title: Evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis-related diabetes: a Mendelian randomization study.
abstract: Circulating immunoreactive trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD). We show in two independent CF populations that a lower newborn IRT estimate is associated with higher CFRD risk among individuals with severe CFTR genotypes, and we provide evidence to support a causal relationship. Increased loge(IRT) at birth was associated with decreased CFRD risk in Canadian and Colorado samples (hazard ratio 0.30 [95% CI 0.15-0.61] and 0.39 [0.18-0.81], respectively). Using Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable since it is known to be associated with IRT birth levels in the CF population, we provide evidence to support a causal contribution of exocrine pancreatic status on CFRD risk. Our findings suggest CFRD risk could be predicted in early life and that maintained ductal fluid flow in the exocrine pancreas could delay the onset of CFRD.
authors.affiliation: Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, CanadaDivision of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Soave
authors.affiliation: Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Keenan
authors.affiliation: Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, CanadaDivision of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.affiliation: Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jiafen
authors.initials: J
authors.lastname: Gong
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Wan
authors.initials: W
authors.lastname: Ip
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Frank
authors.initials: F
authors.lastname: Accurso
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, CanadaDepartment of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.affiliation: Department of Epidemiology, Colorado School of Public Health and University of Colorado Denver, Aurora, CO.
authors.forename: Marci
authors.initials: M
authors.lastname: Sontag
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, CanadaDepartment of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.affiliation: Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, CanadaDivision of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada lisa.strug@utoronto.ca.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D057182:Mendelian Randomization Analysis; D015997:Neonatal Screening; D046790:Pancreas, Exocrine / Q000503:physiopathology*; D010182:Pancreatic Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011237:Predictive Value of Tests
chemical_list: D015415:Biomarkers; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator