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.

Figures

Fig. 1

Cumulative incidence of diabetes grouped by TCF7L2 SNP genotype. Individuals in the primary (family-based) study (a) who were 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=0.001, logrank) or when grouping genotypes according to dominant (p=0.003) or recessive (p=0.007) genetic models. Modelling of these data indicated that each T allele conferred about a 75% increase in risk of developing diabetes compared with PI CF patients of the same age without a T allele (HR 1.75, 95% CI 1.3–2.4; p=0.0006). The age at which the cumulative incidence reached 25% varied by 7 years with the number of high-risk T alleles (C/C genotype: 27.4 years; C/T genotype: 22.6 years; T/T genotype: 20.0 years). Individuals in the replication (case-control) study (b) who were homozygous for the major allele (C/C genotype, solid line) developed diabetes at a significantly lower rate than patients with one or two copies of the minor allele (C/T genotype, dashed line; or T/T genotype, dotted line). In this study (which had a targeted recruitment strategy based on age and lung function) the data were more consistent with a dominant genetic model, with incidence rates for all three genotypes considered separately being less distinct (p=0.06, logrank), and rates for those with one or two copies of the T allele being significantly greater than for those with none (p=0.02, logrank). Modelling of these data showed association under dominant (HR 1.43, 95% CI 1.1–2.0; p=0.02) or additive (HR 1.3, 95% CI 1.04–1.61, p=0.02) genetic models