title: Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate.
abstract: BACKGROUND
  Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed.
  
  
  RESULTS
  A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10(-7)). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28% reduction in type-2 diabetes risk (OR: 0.72, 95% CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30% reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95% CI: 0.53-0.89, P = 0.0001).
  
  
  CONCLUSIONS
  In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia. m.benton@qut.edu.au.
authors.forename: M C
authors.initials: MC
authors.lastname: Benton
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia. rodney.lea@qut.edu.au.
authors.forename: R A
authors.initials: RA
authors.lastname: Lea
authors.affiliation: Kenepuru Science Centre, Institute of Environmental Science and Research, Wellington, 5240, New Zealand. Donia.Macartney@esr.cri.nz.
authors.forename: D
authors.initials: D
authors.lastname: Macartney-Coxson
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia. c.bellis@qut.edu.au.|Texas Biomedical Research Institute, San Antonio, TX, 78227-5301, USA. c.bellis@qut.edu.au.
authors.forename: C
authors.initials: C
authors.lastname: Bellis
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, 78227-5301, USA. mcarless@txbiomed.org.
authors.forename: M A
authors.initials: MA
authors.lastname: Carless
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, 78227-5301, USA. jcurran@txbiomedgenetics.org.
authors.forename: J E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia. michelle.hanna@qut.edu.au.
authors.forename: M
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia. bioinformatics@gringene.org.
authors.forename: D
authors.initials: D
authors.lastname: Eccles
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, 6140, New Zealand. Geoff.Chambers@vuw.ac.nz.
authors.forename: G K
authors.initials: GK
authors.lastname: Chambers
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas, Rio Grande Valley School of Medicine, Brownsville, TX, 78520, USA. Blangero@uthscsa.edu.
authors.forename: J
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia. lyn.griffiths@qut.edu.au.
authors.forename: L R
authors.initials: LR
authors.lastname: Griffiths
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001663:Bilirubin / Q000097:blood*; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D015810:Linkage Disequilibrium; D008542:Melanesia; D024821:Metabolic Syndrome / Q000150:complications / Q000235:genetics; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme