A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis.
OBJECTIVE
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
A genetic variant conferring risk for type 2 diabetes in the general population is a modifier of risk for diabetes in CF.
Blackman
S M
SM
Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hsu
S
S
Ritter
S E
SE
Naughton
K M
KM
Wright
F A
FA
Drumm
M L
ML
Knowles
M R
MR
Cutting
G R
GR
D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D016040:Lung Transplantation; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012129:Respiratory Function Tests; D012307:Risk Factors; D035781:Siblings; D011795:Surveys and Questionnaires; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D005938:Glucocorticoids; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D004247:DNA