title: Genetic modifiers of cystic fibrosis-related diabetes.
abstract: Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5' to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 × 10(-8)). Replication was demonstrated in 694 individuals (124 with CFRD) (HR, 1.47; P = 0.007), with combined analysis significant at P = 9.8 × 10(-10). SLC26A9 is an epithelial chloride/bicarbonate channel that can interact with the CF transmembrane regulator (CFTR), the protein mutated in CF. We also hypothesized that common SNPs associated with type 2 diabetes also might affect risk for CFRD. A previous association of CFRD with SNPs in TCF7L2 was replicated in this study (P = 0.004; combined analysis P = 3.8 × 10(-6)), and type 2 diabetes SNPs at or near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with CFRD (P < 0.004). These five loci accounted for 8.3% of the phenotypic variance in CFRD onset and had a combined population-attributable risk of 68%. Diabetes is a highly prevalent complication of CF, for which susceptibility is determined in part by variants at SLC26A9 (which mediates processes proximate to the CF disease-causing gene) and at four susceptibility loci for type 2 diabetes in the general population.
authors.affiliation: Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Blackman
authors.forename: Clayton W
authors.initials: CW
authors.lastname: Commander
authors.forename: Christopher
authors.initials: C
authors.lastname: Watson
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Arcara
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Stonebraker
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Norris
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
mesh_terms: D000293:Adolescent; D000328:Adult; D017920:Antiporters / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003550:Cystic Fibrosis / Q000453:epidemiology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics*; D000076988:Sulfate Transporters; D014481:United States / Q000453:epidemiology; D012359:tRNA Methyltransferases
chemical_list: D017920:Antiporters; D019941:Cyclin-Dependent Kinase Inhibitor p16; C498779:IGF2BP2 protein, human; D016601:RNA-Binding Proteins; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human