Associations between genetic risk variants for kidney diseases and kidney disease etiology

Abstract

Chronic kidney disease (CKD) is a global health problem with a genetic component. Genome-wide association studies have identified variants associated with specific CKD etiologies, but their genetic overlap has not been well studied. This study examined SNP associations across different CKD etiologies and CKD stages using data from 5,034 CKD patients of the German Chronic Kidney Disease study. In addition to confirming known associations, a systemic lupus erythematosus-associated risk variant at TNXB was also associated with CKD attributed to type 1 diabetes (p = 2.5 × 10 −7 ), a membranous nephropathy-associated variant at HLA-DQA1 was also associated with CKD attributed to systemic lupus erythematosus (p = 5.9 × 10 −6 ), and an IgA risk variant at HLA-DRB1 was associated with both CKD attributed to granulomatosis with polyangiitis (p = 2.0 × 10 −4 ) and to type 1 diabetes (p = 4.6 × 10 −11 ). Associations were independent of additional risk variants in the respective genetic regions. Evaluation of CKD stage showed a significant association of the UMOD risk variant, previously identified in population-based studies for association with kidney function, for advanced (stage ≥G3b) compared to early-stage CKD (≤stage G2). Shared genetic associations across CKD etiologies and stages highlight the role of the immune response in CKD. Association studies with detailed information on CKD etiology can reveal shared genetic risk variants.The prevalence of chronic kidney disease (CKD) is high with >10% of the adult population affected in many countries 1 . Its genetic architecture is complex and incompletely understood. Genome-wide association studies (GWAS) have helped to gain insight into complex disease genetics 2,3 by identifying single-nucleotide polymorphisms (SNPs) in >70 independent risk loci associated with the estimated glomerular filtration rate (eGFR), CKD disease risk and microalbuminuria (MA) 4-6 as well as specific kidney diseases such as IgA 7,8 or membranous nephropathy 9 in case control studies. Because many of these specific kidney diseases are individually rare, only very few studies have collected sufficient numbers of patients with CKD attributed to various of these specific etiologies using one study design and protocol. Consequently, genetic risk variants identified in association with a specific etiology of CKD have so far not been examined for their association with CKD attributed to other etiologies. Capitalizing on data from the large German Chronic Kidney Disease (GCKD) study, we therefore aimed to systematically examine whether risk loci discovered for specific etiologies of CKD, especially for autoimmune conditions 10 , are associated with other CKD etiologies as well. Additionally, we aimed to examine whether risk loci discovered in the general population are also associated with advanced stages of CKD and with CKD in patients for whom the leading cause of disease was hypertension or diabetes, the most common causes of CKD. Subjects and MethodsThe GCKD study 11,12 is an ongoing prospective ob...

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

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