P0036THE EFFECT OF CKD ASSOCIATED SNPS ON THE PROGRESSION OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Authors: Nielsen Marlene Louise , Lildballe Dorte Launholt , Jørgensen Mads , Rasmussen Maria , Birn Henrik 
Published: June 2020

Background and Aims

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent, inherited, cystic kidney disease. It is characterized by formation and growth of renal cysts obstructing normal tubules leading to a decline in renal function and eventually end stage renal disease (ESRD). The disease is mainly caused by mutations in either PKD1 or PKD2. Both the involved genes and the type of mutation have been shown to provide significant prognostic information in relation to the risk of early progression to ESRD. However, even within families, progression of disease varies widely between individuals with the same disease causing mutation. This variation might be explained by other genetic components. Previous studies have suggested genetic components affect the progression of Chronic Kidney Disease (CKD) and ESRD.

To explain the variation in disease progression, not accounted for by the disease causing gene, 15 Single Nucleotide Variants (SNPs) associated to CKD and/or ESRD were chosen for further analysis. In addition, 3 SNPs within CFTR was included, since variants within this gene is known to affect the progression of ADPKD.

Method

A cohort of 120 Danish individuals suffering from ADPKD was sequenced using targeted Next Generation Sequencing (NGS). The targeted NGS panel included PKD1, PKD2, rs13538, rs12460876, rs17319721, rs10109414, rs653178, rs267734, rs1260326, rs347685, rs11959928, rs6420094, rs7805747, rs4744712, rs626277, rs881858, rs12917707, rs213950, rs213965, rs1042180. If no causative variant was identified using the NGS panel, Multiplex Ligation-dependent Probe Amplification was performed to identify larger deletions and duplications. In addition, clinical information was obtained to divide patients into two established or predicted progression groups; fast or slow.

Results

Based on clinical information we identified 39 patients with established or predicted fast progression and 81 with slow progression. The distribution of SNPs in the fast progression group was compared to the distribution within a European population. Out of 18 SNPs, one was significantly different distributed among the fast progressive ADPKD patients, rs13538 (p=0.01); however, in contrast to expected the frequency of the SNP was lower in the fast progression group compared to the European population. To examine if the shift could be associated to a specific disease causing mutation type, the distribution of each SNP within different mutation types were analysed. The mutations were divided into three groups; PKD1 truncating, PKD1 nontruncating and PKD2. A significant difference was observed in all three groups.

Conclusion

A single SNP associated to progression of CKD was observed to have a different distribution in the fast progressive ADPKD patients. The distribution differed for all analysed mutation types, thus no specific mutation type or gene could explain the shift in distribution alone. Hence, none of the analysed SNPs seem to influence the rate of progression in the analysed cohort of ADPKD patients.