Clinical Application of Polygenic Risk Score in IgA Nephropathy

Area of Science:

• Nephrology
• Genetics
• Epidemiology

Background:

• Genome-wide association studies (GWASs) have identified numerous genetic variants associated with IgA nephropathy (IgAN).
• A genetic risk score (GRS) quantifies an individual's genetic predisposition by summing risk alleles.
• The clinical utility of polygenic risk scores for IgAN risk and prognosis remains unclear.

Purpose of the Study:

• To construct and evaluate different genetic risk score (GRS) models for IgA nephropathy (IgAN).
• To assess the association between GRS and clinical variability, including age at diagnosis and prognosis.
• To explore the potential of GRS in predicting IgAN risk and stratifying patients.

Main Methods:

• Constructed three GRS models using 15, 21, and 55 single nucleotide polymorphisms (SNPs) from GWASs.
• Performed case-control analysis with 3365 IgAN patients and 8842 healthy individuals.
• Evaluated GRS association with clinical parameters and prognosis in a prospective cohort of 1747 patients.

Main Results:

• Higher GRS (top 20%) significantly increased IgAN risk (2.42-3.89 fold) compared to lower GRS (bottom 20%).
• GRS correlated positively with microhematuria and mesangial hypercellularity, and negatively with age at diagnosis and BMI.
• Patients with top 20% GRS exhibited a 1.36-1.42 fold higher risk of worse kidney prognosis across models.

Conclusions:

• A higher burden of IgAN risk variants, as indicated by GRS, is associated with earlier disease onset.
• Elevated GRS predicts a higher risk of worse kidney prognosis in IgAN patients.
• GRS models, particularly the 21-SNP model, show potential for IgAN risk prediction and patient stratification.