Two variants on T2DM susceptible gene HHEX are associated with CRC risk in a Chinese population

Abstract

Increasing amounts of evidence has demonstrated that T2DM (Type 2 Diabetes Mellitus) patients have increased susceptibility to CRC (colorectal cancer). As HHEX is a recognized susceptibility gene in T2DM, this work was focused on two SNPs in HHEX, rs1111875 and rs7923837, to study their association with CRC. T2DM patients without CRC (T2DM-only, n=300), T2DM with CRC (T2DM/CRC, n=135), cancer-free controls (Control, n=570), and CRC without T2DM (CRC-only, n=642) cases were enrolled. DNA samples were extracted from the peripheral blood leukocytes of the patients and sequenced by direct sequencing. The χ² test was used to compare categorical data. We found that in T2DM patients, rs1111875 but not the rs7923837 in HHEX gene was associated with the occurrence of CRC (p= 0.006). for rs1111875, TC/CC patients had an increased risk of CRC (p=0.019, OR=1.592, 95%CI=1.046-2.423). Moreover, our results also indicated that the two variants of HEEX gene could be risk factors for CRC in general population, independent on T2DM (p< 0.001 for rs1111875, p=0.001 for rs7923837). For rs1111875, increased risk of CRC was observed in TC or TC/CC than CC individuals (p<0.001, OR= 1.780, 95%CI= 1.385-2.287; p<0.001, OR= 1.695, 95%CI= 1.335-2.152). For rs7923837, increased CRC risk was observed in AG, GG, and AG/GG than AA individuals (p< 0.001, OR= 1.520, 95%CI= 1.200-1.924; p=0.036, OR= 1.739, 95%CI= 0.989-3.058; p< 0.001, OR= 1.540, 95%CI= 1.225-1.936). This finding highlights the potentially functional alteration with HHEX rs1111875 and rs7923837 polymorphisms may increase CRC susceptibility. Risk effects and the functional impact of these polymorphisms need further validation.