The Mediation Effects of Aluminum in Plasma and Dipeptidyl Peptidase Like Protein 6 (DPP6) Polymorphism on Renal Function via Genome-Wide Typing Association

Abstract

Aluminum (Al) toxicity is related to renal failure and the failure of other systems. Although there were some genome-wide association studies (GWAS) in Australia and England, there were no GWAS about Han Chinese to our knowledge. Thus, this research focused on using whole genomic genotypes from the Taiwan Biobank for exploring the association between Al concentrations in plasma and renal function. Participants, who underwent questionnaire interviews, biomarkers, and genotyping, were from the Taiwan Biobank database. Then, we measured their plasma Al concentrations with ICP-MS in the laboratory at Kaohsiung Medical University. We used this data to link genome-wide association (GWA) tests while looking for candidate genes and associated plasma Al concentration to renal function. Furthermore, we examined the path relationship between Single Nucleotide Polymorphisms (SNPs), Al concentrations, and estimated glomerular filtration rates (eGFR) through the mediation analysis with 3000 replication bootstraps. Following the principles of GWAS, we focused on three SNPs within the dipeptidyl peptidase-like protein 6 (DPP6) gene in chromosome 7, rs10224371, rs2316242, and rs10268004, respectively. The results of the mediation analysis showed that all of the selected SNPs have indirectly affected eGFR through a mediation of Al concentrations. Our analysis revealed the association between DPP6 SNPs, plasma Al concentrations, and eGFR. However, further longitudinal studies and research on mechanism are in need. Our analysis was still be the first study that explored the association between the DPP6, SNPs, and Al in plasma affecting eGFR.

Keywords: Taiwan Biobank; aluminum; dipeptidyl peptidase-like protein 6 (DPP6) gene; estimated glomerular filtration rate; genome-wide association; mediation analysis.

Figure 1

The relationship between X (e.g., SNPs), M (e.g., Al concentrations), and Y (e.g., eGFR) using a mediation analysis.

Figure 2

Flow chart for quality control of SNPs and selection of study population.

Figure 3

Scatter plot for eGFR and log-transformed Al concentration.

Figure 4

Manhattan plot for plasma aluminum after controlling for gender, age, smoking, and alcohol consumption. The vertical axis was −log₁₀ (p-value) according to the strength of association. The horizontal axis represents chromosome location according to the genomic location. The red line represents significant levels (p-value < 8 × 10⁻⁸). The blue line represents suggestive levels (p-value < 1 × 10⁻⁶).

Figure 5

The mediation analysis of 3 SNPs within DPP6, ln (aluminum) levels in plasma, and eGFR. (a): rs10224371 was fitted as an additive model effect with 0, 1, and 2 for CC, CT, and TT. (b): rs2316242 was fitted as an additive model effect with 0, 1, and 2 for CC, CT, and TT. (c): rs10268004 was fitted as an additive model effect with 0, 1, and 2 for TT, GT, and GG. (a): each effect with adjusted gender, age, smoke experience, and drinking habits. (b): coefficient; SE, standard error; 95%CI, 95% confidence interval estimated by percentile bootstrap methods. A summary is shown in the right lower quadrant. * p < 0.05.