Genotype and X-chromosome inactivation are associated with disease severity in females with X-linked Alport syndrome.

IF 4.8 2区医学 Q1 TRANSPLANTATION

Nephrology Dialysis Transplantation Pub Date : 2024-08-12 DOI:10.1093/ndt/gfae182

Ryota Suzuki, Nana Sakakibara, Sae Murakami, Yuta Ichikawa, Hideaki Kitakado, Chika Ueda, Yu Tanaka, Eri Okada, Atsushi Kondo, Yuya Aoto, Shinya Ishiko, Shingo Ishimori, China Nagano, Tomohiko Yamamura, Tomoko Horinouchi, Takayuki Okamoto, Kandai Nozu

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Abstract

Background and hypothesis: 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).

Conclusion: Genotype and XCI are factors associated with the severity in females with XLAS.

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基因型和 X 染色体失活与 X 连锁阿尔波特综合征女性患者的疾病严重程度有关。

背景和假设：X 连锁阿尔波特综合征（XLAS）男性患者一般在成年早期或中期出现终末期肾病，并表现出明显的基因型-表型相关性。而女性患者则表现出从无症状到严重的各种表型，且基因型与表型之间没有相关性。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，我们在一个大型日本队列中调查了基因型和 XCI 是否与 XLAS 女性患者的严重程度相关：方法：在我院经基因诊断为 XLAS 的 139 名女性患者中，我们使用人类雄激素受体测定法对外周血白细胞进行了 XCI 分析，并对两个队列进行了分析。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（肌酐估算的肾小球滤过率 [Cr-eGFR]，根据日本人进行了优化）与基因型/XCI 之间的相关性；在 65 名儿童女性患者中，我们使用多变量线性回归分析评估了肾功能（Cr-eGFR，根据日本人进行了优化）与基因型/XCI 之间的相关性。我们还使用多变量考克斯比例危险分析法研究了蛋白尿（尿蛋白与肌酐比值高于患者年龄的正常值）的发生与基因型/XCI 之间的相关性：在成年女性患者中，XCI 模式与 Cr-eGFR 显著相关（回归系数估计值 = -0.53，P = 0.004），而基因型与之无关（P = 0.892）。在儿科女性患者中，基因型和 XCI 模式都是出现蛋白尿的重要独立危险因素（危险比 [HR]，3.702；95% 置信区间 [CI]，1.681-8.150；P = 0.001 和 HR，1.043；95% CI，1.061-1.070；P = 0.001），而基因型和 XCI 模式与 Cr-eGFR 无关（P = 0.20 和 P = 0.67）：结论：基因型和XCI是与XLAS女性患者病情严重程度相关的因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nephrology Dialysis Transplantation 医学-泌尿学与肾脏学

CiteScore

10.10

自引率

4.90%

发文量

1431

审稿时长

1.7 months

期刊介绍： Nephrology Dialysis Transplantation (ndt) is the leading nephrology journal in Europe and renowned worldwide, devoted to original clinical and laboratory research in nephrology, dialysis and transplantation. ndt is an official journal of the [ERA-EDTA](http://www.era-edta.org/) (European Renal Association-European Dialysis and Transplant Association). Published monthly, the journal provides an essential resource for researchers and clinicians throughout the world. All research articles in this journal have undergone peer review. Print ISSN: 0931-0509.