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

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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.

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Notes

  1. Although some moderate variability in co-morbidities may be explained by the spectrum of these severe CFTR mutations (Ooi et al. 2011; Gonska et al. 2012), power to detect these small effect sizes in realistic sample sizes is challenging, reflecting the low frequency of the individual mutations and anticipated modest contribution beyond the “severe” CFTR genotype dichotomy.

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Acknowledgments

The authors would like to thank the patients and families who participated in this study. We would like to thank Yves Berthiaume MD (University of Montreal), and Andrew Sandford PhD and Peter Pare MD (University of British Columbia) for ascertainment of Canadian phenotype data and DNA; and the contributing Canadian CF centers and principal investigators. This work was supported in part by Genome Canada through the Ontario Genomics Institute as per research agreement 2004-OGI-3-05 with the Ontario Research Fund, Research Excellence Program; Cystic Fibrosis Canada (CF Canada) grants to PD and LJS; Natural Sciences and Engineering Research Council of Canada (NSERC) to LJS; Canadian Institutes of Health Research (CIHR) 119556 to LJS; NSERC and CIHR grants to LS. Funds for genome-wide genotyping of Canadian participants were generously provided by the U.S. CFF. This research was also supported by funding from Training grant GET-101831. Trainees WL, MRM, and DS are fellows of CIHR STAGE (Strategic Training for Advanced Genetic Epidemiology)—CIHR Training Grant in Genetic Epidemiology and Statistical Genetics. WL is also supported by NSERC. The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5T 3M7, Canada

    Weili Li, David Soave, Lei Sun & Lisa J. Strug

  2. Program in Child Health Evaluative Sciences, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Weili Li, David Soave, Melissa R. Miller, Jiafen Gong, Theodore Chiang & Lisa J. Strug

  3. Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Katherine Keenan & Peter Durie

  4. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Fan Lin & Johanna Rommens

  5. Adult Cystic Fibrosis Program, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, M5B 1W8, Canada

    Anne L. Stephenson

  6. Department of Medicine, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Anne L. Stephenson

  7. Department of Pediatrics, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Peter Durie

  8. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Johanna Rommens

  9. Department of Statistical Sciences, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Lei Sun

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  1. Weili Li
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Correspondence to Lisa J. Strug.

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Li, W., Soave, D., Miller, M.R. et al. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities. Hum Genet 133, 151–161 (2014). https://doi.org/10.1007/s00439-013-1363-7

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