The deCODE T2™ gene markers

deCODE T2™ measures four of the strongest gene markers validated for T2D risk.  The DNA markers included in deCODE T2™ are located in or near the following genes: TCF7L2, PPARG, CDKAL1, and CDKN2A and have each been widely replicated in 10 to 40 independent populations. 

TCF7L2
The TCF7L2 gene is by far the strongest genetic risk factor discovered so far for Type 2 diabetes and is responsible at the population level for more T2D cases than all the other identified variants combined.  Since deCODE’s publication in 2006 (Grant, S.F., et al., Nat Genet, 2006. 38(3): p. 320-3) about 40 independent studies around the globe have validated its association to T2D.  About 8 - 11% of the general population (of European or African descent) carry two copies of the risk variant, compared to about twice that number of type 2 diabetics.  The frequencies are lower in Asian and Hispanic populations but the relative risk is the same.

Having two copies of the risk variant has been shown to correspond to an approximate doubling of the likelihood of developing T2D compared to the most common genotype (no copies).   (Remember that we all have two copies of each chromosome in every cell in our bodies. We inherit one copy from our mother, and one from our father.) The risk variant is the T allele of SNP rs7903146, located within the transcription factor 7-like 2 (TCF7L2) gene.

A published U.S. government supported clinical trial involving thousands of overweight and obese prediabetics, the Diabetes Prevention Program, and a European study, the Diabetes Prevention Study, showed that prediabetics with two copies of the risk variant were at a 1.8 to 2 times greater risk of progressing to type 2 diabetes within the next three to four years as were prediabetics with one or no copies of the risk variant (that is a 50 to 70% absolute risk to convert compared to a baseline conversion rate of 30 to 35% for overweight and obese prediabetics).   Approximately 20% of prediabetics who went on to develop T2D in these studies carried two copies of the risk variant compared to 11% of study participants overall.

Importantly, this study also showed that this increased risk could be effectively reduced through weight loss and treatment with metformin.  Furthermore, the 2008 ADA guidelines :  “In addition to lifestyle counseling, metformin may be considered in those who are at very high risk (combined IFG and IGT plus other risk factors) and who are obese and under 60 years of age.” 
Increased genetic risk results according to deCODE T2™, including TCF7L2 is one of the strongest risk factors for conversion.

CDKAL1
deCODE genetic has recently shown that a sequence variant in the CDKAL1 gene can increase the risk of developing type 2 diabetes by about 30%. (Steinthorsdottir, V et al. Nat Genet. 2007; 39:770-5). The function of the CDKAL1 gene is unknown but it is expressed in the insulin secreting pancreatic beta cells. Furthermore, this variant affects pancreatic beta cell function as carriers secrete less insulin in response to glucose than those who do not carry the variant.


PPARG
A large number of studies have shown that a sequence variant in the PPARG gene affects the risk of developing type 2 diabetes (Deeb, SS et al. Nat Genet. 1998; 20:284-287; Altshuler, D et al. Nat Genet. 2000; 26:76-80; Saxena, R et al Science 2007; 316:1331-6; Zeggini, E et al Science 2007; 316:1336-41; Scott, LJ et al. Science 2007; 316:1341-5). This variant is termed Pro12Ala as it changes a proline in position 12 in one isoform of the protein to an alanine. The common proline variant is thought possibly to confer increased risk of T2D through a decrease in insulin sensitivity. A meta-analysis of three large studies, including a total of 14,586 cases and 17,968 control individuals of European decent, shows that each copy of the major allele of this variant carries with it a 1.14 fold increase in risk of developing T2D compared to those who do not carry the variant. (Altshuler, D et al. Nat Genet. 2000; 26:76-80). Even though the PPAR gamma protein is a receptor for thiazolidinediones (class of T2D drugs), current evidence to suggest that the Pro12Ala variant has no effect on the therapeutic efficacy of this class of drugs.

CDKN2A
A sequence variant on chromosome 9p21 was recently shown to confer risk of type 2 diabetes with a relative risk of 1.06 compared to the general population (Saxena, R et al Science 2007; 316:1331-6; Zeggini, E et al Science 2007; 316:1336-41; Scott, LJ et al. Science 2007; 316:1341-5). There are no genes overlapping this variant but the nearest genes are CDKN2A and CDKN2B. It is not known if the sequence variant exerts its effect on type 2 diabetes through these genes or through some other unknown mechanism.