NR3C1,编码糖皮质激素受体的基因,多态性呈现许多单核苷酸多态性(SNP),其中一些正在成为人类疾病中对糖皮质激素的表现和/或反应变异性的主要原因。由于60-80%的患者患有DiamondBlackfan贫血(DBA),由核糖体蛋白基因突变诱导的遗传性纯红细胞再生障碍在糖皮质激素治疗后独立于输血,我们调查了临床相关NR3C1SNP是否与DBA的疾病表现相关.在91名欧洲DBA患者的队列中调查了8个SNPrs10482605、rs10482616、rs7701443、rs6189/rs6190、rs860457、rs6198、rs6196和rs33388/rs33389。将结果与健康志愿者(n=37)或意大利和欧洲人群的公共基因组数据库中观察到的结果进行了比较。虽然,案例与对照分析表明,相对于健康对照或意大利或其他欧洲注册,DBA患者中一些次要等位基因的频率发生了显着变化。不同组之间的关联缺乏一致性表明,总体而言,这些SNP在DBA中的频率与一般人群没有差异.81名患者的人口统计学数据(47名女性和31名男性)和驱动突变(44个S和29个L基因以及8个未知突变)是已知的,而糖皮质激素反应是已知的,分别,81例(36例有反应和45例无反应)和79例(4月龄前55例和4月龄后24例)患者的疾病发病年龄。性别或前导突变均与次要等位基因或疾病表现无关。此外,没有一个SNP满足响应中的阈值与无反应的群体。然而,在4个月大之前表现出疾病的患者中富集了两个SNP(rs6196和rs860457)。虽然这些SNP的确切生物力学后果是未知的,它们的构型与调节区的构型一致的事实表明,它们调节个体发育过程中糖皮质激素反应的变化.该假设得到了体外扩增的红系细胞的磷酸化蛋白质组学分析的支持,表明糖皮质激素激活了脐带血细胞中的核糖体特征,而不是成人血液中的核糖体特征。可能为出生前在DBA中观察到的驱动突变提供代偿机制。
NR3C1, the gene encoding the glucocorticoid receptor, is polymorphic presenting numerous single nucleotide polymorphisms (SNPs) some of which are emerging as leading cause in the variability of manifestation and/or response to glucocorticoids in human diseases. Since 60-80% of patients with Diamond Blackfan anemia (DBA), an inherited pure red cell aplasia induced by mutations in ribosomal protein genes became transfusion independent upon treatment with glucocorticoids, we investigated whether clinically relevant NR3C1 SNPs are associated with disease manifestation in DBA. The eight SNPs rs10482605, rs10482616, rs7701443, rs6189/rs6190, rs860457, rs6198, rs6196, and rs33388/rs33389 were investigated in a cohort of 91 European DBA patients. Results were compared with those observed in healthy volunteers (n=37) or present in public genome databases of Italian and European populations. Although, cases vs. control analyses suggest that the frequency of some of the minor alleles is significantly altered in DBA patients with respect to healthy controls or to the Italian or other European registries, lack of consistency among the associations across different sets suggests that overall the frequency of these SNPs in DBA is not different from that of the general population. Demographic data (47 females and 31 males) and driver mutations (44 S and 29 L genes and eight no-known mutation) are known for 81 patients while glucocorticoid response is known, respectively, for 81 (36 responsive and 45 non-responsive) and age of disease onsets for 79 (55 before and 24 after 4months of age) patients. Neither gender nor leading mutations were associated with the minor alleles or with disease manifestation. In addition, none of the SNPs met the threshold in the response vs. non-responsive groups. However, two SNPs (rs6196 and rs860457) were enriched in patients manifesting the disease before 4months of age. Although the exact biomechanistical consequences of these SNPs are unknown, the fact that their configuration is consistent with that of regulatory regions suggests that they regulate changes in glucocorticoid response during ontogeny. This hypothesis was supported by phosphoproteomic profiling of erythroid cells expanded ex vivo indicating that glucocorticoids activate a ribosomal signature in cells from cord blood but not in those from adult blood, possibly providing a compensatory mechanism to the driving mutations observed in DBA before birth.