TCF7L2 genetic structure, T2D risk SNP locations, and protein structure. A) The human TCF7L2 gene, located on chromosome 10q25.3, consists of 17 exons (boxes). At least five exons are alternatively spliced (white boxes). Five SNPs were originally determined to be associated with T2D risk in a variety of ethnic backgrounds, all of which are located within the large intronic regions surrounding exon 5. Two additional T2D risk SNPs (yellow) were subsequently identified in Han Chinese populations. The TCF7L2 gene undergoes a significant amount of alternative splicing that produces a large number of transcripts which give rise to a number of isoforms. The major isoforms of size 79 and 58 kDa result from alternative stop codons. A novel transcription start site (called Ex1b-e) was recently identified upstream of exon 6 which leads to the production of a dominant-negative TCF7L2 isoform of size 35–40 kDa. B) The full-length TCF7L2 protein consists of two major domains including the β-cat binding domain at the N-terminal as well as the HMG-box for binding to DNA. In addition, TCF7L2 binds to a number of other factors, depicted in this figure. SNP, single nucleotide polymorphism. HMG, high-mobility group. HBP1, HMG-box transcription factor 1.