Additive Effects of Obesity and TCF7L2 Variants on Risk for Type 2 Diabetes Among Cardiac Patients

The role of the Wnt signaling pathway in incretin hormone production and function

“…Heterozygous and homozygous carriers of the at-risk alleles had relative T2D risks of 1.45 and 2.41, respectively, (Grant et al, 2006). During the past six years, the findings in this hallmark publication have been repeated in many ethnic groups by numerous research teams (Cauchi et al, 2006; Florez et al, 2006; Groves et al, 2006; Chang et al, 2007; Duan et al, 2007; Florez, 2007, 2008; Lyssenko et al, 2007, 2008; Schafer et al, 2007; Gonzalez-Sanchez et al, 2008; Ng et al, 2008; Shu et al, 2008, 2009; Cornelis et al, 2009; da Silva Xavier et al, 2009; Gloyn et al, 2009; Pilgaard et al, 2009; Alibegovic et al, 2010; Groop, 2010; Dabelea et al, 2011; Gjesing et al, 2011). As shown in Figure 7, the T2D risk TCF7L2 SNPs are mainly localized within the two large intronic regions surrounding exon 5.…”

The clinical utility of genetic risk variants in type 2 diabetes

“…Since then, at least 40 peer-reviewed publications have demonstrated replication in over 60 independent populations (see Table 1 for partial list) . The replication studies have included prospective and retrospective case control studies in Caucasian populations [1,4,5,7,8,10,12,13,17,[20][21][22][23]26,28,29,[31][32][33]36] , African or Afro-Caribbean populations [14,16,37,38] , Hispanic populations [19,25] , Japanese populations [13,15,39] , Chinese populations [40,41] , South Asian populations [6,16,[42][43][44] and Middle Eastern populations [45] . Almost all of these populations show a comparable degree of association to the TCF7L2 variants as found in the original Caucasian populations -so there is no 'winner's curse'.…”

“…This may be due to how common these variants are and how little risk most variants confer individually, although even the TCF7L2 variant has risk independent of family risk. Another feature of the type 2 variants is that they are largely independent of obesity, that is, the risk conferred is similar between obese diabetes patients and non-obese diabetes patients [55] . Risk factors that are independent (i.e., without terms of interaction) may be multiplied together to define a composite relative risk as long as the reference population is the same -so all risk markers are converted to relative risk compared with that risk in the general population before combining.…”

The WNT signalling pathway and diabetes mellitus

“…The investigators found that two of five SNPs investigated within introns 4 and 5 of TCF7L2, namely rs12255372 and rs7903146, were in strong linkage disequilibrium with DG10S478 and showed similarly robust associations with type 2 diabetes [20]. This discovery has drawn attention globally [15][16][17][18][19][61][62][63][64][65][66][67][68][69][70][71], and studies in many other ethnic groups have confirmed that rs12255372 and rs7903146 are the two SNPs most strongly associated with type 2 diabetes [72,73], with the SNP rs7903146 reported to have the greatest effect in white individuals [73,74]. The two SNPs occur at relatively low frequencies in Asian populations, although an association with type 2 diabetes was identified in two large Japanese cohorts [75,76].…”