GENOMIC ARCHITECTURE OF CHRONIC KIDNEY DISEASE IN AUSTRALIA’S FIRST PEOPLES
Simon Lee1, Vignesh Arunachalam2, Sudhir Jadhao1, Wendy Hoy2, Shivashankar Nagaraj2 1Faculty of Health – Queensland University of Technology, Brisbane, QLD, Australia2Faculty of Medicine – University of Queensland, Brisbane, QLD, Australia
Abstract
Aim: To identify highly enriched pathogenic variants in the Tiwi population that are associated with kidney function.
Background: Indigenous Australians experience higher rates of chronic kidney disease (CKD) compared to non-Indigenous Australians. Consequently, end-stage renal disease occurs at a substantially higher rate, particularly in remote populations, such as the Tiwi Islands. However, despite the significant disease burden, there is limited research on the genomic contribution to these diseases.
Methods: Whole genome Sequencing (WGS) was performed on 475 Tiwi individuals, and single nucleotide polymorphisms (SNPs) and structural variants (SVs) were evaluated. Kidney relevant genes were examined for the presence of pathogenic SNPs and SVs that were enriched in the Tiwi population compared to the 1KGP and UKBB. The resulting SNPs and SV were then examined for association with Albumin Creatinine Ratio (ACR), hba1c, and estimated Glomerular Filtration Rate (eGFR).
Results: We identified 232 variants, including 15 pathogenic SNPs that are relevant to kidney function, 127 potentially pathogenic variants, and 90 novel variants. Notably, we observed pathogenic mutations in SPINK1 (rs17107315) and HNF4A (rs1800961), which are associated with nephrotic syndrome and diabetes, respectively. Furthermore, we detected four potentially pathogenic copy number variations (CNVs) in genes linked to CKD. We found that a C4B deletion was significantly associated with a reduction in eGFR (p<0.05) and increase in ACR (p<0.01).
Conclusion: This study is the most in-depth WGS analysis of genetic determinants of CKD in the Indigenous community to date. Consequently, we have identified several variants associated with increased prevalence of CKD risk factors among Tiwi people. These variants may reveal potential avenues for treatment and prevention of kidney disease in the Tiwi population, and other underrepresented Indigenous groups.