Clinical Application of Polygenic Risk Score in IgA Nephropathy

Abstract

Genome-wide association studies (GWASs) have identified 30 independent genetic variants associated with IgA nephropathy (IgAN). A genetic risk score (GRS) represents the number of risk alleles carried and thus captures an individual's genetic risk. However, whether and which polygenic risk score crucial for the evaluation of any potential personal or clinical utility on risk and prognosis are still obscure. We constructed different GRS models based on different sets of variants, which were top single nucleotide polymorphisms (SNPs) reported in the previous GWASs. The case-control GRS analysis included 3365 IgAN patients and 8842 healthy individuals. The association between GRS and clinical variability, including age at diagnosis, clinical parameters, Oxford pathology classification, and kidney prognosis was further evaluated in a prospective cohort of 1747 patients. Three GRS models (15 SNPs, 21 SNPs, and 55 SNPs) were constructed after quality control. The patients with the top 20% GRS had 2.42-(15 SNPs, p = 8.12 × 10^-40), 3.89-(21 SNPs, p = 3.40 × 10^-80) and 3.73-(55 SNPs, p = 6.86 × 10^-81) fold of risk to develop IgAN compared to the patients with the bottom 20% GRS, with area under the receiver operating characteristic curve (AUC) of 0.59, 0.63, and 0.63 in group discriminations, respectively. A positive correlation between GRS and microhematuria, mesangial hypercellularity, segmental glomerulosclerosis and a negative correlation on the age at diagnosis, body mass index (BMI), mean arterial pressure (MAP), serum C3, triglycerides can be observed. Patients with the top 20% GRS also showed a higher risk of worse prognosis for all three models (1.36, 1.42, and 1.36 fold of risk) compared to the remaining 80%, whereas 21 SNPs model seemed to show a slightly better fit in prediction. Collectively, a higher burden of risk variants is associated with earlier disease onset and a higher risk of a worse prognosis. This may be informational in translating knowledge on IgAN genetics into disease risk prediction and patient stratification.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-023-00138-6.

Keywords: Genomics; IgA nephropathy; Polygenic score; Prognosis; Risk prediction.

Fig. 1

The flow chart of this study. A total of 116 SNPs were retrieved based on previous GWASs (Kiryluk et al. , , ; Li et al. , ; Yu et al. 2011), including genome-wide significant loci (p < 5.0E−08) associated with IgAN and suggestive loci in the combined trans-ethnic meta-analysis or additionally East Asians-specific suggestive loci (p < 5.0E−05) from the more recent GWAS-meta study by Kiryluk et al. (2023). Nine of these SNPs were not genotyped or imputed in our data. Firstly, we analyzed associations between disease susceptibility and 107 SNPs in 3495 patients and 9101 healthy controls (IgAN susceptibility association analysis). 1803 of the 3495 patients were routinely followed up, so we further analyzed the association between the 107 SNPs and the clinical phenotypes (sub-phenotype and prognosis analysis) in 1803 patients. After quality control, a total of 3365 patients and 8842 healthy controls with complete information of 55 SNPs were left to construct GRS models. To check the cumulative effect of these SNPs together, lastly, we also analyzed the association of GRS models with disease susceptibility, clinical subphenotypes, and disease prognosis

Fig. 2

The different GRS distribution and performance according to Receiver-operating curve (ROC). Density plots showing the distribution of standardized GRS among IgAN patients and healthy controls for a 15 SNPs-GRS, b 21 SNPs-GRS, and c 55 SNPs-GRS, respectively. The ROC curve of d15 SNPs-GRS, e 21 SNPs-GRS, and f 55 SNPs-GRS, respectively

Fig. 3

Prognostic association of the GRS for IgA nephropathy. Survival analysis of a lifetime of ESKD for IgAN cases in the top 20% of a 15 SNPs-GRS distribution, b 21 SNPs-GRS distribution, and c 55 SNPs-GRS distribution, respectively. Survival analysis of a lifetime of a combined event (ESKD or ≥ 50% reduction in eGFR after diagnostic kidney biopsy) for IgAN cases in the top 20% of d 15 SNPs-GRS distribution, e 21 SNPs-GRS distribution, and f 55 SNPs-GRS distribution, respectively. The x-axis shows age, the y-axis shows survival probability without ESKD/combined event with the number of participants at risk at each age cut-off of 20, 40, 60 and 80 years depicted below