecia areata (AA) is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. It is mostly considered to be a cell-mediated autoimmune disease, in which autoreactive cytotoxic T cells recognize melanocyte-associated proteins, such as tyrosinase. Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-activated nuclear receptors superfamily, regulating the transcription of various genes. There are three isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ, each encoded by different genes and distributed differently. PPAR-γ has been discovered to exert anti-inflammatory actions and to be involved in hair follicle development, morphogenesis, and maintenance. It also shares in the protection of hair follicle immune privilege. This current work aimed to assess PPAR-γ gene expression levels in tissue samples of alopecia areata patches and detect the correlation between PPAR-γ gene polymorphism and the risk of development of alopecia areata. It also evaluates the association between PPAR-γ gene polymorphism (Pro12Ala) and the levels of PPAR-γ tissue expression in alopecia areata patients and correlates its levels with the severity and different parameters of the disease. This case-control study was conducted on 100 patients of both sexes who were diagnosed with AA of various types and degrees of severity not receiving any topical or systemic treatment for one month prior to sample collection. In addition, 100 apparently healthy individuals of matched age and sex were chosen as a control group. The study was approved by the local ethical committee of Benha Faculty of Medicine. An informed consent was taken from each participant before being included in the study. All patients were subjected to complete history taking, complete general examination, dermatological examination to diagnose AA and assessed by SALT score. Skin biopsy was obtained from AA patch in patients or healthy scalp in controls. All samples were subjected to molecular biological analysis for PPAR-γ gene polymorphism using RFLP-PCR technique, and tissue expression of PPAR-γ1 and PPAR-γ2 using quantitative real time-PCR. The results of this study showed that: • The polymorphic genotypes of PPAR-γ gene (CG+GG) and the G allele were significantly predominant in patients when compared to control group. • Polymorphic genotypes (CG+GG) were associated with significantly lower tissue expression levels of PPAR-γ1 higher number of AA patches and higher SALT score. • The tissue expression level of PPAR-γ1 was significantly lower in patients than in controls while there was insignificant difference in PPAR-γ2 between patients and controls. • There was a significant negative correlation between PPAR-γ1tissue expression levels and number of AA patches and SALT score. • Tissue expression levels of PPAR-γ1 were significantly reduced in patients with alopecia totalis, eyebrows, eyelashes affection. • At a cut-off level of < 0.74, the tissue expression levels of PPAR-γ1 show high sensitivity (72%) and specificity ( |