"Autoimmunity, Cancer and Immunogenetics" Research Laboratory (LR18SP12), Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
Dermatology Department, HediChaker Hospital, University of Sfax, Sfax, Tunisia.
Mol Genet Genomic Med. 2022 Dec;10(12):e2080. doi: 10.1002/mgg3.2080. Epub 2022 Nov 9.
Almost 5% of the world's population develops an autoimmune disease (AID), it is considered the fourth leading cause of disability for women, who represent 78% of cases. The sex ratio when it comes to the most prevalent AID varies from 9:1 in systemic lupus erythematosus (SLE) to 13:1 in endemic Tunisian pemphigus foliaceus (PF).
To test the potential involvement of skewed x-inactivation in the pathogenesis of Tunisian PF, we analyzed the methylation status of a highly polymorphic CAG repeat in the androgen receptor gene and evaluated the x chromosome inactivation (XCI) patterns in peripheral blood-leukocyte-derived DNA samples of female patients with PF (n = 98) compared to healthy control (HC) subjects (n = 150), as well as female patients with SLE (n = 98) were enrolled as a reference group.
XCI status was informative for 50 of the 98 PF patients (51%) and 70 of the 150 HC women (47%). Extremely skewed XCI patterns were more frequent in PF and SLEwomen than HC, but the difference was statistically significant only in women with SLE. No statistical difference was observed in XCI patterns between PF and SLE patients. PF phenotype-XCI correlation analysis revealed that (i) skewed XCI patterns may be involved in the disease's subtype and (ii) it was more pronounced in the endemic group than the sporadic one. Furthermore, preferential XCI showed an increase in heterozygote genotypes of PF's susceptibility polymorphisms in immunity-related X genes (FOXP3, AR, and TLR7) in PF patients compared to HC.
Our results suggest that skewed XCI could lead to hemizygosity of X-linked alleles that might unmask X-linked deleterious alleles.
全球近 5%的人口患有自身免疫性疾病 (AID)，它被认为是导致女性残疾的第四大主要原因，而女性患者占 78%。在最常见的自身免疫性疾病中，性别比例从系统性红斑狼疮 (SLE) 的 9:1 到地方性突尼斯类天疱疮 (PF) 的 13:1 不等。
为了测试偏置 X 失活在突尼斯 PF 发病机制中的潜在作用，我们分析了雄激素受体基因中高度多态性的 CAG 重复的甲基化状态，并评估了 PF 女性患者 (n=98) 与健康对照 (HC) 受试者 (n=150) 以及 SLE 女性患者 (n=98) 外周血白细胞衍生 DNA 样本中的 X 染色体失活 (XCI) 模式。作为参考组。
98 例 PF 患者中有 50 例 (51%) 和 150 例 HC 女性中有 70 例 (47%) 的 XCI 状态具有信息性。PF 和 SLE 女性的极偏置 XCI 模式比 HC 更为频繁，但仅在 SLE 女性中具有统计学意义。PF 和 SLE 患者之间的 XCI 模式无统计学差异。PF 表型-XCI 相关性分析表明：(i)偏置 XCI 模式可能参与疾病的亚型，(ii)在地方性组中比散发性组更为明显。此外，与 HC 相比，PF 患者中免疫相关 X 基因 (FOXP3、AR 和 TLR7) 的 PF 易感性多态性的杂合基因型显示出优先 XCI，表明 X 连锁等位基因的半合子状态可能导致 X 连锁有害等位基因的暴露。
我们的结果表明，偏置 XCI 可能导致 X 连锁等位基因的半合子状态，从而可能使 X 连锁有害等位基因暴露。
