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01.09.2009 | Article | Ausgabe 9/2009

Diabetologia 9/2009

A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis

Zeitschrift:
Diabetologia > Ausgabe 9/2009
Autoren:
S. M. Blackman, S. Hsu, S. E. Ritter, K. M. Naughton, F. A. Wright, M. L. Drumm, M. R. Knowles, G. R. Cutting
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00125-009-1436-2) contains supplementary material, which is available to authorized users.

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.

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Zusatzmaterial
ESM Fig. 1 Cumulative incidence of diabetes in 405 patients treated with systemic steroids within the last year, grouped by TCF7L2 SNP genotype. Variation of TCF7L2 did not significantly associate with the cumulative incidence of diabetes in the subset of patients in the primary (family-based) study who were treated with systemic steroids (p = 0.2, logrank). No significant effect was seen by regression for an additive genetic model (HR 1.4 per allele, 95% CI 0.9–2.1; p = 0.1), dominant model (HR 1.6, 95% CI 0.9–2.7, p = 0.09), or recessive model (HR 1.1, 95% CI 0.3–3.6, p = 0.8) C/C genotype, solid line; C/T genotype, dashed line; T/T genotype, dotted line (PDF 30 kb)
125_2009_1436_MOESM1_ESM.pdf
ESM Fig. 2 Cumulative incidence of diabetes in 485 patients not treated with systemic steroids, grouped by TCF7L2 SNP genotype. Variation of TCF7L2 was correlated with increased cumulative incidence of diabetes in the primary (family-based) study. Individuals homozygous for the major allele (C/C genotype, solid line) developed diabetes at a significantly lower rate than patients heterozygous (C/T genotype, dashed line) or homozygous for the minor allele (T/T genotype, dotted line). Results were similar when comparing all three genotypes separately as shown (additive genetic model; \( p = 3.0 \times {10^{ - 7}} \), logrank) or when grouping genotypes according to dominant (p = 0.005) or recessive \( \left( {p = 1.8 \times {{10}^{ - 6}}} \right) \) genetic models. Modelling of these data indicated that each T allele conferred about a 190% increase in risk of developing diabetes compared with PI CF patients of the same age without a T allele (HR 2.9, 95% CI 1.7–4.9; \( p = 1.1 \times {10^{ - 4}} \)) (PDF 30 kb)
125_2009_1436_MOESM2_ESM.pdf
ESM Table 1 Distribution of TCF7L2 genotypes (SNP rs7903146) among cystic fibrosis patients stratified by diabetes phenotype (PDF 38.5 kb)
125_2009_1436_MOESM3_ESM.pdf
ESM Table 2 Association of TCF7L2 with diabetes after adjusting for steroid treatment (n = 794) (PDF 9 kb)
125_2009_1436_MOESM4_ESM.pdf
Literatur
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