Membranoproliferative Glomerulonephritis Susceptibility Loci: A Genome-Wide Association Study

Membranoproliferative glomerulonephritis (MPGN) is a glomerular injury pattern with poorly understood genetic underpinnings, particularly in non-European cohorts. This study aimed to identify genetic susceptibility loci for MPGN in a Chinese population and elucidate their functional mechanisms.

Case-control genetic association study design.

739 Chinese patients diagnosed with MPGN and 7,110 ethnically matched controls.

Over 3,000,000 single-nucleotide polymorphisms (SNPs) were tested for association.

Primary biopsy-proven MPGN.

Generalized linear model statistical methods. Functional annotation, phenome-wide association, and structural modeling were also implemented.

A genome-wide significant locus was identified at rs362535 (P = 6.69×10^-9) within the HLA class I region, mapping to the ubiquitin D (UBD) gene. Functional annotation and colocalization analyses supported a link between the MPGN risk signal and kidney tubulointerstitial UBD expression. Functional annotation identified rs7757931 as a likely causal variant, demonstrating kidney tubule-specific UBD regulation (β = 0.55, P = 2.07×10^-7) and structural remodeling of UBD-IκBα interactions, leading to a 42% increased binding surface area. Transcriptome-wide analysis revealed significant enrichment of the NF-κB pathway (P_FDR = 7.31×10^-6). Clinically, the risk allele at rs362535 was associated with a higher prevalence of glomerulosclerosis (14% vs. 11%, P = 0.04).

The study was conducted in a Chinese population, limiting generalizability to other ancestries without further validation.

Distinct from European studies that have implicated HLA class II associations, this study identified UBD, which encodes a ubiquitin-like modifier regulating NF-κB signaling, as an ancestry-specific susceptibility locus for MPGN in Chinese individuals. These findings inform the search for potential therapeutic targets in MPGN and highlight the importance of population diversity in genetic association research.