Abstract
Hepatocellular carcinoma is a complex polygenic disease. Despite the huge advances in genetic epidemiology, it still remains a challenge to unveil the genetic architecture of hepatocellular carcinoma. We, therefore, decided to meta‐analytically assess the association of six non‐synonymous coding variants from XRCC1,XRCC3 and XPD genes with hepatocellular carcinoma risk by pooling the results of 20 English articles. This meta‐analysis was conducted according to the PRISMA statement, and data collection was independently completed in duplicate. In overall analyses, the minor alleles of four variants, Arg280His (odds ratio, 95% confidence interval, P: 1.37, 1.13–1.66, 0.001), Thr241Met (1.93, 1.17–3.20, 0.011), Asp312Asn (1.22, 1.08–1.38, 0.001) and Lys751Gln (1.42, 1.02–1.97, 0.038), were associated with the significant risk for hepatocellular carcinoma. There were low probabilities of publication bias for all variants. Subgroup analyses revealed significant association of XRCC1 gene Arg399Gln with hepatocellular carcinoma in Chinese especially from south China (odds ratio, 95% confidence interval, P: 1.57, 1.16–2.14, 0.004), in larger studies (1.48, 1.11–1.98, 0.007) and in studies with population‐based controls (1.33, 1.06–1.68, 0.016). Taken together, our findings demonstrated that XPD gene Asp312Asn and XRCC1 gene Arg399Gln might be candidate susceptibility loci for hepatocellular carcinoma. Considering the ubiquity of genetic heterogeneity, further validation in a broad range of ethnic populations is warranted.
Highlights
Liver cancer is rapidly escalating to epidemic proportions worldwide, and it constitutes a major burden on individual and public health
The association of minor alleles of six examined variants with hepatocellular carcinoma risk was statistically significant for Arg280His (OR, 95% confidence interval (95% CI), P: 1.37, 1.13–1.66, 0.001), Thr241Met (1.93, 1.17–3.20, 0.011), Asp312Asn (1.22, 1.08–1.38, 0.001) and Lys751Gln (1.42, 1.02–1.97, 0.038) only, and no indication of heterogeneity was observed for Thr241Met (I2 = 16.5%) and Asp312Asn (I2 = 0.0%) (Table 2)
The key findings of this meta-analysis are that XPD gene Asp312Asn was a candidate locus predisposing individuals to hepatocellular carcinoma, and for the widely evaluated variant Arg399Gln in XRCC1 gene, country, sample size, hepatitis B virus infection and source of controls might confound its association with hepatocellular carcinoma
Summary
Liver cancer is rapidly escalating to epidemic proportions worldwide, and it constitutes a major burden on individual and public health. The most common type of liver cancer is hepatocellular carcinoma, which accounts for more than 70% of cases [2]. DNA damage is widely recognized as a major primary cause of cancer, and without correct repair, such damage can give rise to genetic instability and eventually carcinogenesis [5, 6]. The task of moving from the selection of candidate DNA repair genes to the enumeration of causal variants poses a challenge. We in this study decided to employ a meta-analytical method to assess the association of six widely evaluated non-synonymous coding variants from three DNA repair genes, that is, XRCC1 (gene ID: 7515), XRCC3 (gene ID: 7517) and XPD (gene ID: 2068), in susceptibility to hepatocellular carcinoma, by pooling the summarized data from 20 English articles from medical literature
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