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.

Screening for cystic fibrosis-related diabetes: a systematic review.

“…46 The risk of CFRD may be increased if there is a family history of type 2 diabetes mellitus (T2DM), possibly because a gene linked to T2DM increases the risk and lowers the age of onset of CFRD. 47 …”

The Influence of Genetics on Cystic Fibrosis Phenotypes

“…Whereas the morphometric and biochemical risk factors for T2DM do not appear to be risk factors for CFRD, the genetics point to a relationship between T2DM and CFRD. For example, having a relative with T2DM increases the risk of a CF patient for developing CFRD (Blackman et al 2009a). In fact, the heritability of CFRD is high, approaching 1 (Table 1), substantially higher than for T2DM, suggesting that CFRD is much less influenced by environmental factors, such as diet, than T2DM with which it appears to share genetic etiology.…”

Cystic fibrosis-related diabetes: links, challenges, and future directions

“…Twin studies suggest that the risk of CFRD closely correlates with certain genes associated with T2DM, such as TCF7L2. 55 Genome-wide association studies have identified four more novel genetic modifiers of CFRD: SLC26A9, CDKAL1, CDKN2A/B, and IGF2BP2, all of which are known susceptibility alleles for T2DM. 56 Given the variable development of CFRD in CF patients with DF508 and genes associated with T2DM, epigenetic factors may play a yet unknown role in the pathogenesis of CFRD.…”