@article{d25e0fe59a1743ddbaba68d3950e8155,
title = "A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis",
abstract = "Aims/hypothesis: Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF. Methods: We tested whether a family history of type 2 diabetes affected diabetes risk in CF patients in 539 families in the CF Twin and Sibling family-based study. A type 2 diabetes susceptibility gene (transcription factor 7-like 2, or TCF7L2) was evaluated for association with diabetes in CF using 998 patients from the family-based study and 802 unrelated CF patients in an independent case-control study. Results: Family history of type 2 diabetes increased the risk of diabetes in CF (OR 3.1; p∈=∈0.0009). A variant in TCF7L2 associated with type 2 diabetes (the T allele at rs7903146) was associated with diabetes in CF in the family study (p∈=∈0.004) and in the case-control study (p∈=∈0.02; combined p∈=∈0.0002). In the family-based study, variation in TCF7L2 increased the risk of diabetes about three-fold (HR 1.75 per allele, 95% CI 1.3-2.4; p∈=∈0.0006), and decreased the mean age at diabetes diagnosis by 7 years. In CF patients not treated with systemic glucocorticoids, the effect of TCF7L2 was even greater (HR 2.9 per allele, 95% CI 1.7-4.9, p∈=∈0.00011). Conclusions/ interpretation: A genetic variant conferring risk for type 2 diabetes in the general population is a modifier of risk for diabetes in CF.",
keywords = "Association, CFRD, Corticosteroid, Cystic fibrosis, Diabetes, Genetics, Glucocorticoid, Modifier gene, TCF7L2",
author = "Blackman, {S. M.} and S. Hsu and Ritter, {S. E.} and Naughton, {K. M.} and Wright, {F. A.} and Drumm, {M. L.} and Knowles, {M. R.} and Cutting, {G. R.}",
note = "Funding Information: Acknowledgements The authors gratefully acknowledge the participation of the many CF patients, families, research coordinators and clinicians in the CF Twin and Sibling Study, the Genetic Modifiers of CF Study, and the Canadian Consortium for CF Genetic Studies. Portions of this work have been published previously in abstract form at the 2007 North American Cystic Fibrosis Conference and the 2007 meeting of the American Society of Human Genetics. The JHU CF Twin and Sibling Study is supported by NIH grant DK076446 (S. M. Blackman), DK044003 and HL068927 (G. R. Cutting) and CF Foundation funding CUTTIN06P0 (G. R. Cutting). The UNC/CWRU Genetic Modifiers Study is supported by the CF Foundation (KNOWLE00A0) and NIH grants HL068890, DK066368 (M. R. Knowles) and RR000046. The funding sources had no role in the study design, collection, analysis, and interpretation of data, writing of the report, or the decision to submit for publication. The authors thank L. L. Vanscoy, J. M. Collaco, L. B. Henderson and D. Green for assistance in defining important clinical covariates in the JHU study, P. Sosnay and K. McDougal for helpful discussions, P. Cornwall for administrative help, K. Yao for aid in SNP testing, and D. J. Cutler for guidance in data analysis. The authors also thank R. Pace for coordination of the UNC/CWRU molecular biology of the study; K. Mohlke for advice about SNP selection; J. Luo, Director of the Human Molecular Genotyping Core, for SNP testing; S. Wood and L. Charnin for coordination of the clinical phenotyping; H. Calloway for assistance in data analysis and illustrations; D. Fargo and A. Xu for Bioinformatics support; and the Gene Modifier Study Group. The authors also thank P. Durie, R. Dorfman, J. Zielenski, and M. Corey (Hospital for Sick Children, Toronto, Canada) for proofreading the manuscript. The authors declare that there is no duality of interest associated with this manuscript.",
year = "2009",
month = sep,
doi = "10.1007/s00125-009-1436-2",
language = "English (US)",
volume = "52",
pages = "1858--1865",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "9",
}