Integrative genomic analysis of RNA-modification-single nucleotide polymorphisms associated with kidney function

Introduction: Increasing evidence suggests that RNA modification plays a significant role in the kidney and may be an ideal target for the treatment of kidney diseases. However, the specific mechanisms underlying RNA modifications in the pathogenesis of kidney disease remain unclear. Genome-wide association studies (GWAS) have identified numerous genetic loci involved in kidney function and RNA modifications. The identification and exploration of RNA modification-related single-nucleotide polymorphisms (RNAm-SNPs) associated with kidney function can help us to comprehensively understand the underlying mechanism of kidney disease and identify potential therapeutic targets.

Methods: First, we examined the association of RNAm-SNPs with eGFR. Second, we performed expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL) analyses to explore the functions of the identified RNAm-SNPs. Finally, we evaluated the causality between RNAm-SNP-associated gene expression and circulating proteins and kidney function using a Mendelian randomization (MR) analysis.

Results: A total of 252 RNA m-SNPs related to m⁶A, m¹A, A-to-I, m⁵C, m⁷G, and m⁵U were identified. All these factors were significantly associated with the eGFR. A total of 119(47.22 %) RNAm-SNPs showed cis-eQTL effects in blood cells, whereas 72 (28.57 %) RNAm-SNPs showed cis-pQTL effects in plasma. 47 (18.65 %) RNAm-SNPs exhibited cis-eQTL and cis-pQTL effects. In addition, we demonstrated a causal association between RNAm-SNP-associated gene expression, circulating protein levels, and eGFR decline. Some of the identified genes and proteins have been reported to be associated with kidney diseases, such as CDK10 and SDCCAG8.

Conclusions: This study reveals an association between RNAm-SNPs and kidney function. These SNPs regulate gene expression and protein levels through RNA modifications, eventually leading to kidney dysfunction. Our study provides novel insights that connect the genetic risk of kidney disease to RNA modification and suggests potential therapeutic targets for the prevention and treatment of kidney disease.