Background: Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of\nNorfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular\ndisease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique\ngenomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide\nassociation study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was\nperformed.\nResults: A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with\n29 SNPs reaching statistical significance (P < 1.84 Ã?â?? 10âË?â??7). Strong linkage disequilibrium was observed across a 200 kb\nregion spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin.\nGiven the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further\nexplored potential associations using stepwise multivariate regression, revealing significant association between\ndirect bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was\nassociated with a 28 % reduction in type-2 diabetes risk (OR: 0.72, 95 % CI: 0.57-0.91, P = 0.005). When adjusted for\ngenotypic effects the overall model was validated, with the adjusted model predicting a 30 % reduction in type-2\ndiabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95 % CI: 0.53-0.89, P = 0.0001).\nConclusions: In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population\nhas identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn\nimplicated with reduced risk of developing type-2 diabetes within this population.
Loading....