目的:男性X连锁Alport综合征(XLAS)患者通常在成年早期或中期发展为终末期肾病,并表现出明显的基因型-表型相关性。女性患者,然而,显示从无症状到严重的各种表型,没有基因型-表型相关性。然而,影响女性患者XLAS严重程度的因素尚不清楚.由于X染色体失活(XCI)会影响某些女性X连锁疾病的严重程度,我们调查了日本大型队列中女性患者的基因型和XCI是否与XLAS严重程度相关.
方法:在我们机构的139名基因诊断为XLAS的女性患者中,我们使用人类雄激素受体检测方法对外周血白细胞进行了XCI分析,并分析了两个队列.在74名成年女性患者中,我们使用多变量线性回归分析评估了肾功能(针对日本个体优化的肌酐估算肾小球滤过率[Cr-eGFR])与基因型/XCI之间的相关性,在65名儿科女性患者中,我们使用多变量线性回归分析评估了肾功能(针对日本个体优化的Cr-eGFR)与基因型/XCI之间的相关性.我们还使用多变量Cox比例风险分析研究了蛋白尿(患者年龄的尿蛋白与肌酐比值高于正常值)与基因型/XCI之间的相关性。
结果:在成年女性患者中,XCI模式与Cr-eGFR显著相关(回归系数估计=-0.53,P=0.004),而基因型则没有(P=0.892)。在儿科女性患者中,基因型和XCI模式都是蛋白尿发展的显著独立危险因素(风险比[HR],3.702;95%置信区间[CI],1.681-8.150;P=0.001,HR,1.043;95%CI,1.061-1.070;分别为P=0.001),而基因型和XCI模式均与Cr-eGFR无关(分别为P=0.20,P=0.67).
结论:基因型和XCI是与女性XLAS严重程度相关的因素。
OBJECTIVE: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. Female patients, however, show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. However, the factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort.
METHODS: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leukocytes using the human androgen receptor assay method and analyzed two cohorts. In 74 adult female patients, we evaluated the correlation between kidney function (creatinine-estimated glomerular filtration rate [Cr-eGFR] optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis, and in 65 pediatric female patients, we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein-to-creatinine ratio above normal for the patient\'s age) and genotype/XCI using multivariable Cox proportional hazard analysis.
RESULTS: In adult female patients, XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate = -0.53, P = 0.004), whereas genotype was not (P = 0.892). In pediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria (hazard ratio [HR], 3.702; 95% confidence interval [CI], 1.681-8.150; P = 0.001 and HR, 1.043; 95% CI, 1.061-1.070; P = 0.001, respectively), whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = 0.20, P = 0.67, respectively).
CONCLUSIONS: Genotype and XCI are factors associated with the severity in females with XLAS.