Gene-gene interactions in renin-angiotensin-aldosterone system contributes to end-stage renal disease susceptibility in a Han Chinese population

Abstract

Objective: In this study, we investigated whether RAAS gene single nucleotide polymorphisms (SNPs) and their interactions were associated with end-stage renal stage (ESRD).

Methodology and results: This was a case-control study for 647 ESRD cases and 644 controls. AGT (M235T (rs699) and T174M (rs4762)), AGTR1 (A1166C (rs5186) and C573T (rs5182)), ACE (I/D (rs1799752) and G2350A (rs4343)), and CYP11B2 C-344T (rs1799998) were genotyped and compared between cases and controls to identify SNPs associated with ESRD susceptibility. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. Several RAAS genes were associated with ESRD: AGT M235T, ACE I/D, ACE G2350A, and CYP11B2 C-344T. By MDR analysis, a three-locus model (ACE ID/ACE G2350A/CYP11B2 C-344T) of gene-gene interaction was the best for predicting ESRD risk, and its maximum testing accuracy was 56.08% and maximum cross-validation consistency was 9/10. ESRD risk was higher with the simultaneous occurrence of ACE I/D DD-ACE G2350A AA. AGT, ACE, and CYP11B2 gene polymorphisms are associated with ESRD.

Conclusions: The gene-gene interaction effects of ACE I/D, ACE G2350A, and CYP11B2 C-344T polymorphisms are more important than individual factors for ESRD development among Han Chinese.

Figure 1

The distribution of cases (left bars) and controls (right bars) for each genotype combination from the three SNPs (ACE I/D, ACE G2350A, and CYP11B2 C-344T) identified in the overall best model by MDR analysis.

Figure 2

Interaction map for ESRD risk. The values inside boxes indicate information gain (IG) of individual attribute or main effects, whereas values between nodes exemplify IG of pairwise combinations of attributes or interaction effects. A positive entropy (plotted in red or orange) indicates interaction while a negative (plotted in green) indicates redundancy.