Genetic Dissection of Diabetes: Facing the Giant

Cystic fibrosis (CF) is the most common inherited disorder of childhood and is caused by autosomal recessive mutations in the CF transmembrane conductance regulator (CFTR) gene (1). CF is most common among Caucasian individuals, with a prevalence of 1 in 2,500 newborns (2). CF can be diagnosed before birth by genetic testing or by a sweat test in early childhood (3,4). Complications of CF include bowel obstruction due to meconium ileus in newborns, poor growth, sinus infections, biliary disorders, infertility, chronic pulmonary infections, and lung disease that requires lung transplantation as CF worsens (2). Exocrine pancreatic insufficiency is observed in 90% of CF patients. Abnormal chloride channel function results in thick viscous secretions that obstruct pancreatic ducts and lead to the retention of digestive enzymes and to pancreas tissue destruction and fibrosis (5). CF-related diabetes (CFRD) is highly prevalent among CF patients and is thought to result from the progressive destruction of islets of Langerhans by pancreatic fibrosis (5). CFRD affects 2% of children, 19% of adolescents, and 40–50% of adults (6). As CFRD is associated with worse pulmonary function (7), failure to maintain weight (8), and higher mortality rates (6), the World Health Organization has recommended annual screening for CFRD using an oral glucose tolerance test. CFRD is considered a clinical entity distinct from that of type 1 diabetes or type 2 diabetes (T2D) and is included in the category “other specific types of diabetes” by the American Diabetes Association (9). Nondiabetic CF patients already display impaired firstphase of insulin secretion in response to intravenous challenges to glucose and delayed and blunted insulin secretion in response to the oral glucose tolerance test (10–12), and these abnormalities are more pronounced when glycemic status worsens (11–13). Insulin therapy is therefore the recommended treatment for CFRD patients (5). While abnormal chloride channel function induced by CFTR mutations is necessary for CFRD to develop, a recent twin study has suggested that genetic modifiers are the primary cause of diabetes in CF subjects (14). To gain insight into the pathophysiology of CFRD, Blackman et al. (15) report a genome-wide association study (GWAS) of 3,059 individuals with CF (644 with CFRD) in this issue. They found a genome-wide significant association between CFRD and two single nucleotide polymorphisms (SNPs) in complete linkage disequilibrium (rs4077468 and rs4077469) located within and 59 to the SLC26A9 gene. A directionally consistent association of the polymorphism rs4077468 with CFRD was observed in an independent sample of 409 individuals with CF (124 with CFRD). A joint analysis of discovery and replication samples supports the association of rs4077468 with CFRD (hazard ratio, 1.39 per allele [95% CI 1.25–1.54]; P = 9.8 3 10). Beyond the stringent evidence of association observed in this relatively modest sample (ntotal = 3,753 including 768 cases), the biological function of the SLC26A9 gene makes the possibility of a false-positive association signal unlikely (16). The SLC26A9 gene indeed encodes an anion transporter that conducts chloride (17). CFTR physically interacts with SLC26A9 and is required to regulate SLC26A9 chloride anion conductance in human embryonic kidney cells (18). The location of CFRD-associated SNPs in the promoter and first intron region of SLC26A9 suggests a possible role in splicing or expression. Consistent with this hypothesis, in silico analyses predict that SNPs 59 of SLC26A9 flank a region of DNase I hypersensitivity that binds transcription factors, whereas SNPs in first intron are located near three regions that may represent transcription factor binding sites active in multiple tissues. Family history of T2D triples the risk of CFRD, indicating that CFRD and T2D may share common molecular determinants (19). To test this hypothesis, Blackman et al. analyzed 13 common variants in 8 loci contributing the most to T2D in their discovery sample (n = 3,059 individuals with CF including 644 CFRD cases). They found significant associations for SNPs at the TCF7L2, CDKN2A/B, CDKAL1, and IGF2BP2 loci, the risk alleles being the same for T2D and CFRD. Conversely, Blackman et al. investigated the provocative hypothesis that polymorphisms in the CFRD-associated gene SLC26A9 may be associated with common T2D in 9,580 case subjects and 53,810 control subjects of European descent as part of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. They found a modest association between SNPs rs4077468 and rs4077469 in/near SLC26A9 and T2D (odds ratio [OR] 1.06; P = 0.003), but the risk alleles for CFRD were protective against T2D. The original study (15) supports a dual molecular origin for CFRD. Whereas abnormal chloride channel function resulting from CFTR mutations and SNPs at the SLC26A9 locus plays a substantial role in CFRD pathogenesis, at least in part through progressive pancreatic exocrine tissue destruction, impairment of b-cell function (and possibly of insulin sensitivity) conferred by T2D predisposing variants at TCF7L2, CDKN2A/B, CDKAL1, and IGF2BP2 loci worsens the risk of developing diabetes in the high-risk CF population. Furthermore, this study may suggest that the same genetic alterations in SLC26A9 may have the opposite role in CFRD and common T2D predisposition, either by normalizing or exacerbating ion transport abnormalities depending on whether CFTR is functional or not. From the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; and the Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Corresponding author: David Meyre, [email protected]. DOI: 10.2337/db13-1154 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 3627.