| Hepatocellular Carcinoma (HCC) is the third most common cancer worldwide secondary to gastric cancer and esophageal cancer. It is relatively rarely found in American and European countries. However, the incidence of HCC in China is as nearly 10 times as higher than that of the western world, becoming the second most common malignance following lung cancer in China. Recently, according to a worldwide data, the number of HCC patient and the death rate of HCC in China is 55% and 45%, respectively. Past etiologic studies on HCC showed that, the pathogenesis of HCC may involve multiple factors including hepatitis B and C virus infections, hepatocirrhosis, aflatoxin, cigarette smoking and alcoholism. Nevertheless, only a small proportion of individuals exposuring to these factors develop HCC, implying that the individual or population susceptibility may play an important role in its development. Peroxisome proliferators-activated receptor (PPAR), a ligand-activated transcription factor belonging to the nuclear receptor superfamily, has been shown to participate in the regulation of transcription in different cells. Three PPAR subtypes have been identified: PPARα, PPARβand PPARγ. These receptors combine with the retinoid X receptors to form heterodimers that regulate various genes involved in lipid and glucose metabolism, fatty acid transport, adipocyte differentiation, carcinogenesis, and inflammation. In these receptors, PPARγ, further subtyped into PPARγ1, 2, 3 and 4, has been deeply studied and found to play important roles in regulating gene transcription by inducing differentiation and apoptosis or inhibiting the proliferation of cancer cell when activated by specific ligands.OBJECTIVES: the aim of this study is to explore the potential association of PPARγgene polymorphisms with the HCC susceptibility.METHODS: hospital based case-control research model is employed. SNaPshot technique is performed to type the PPARγgene in 12 loci for 510 newly diagnosed HCC patients and 594 healthy controls from Jiangsu, Zhejiang, Anhui and Shanghai, then different genotypes were compared between the two groups and their association with HCC were analyzed.RESULTS: rs7620165, rs12490265 and rs13306745 were found to be associated with the susceptibility of HCC by Chi-square test. Logistic regression analyses revealed that individuals with rs7620165 wildtype A allele reduce the HCC risk up to 65% comparing to who carry mutant G allele (P=0.02, adjusted OR=0.353, 95%CI=0.147-0.847); similarly, on rs12490265 locus, individuals with rs12490265 wildtype A allele have protective effect to HCC comparing to that of mutant G allele carriers (P=0.003, adjusted OR=0.687, 95%CI= 0.535-0.881); the wildtype G allele on rs13306745 also showed significant protective effect when compared to the mutant T allele (P=0.022, adjusted OR=0.636, 95%CI= 0.431-0.938). Further Logistic regression analyses revealed that the risk of HCC occurrence in rs7620165 AG carriers was nearly 63% lower than individuals with AA genotype (P=0.029, adjusted OR=0.371, 95%CI= 0.152-0.903) and 60% lower than individuals with AA+GG (P=0.034, adjusted OR=0.383, 95%CI= 0.158-0.931); rs7620165 AG+GG carriers were 60% lower risk in developing HCC than AA carriers (P=0.035, adjusted OR=0.385, 95%CI =0.158-0.936). Under the codominant model of rs12490265 locus, individuals with genotype AA+GG reduce the risk of HCC up to 35% compared to AG carriers (P=0.004, adjusted OR=0.642, 95%CI=0.476-0.866); under recessive model, individuals with homozygotic mutation GG showed 48% lower risk than AA+AG carriers (P=0.002, adjusted OR=0.621, 95%CI=0.463-0.835). Marginally significant results (P=0.047) were observed on rs13306745 locus with HCC after adjusting for age, sex, pack-years of smoking and HBV infection. Both mutant rs13306745 GT and GT+TT carriers showed 40% lower incidence of HCC when compared to wild type GG (P=0.013, adjusted OR=0.588, 95%CI=0.386-0.896; P=0.028, adjusted OR=0.627, 95 % CI= 0.414-0.95, respectively). Individuals with GT genotype also showed 40% lower risk than whose with GG+TT (P=0.014, adjusted OR = 0.594, 95 % CI= 0.391-0.902). Stratification analysis showed that after stratifying with sex, age, smoking, alcohol drinking, hepatitis B history and hepatocirrhosis, individuals with rs7620165 AG genotype had protective effect among male individuals who had hepatitis B history and hepatocirrhosis compared to genotype AA; in non-drinking males, rs7620165 AG has more protective effect than that of AA+GG; in non-drinking individuals with hepatocirrhosis, rs7620165 AG+GG had more positive effect against HCC than rs7620165 AA. Individuals with rs12490265 AA+GG all showed protective effect on HCC as compared to rs12490265 AG except for drinking individuals without HBV history and cirrhosis. rs12490265 GG, as compared to AA+AG, also showed protective effect for HCC in all individuals except female subjects without cirrhosis. rs13306745 GT had more protective effect than that of rs13306745 GG in smoking, non drinking males; rs13306745 GT non-drinking individuals had less susceptibility of HCC than rs13306745 GG+TT; rs13306745 GT+TT showed more protective role than rs13306745 GG in smoking, non drinking males.CONCLUSIONS: the polymorphisms of PPARγgene are associated with HCC susceptibility and may involve in the occurrence and the development of HCC; rs7620165, rs12490265 and rs13306745 all showed protective effect on HCC.
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