Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy.
Department of Medical Sciences and Public health, Multiple Sclerosis Centre, University of Cagliari, Cagliari, Italy.
Mult Scler. 2021 Aug;27(9):1332-1340. doi: 10.1177/1352458520963937. Epub 2020 Oct 14.
Defective alleles within the gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm.
The aim of this study was to determine the function of hypomorph g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D).
We cross-compare the association data for mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians.
We report that , is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia = 2.06 × 10, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D = 1.04 × 10, OR = 0.82.
Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
穿孔蛋白形成蛋白穿孔素基因内的缺陷等位基因与环境因素相结合，导致家族性 2 型噬血细胞性淋巴组织细胞增生症（FHL2），这是一种罕见的、严重的常染色体隐性儿童疾病，其特征是大量细胞因子释放-细胞因子风暴。
本研究旨在确定 g.72360387 G > A 突变在多发性硬化症（MS）和 1 型糖尿病（T1D）中的功能。
我们在撒丁岛人群中对成人 MS 和儿科 T1D 的 GWAS 衍生 突变的关联数据进行交叉比较。在撒丁岛、英国和苏格兰的 12584 例病例和 17692 例对照的荟萃分析中复制了与 T1D 的新关联。为了剖析这种突变的功能，我们在撒丁岛的另一组普通人群中搜索了与免疫表型一致的关联。
我们报告 与淋巴细胞水平升高有关，特别是在细胞毒性记忆 T 细胞中，在普通人群中这些细胞的白细胞介素 7 受体表达减少。该次要等位基因增加了 MS 的风险，在撒丁岛的 2903 例病例和 2880 例对照中， = 2.06×10 ，比值比 OR = 1.29，复制了先前的发现，而它保护 T1D = 1.04×10 ，OR = 0.82。
我们的结果表明细胞毒性 T 细胞在 MS 和 T1D 发病机制中具有相反的作用。
