Founder Effect for the APOE Tokyo-Maebashi Variant in the Northern Chinese Population

Background: Lipoprotein glomerulopathy (LPG) is a rare hereditary kidney disorder characterized by lipoprotein thrombi in glomeruli, often linked to APOE gene mutations. Predominantly found in China and Japan, LPG remains understudied. Notable regional APOE mutations include APOE Kyoto (p.R43C) in West China and APOE-Sendai (p.R163P) in eastern Japan. This study investigates the genetic causes of LPG in northern Han Chinese and explores genotype-phenotype correlations. Methods: Patients suspected or diagnosed with LPG were recruited at a nephrology center in Northern China from 2000 to 2023. Inclusion criteria: (1) Renal biopsy showing Oil Red O-positive lipid thrombi in glomeruli; (2) Known pathogenic APOE mutations via genetic testing. Exclusion criteria: Incomplete genetic testing post-biopsy or unavailable DNA samples. Whole exome sequencing (WES) was used to identify mutations, with clinical data collected at enrollment. Results: The study included 28 LPG patients from 24 families, with an average age of 34.2 years (range 17-54). The male-to-female ratio was 19:9. The mean proteinuria level was 4.94 g/24h, the mean eGFR was 78.3 mL/min/1.73 m2, and hyperlipidemia was observed in all cases. Three variants were identified in 25 cases: 15 had APOE Tokyo-Maebashi (p.L162_K164del), 8 had APOE Kyoto (p.C43R), and 2 had APOE Chengdu (p.L173P). APOE Tokyo-Maebashi was most frequent, mainly in Hebei Province. Haplotype analysis suggested a founder effect for APOE Tokyo-Maebashi. Genotype-phenotype analysis showed a trend towards higher eGFR and lower urinary total protein (UTP) and urinary red blood cells (URBC) in APOE Tokyo-Maebashi carriers, though differences were not statistically significant. Conclusion: WES is instrumental in identifying molecular pathogenic variants in LPG patients and genetic hotspot mutations in specific populations. Despite high phenotypic variability in APOE-associated LPG, the APOE Tokyo-Maebashi variant is the most common mutation in Northern China, presenting with relatively milder clinical manifestations.