Evidence for a Causal Relationship Between Early Exocrine Pancreatic Disease and Cystic Fibrosis–Related Diabetes: A Mendelian Randomization Study
- David Soave1,2,
- Melissa R. Miller1,
- Katherine Keenan3,
- Weili Li1,2,
- Jiafen Gong1,
- Wan Ip3,
- Frank Accurso4,
- Lei Sun2,5,
- Johanna M. Rommens6,7,
- Marci Sontag8,
- Peter R. Durie3,9 and
- Lisa J. Strug1,2⇑
- 1Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
- 2Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- 3Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
- 4Department of Pediatrics, University of Colorado Denver School of Medicine, Denver, CO
- 5Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada
- 6Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
- 7Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- 8Department of Epidemiology, Colorado School of Public Health and University of Colorado Denver, Aurora, CO
- 9Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
- Corresponding author: Lisa J. Strug, .
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.
- Received September 21, 2013.
- Accepted February 13, 2014.
- © 2014 by the American Diabetes Association.
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