Additionally, we also
found some evidence of multiplicative interaction between XRCC4 and GSTM1 (ORinteraction = 2.13 [95% CI: 1.87-2.42]; Pinteraction buy BAY 80-6946 = 1.56 × 10−30; data not shown). To assess possible interactive effects of matching factors and rs28383151 polymorphism on HCC risk, we performed a series of bivariate stratified analyses by matching factors, such as HBV and HCV infection, age, race, and sex, on this polymorphism and did not find that these factors modulated the effect of this polymorphism on HCC risk (Pinteraction > 0.05; Supporting Table 8). This implied that these matching factors should be effectually manipulated and should not modify the association Smoothened Agonist concentration between rs28383151 polymorphism and HCC related to AFB1 exposure. To study the correlation between rs28383151 polymorphism and AFB1 exposure years in the risk for HCC, we analyzed the joint effects of AFB1 exposure years and XRCC4 genotypes on HCC risk (Table 2). In this analysis, we used as a reference the lowest risk group: those who had rs28383151-GG and short-term AFB1-exposure years. We observed that increasing the number of exposure years consistently increased HCC risk; moreover, this risk was more pronounced among subjects with the risk
genotypes of XRCC4 (OR, >1). We found some evidence of multiplicatively interactive effects of genotypes and exposure years on HCC risk (19.61 > 5.28 × 1.98) according to the previously published formula (OReg > OReg’ × ORe’g).15 Additionally, a similar increased-risk trend was also found in the sequential joint-effects analysis of this polymorphism MCE and AFB1 exposure levels for HCC risk (11.26 > 5.76 × 1.35; Table 2). To investigate the potential effects of rs28383151 polymorphism on XRCC4
expression, we analyzed the association between this polymorphism and XRCC4 protein using immunohistochemistry (IHC) in the cancerous tissues of 1,499 HCC cases. The data showed that the genotypes with rs28383151 A alleles were significantly related to decreased XRCC4 expression in hepatocellular tumor tissues, compared with rs28383151-GG (Fig. 1A; P < 0.01). To further analyze this correlation, subjects were divided into three groups based on XRCC4 expression scores in the tumors, representing low (immunoreactive score [IRS]: 1-3), medium (IRS, 4-6), and high (IRS, >6) expression of XRCC4. Spearman’s r test exhibited this polymorphism negatively related to the levels of XRCC4 protein (r = −0.242; Supporting Table 9). Representative photographs exhibit the aforementioned correlation between genotypes and expression levels (Fig.