W E HOY1,2, S JADHAO3, R THOMSON4, J MATHEWS5, S FOOTE6, J SAVIGE7, B MCMORRAN8, S H NAGARAJ3
1Faculty of Medicine, The University Of Queensland, Brisbane, Australia, 2NHMRC CKD.CRE and CKD.QLD, Brisbane, Australia, 3Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia, 4Centre for Research in Mathematics and Data Science, School of Computing, Mathematics and Data Science, Western Sydney University, Sydney, Australia, 5Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia, 6Australian National University, Canberra, Australia, 7Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia, 8Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Acton, Australia
Aim: To seek, through whole genome sequencing (WGS) in Tiwi Aboriginal people, gene variants which might predispose to chronic kidney disease (CKD),
Background: Rates CKD are greatly elevated remote-living Australian Aborigines. Frequencies of specific disease-associated alleles vary among populations, and their identification might be useful for diagnosis, treatment and prevention. We present selected data from whole genome sequence (WGS) in 188 Tiwi Aboriginal people, with equal numbers with established CKD and without CKD.
Methods: WGS was performed at 30x coverage, using Genome Analysis Toolkit (GATK) pipeline. Disease association was determined using ClinVar, GAD, GWAS databases, literature and gene panels. A Minor Allele Frequency statistical comparison with 1000 Genome (1000G) data was done using PLINK.
Results: There was at least 2-fold allelic difference between cases and controls for 389 polymorphic variants linked to CKD and associated disorders, of which 368 variants were not present in the 1000G dataset. There were four variants with high allele frequency that may be associated with Alport syndrome- COL4A4 (rs200668675), COL4A3 (rs200562865), COL4A5 (rs2272946) and COL4A5 (rs763147642). Homozygous mutation in COL4A3 and COL4A4 genes may lead to autosomal recessive form of Alports, while heterozygous mutations may cause benign familial hematuria, and mutations in COL4A5 gene can cause X linked dominant Alport syndrome. Variants rs200668675 and rs763147642 are of uncertain significance as per ACMG classification, while rs200562865 and rs2272946 are benign for Alport syndrome.
Conclusion: Population-specific CKD risk alleles exist in Tiwi people. We are undertaking further association studies and considering interaction effects with environmental factors. Genomic data combined with 28 years of phenotypic data constitute an invaluable resource that could be harnessed to improve health of Tiwi and other Indigenous Australians.
Professor Wendy Elizabeth Hoy AO is a Fellow of the Australian Academy of Science (FAA), the Director of the Centre for Chronic Disease at the University of Queensland, Australia, and was appointed an Officer of the Order of Australia (AO) in 2010 and elected as a member of the Australian Academy of Sciences in 2015. Hoy’s research has involved developing new types of kidney imaging and improving health and lives for indigenous populations, in Australia, Sri Lanka and the USA