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

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

doi:10.1093/ndt/gfae182

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

Nephrol Dial Transplant. 2024 Aug 12:gfae182. doi: 10.1093/ndt/gfae182. Online ahead of print.

Authors

Ryota Suzuki^{1

2}, Nana Sakakibara¹, Sae Murakami³, Yuta Ichikawa¹, Hideaki Kitakado¹, Chika Ueda¹, Yu Tanaka¹, Eri Okada¹, Atsushi Kondo¹, Yuya Aoto¹, Shinya Ishiko¹, Shingo Ishimori¹, China Nagano¹, Tomohiko Yamamura¹, Tomoko Horinouchi¹, Takayuki Okamoto², Kandai Nozu¹

Affiliations

¹ Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
² Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
³ Clinical and Translational Research Center, Kobe University Hospital.

PMID: 39134512
DOI: 10.1093/ndt/gfae182

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.

Keywords: COL4A5; X-chromosome inactivation; X-linked Alport syndrome; female; genotype.