Combined Genetic Association and Differed Expression Analysis of Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy.

INTRODUCTION

IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN.

METHODS

We firstly analyzed the association of variants in the region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between and the expression levels of genes involved in Gd-IgA1 production were also explored.

RESULTS

The rs131654 showed the most significant association signal in region (OR: 1.10, 95% CI: 1.04-1.16, = 2.29 × 10), whose genotypes were also associated with the levels of Gd-IgA1 ( = 0.04). The rs131654 was observed to exert eQTL effects on in various tissues and cell types, particularly in immune cell types in multiple databases. The , , and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of were not only associated with higher proteinuria ( = 0.34, = 0.01) and lower eGFR ( = -0.28, = 0.04), but also positively correlated with the gene expression of and other proteasome subunits. Additionally, mRNA expression levels of were also positively correlated with IL-6 and , but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including and .

CONCLUSION

In conclusion, by combined genetic association and differed expression analysis of , our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.