Human Genetics

, Volume 133, Issue 2, pp 151–161

Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities

  • Weili Li
  • David Soave
  • Melissa R. Miller
  • Katherine Keenan
  • Fan Lin
  • Jiafen Gong
  • Theodore Chiang
  • Anne L. Stephenson
  • Peter Durie
  • Johanna Rommens
  • Lei Sun
  • Lisa J. Strug
Original Investigation

DOI: 10.1007/s00439-013-1363-7

Cite this article as:
Li, W., Soave, D., Miller, M.R. et al. Hum Genet (2014) 133: 151. doi:10.1007/s00439-013-1363-7

Abstract

The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10−6 at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Weili Li
    • 1
    • 2
  • David Soave
    • 1
    • 2
  • Melissa R. Miller
    • 2
  • Katherine Keenan
    • 3
  • Fan Lin
    • 4
  • Jiafen Gong
    • 2
  • Theodore Chiang
    • 2
  • Anne L. Stephenson
    • 5
    • 6
  • Peter Durie
    • 3
    • 7
  • Johanna Rommens
    • 4
    • 8
  • Lei Sun
    • 1
    • 9
  • Lisa J. Strug
    • 1
    • 2
  1. 1.Division of Biostatistics, Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  2. 2.Program in Child Health Evaluative SciencesThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Program in Physiology and Experimental MedicineThe Hospital for Sick ChildrenTorontoCanada
  4. 4.Program in Genetics and Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  5. 5.Adult Cystic Fibrosis ProgramLi Ka Shing Knowledge Institute, St. Michael’s HospitalTorontoCanada
  6. 6.Department of MedicineUniversity of TorontoTorontoCanada
  7. 7.Department of PediatricsUniversity of TorontoTorontoCanada
  8. 8.Department of Molecular GeneticsUniversity of TorontoTorontoCanada
  9. 9.Department of Statistical SciencesUniversity of TorontoTorontoCanada