Table 9 Examples of genetic loci implicated in T2D risk by GWAS
GeneFunction of encoded product(s)Comments
PPARGPeroxisome proliferator-activator receptor-γ; a transcription factor of the PPAR family which have roles in regulating cell differentiation, and metabolism of glucose and lipidsThis receptor is a target for thiazolidinediones, which are insulin-sensitising drugs used in T2D treatment. Variant p.Pro12Ala (representing 12% of Caucasian and East Asian alleles) is protective for T2D
TCF7L2Transcription factor, involved in stimulation of pancreatic β-cell proliferation and in production of GLP-1, which stimulates insulin secretionThe T allele of SNP rs7903146 is not only a strong risk factor for T2D, but this allele has also been associated with better response to two common T2D medications: sulphonylurea and metformin
HNF1AHepatocyte nuclear factor 1 α; transcription factor required for normal development and function of liver and pancreatic islets.Variant p.Glu508Lys is globally extremely rare (approximately 5 per 10000 alleles), and predominantly occurs in individuals of Native American ancestry. This allele was five times more common in a Mexican cohort with T2D than Mexican controls
HNF1BHepatocyte nuclear factor 1 β; transcription factor required for normal development and function of liver and pancreatic isletsA common variant (rs4430796) which is protective for T2D is associated with increased risk of prostate cancer
KCNJ11Subunit of potassium channels, required in pancreatic β-cells for regulation of glucose-stimulated insulin secretionThese potassium channels are targeted by sulphonylurea, a treatment for T2D. Activating variants are associated with neonatal diabetes, while loss-of-function variants lead to hyperinsulinaemia in infancy
KCNQ1Voltage-gated potassium channel, required in pancreatic β-cells for regulation of glucose-stimulated insulin secretionFor two SNPs in KCNQ1 (which lies within an imprinted region of the genome), increased risk of T2D is only seen when the risk allele is maternally transmitted
SLC30A8Zinc transporter; zinc is required as a cofactor by many proteins, and as a signal ionA common missense variant, p.Trp325Arg, is associated with increased risk for diabetes, while several rare loss-of-function variants are protective
CDKN2A/2BCDKN2A encodes two proteins: cyclin-dependent kinase inhibitor p16INK4 and the p14ARF protein, both of which function in the p53/RB pathways. CDKN2B generates an antisense, non-coding transcript from the same locusVariants within this genomic region have shown association with cardiovascular disease, cancer, periodontitis and glaucoma (but note that it is quite feasible that an individual variant might lead to increased risk for one disease while being protective for another!)
CDKAL1Methylthiotransferase that modifies tRNA for lysine to increase stability of the codon–anticodon interaction, and thereby increase fidelity of lysine incorporation during translationProinsulin contains two lysine residues, one of which is at the cleavage site used to generate insulin. Mistranslation of this lysine codon may generate cleavage-resistant proinsulin
FTOFat mass- and obesity-associated gene; encodes a nucleic acid demethylaseFTO is the most significant locus identified in GWASs designed to identify obesity-related genes