Single Nucleotide Polymorphisms In Aflatoxin B1 Response Related Genes: Implication In Evolutionary Genetics,Relevance In Pharmacogenetics, And Association With Hepatocellular Carcinoma

Lifetime dietary exposure to mycotoxin aflatoxin Bl and chronic infection with hepatitis B virus are two major risk factors for HCC in the endemic regions in China. However, not all individuals with comparable AFB1 exposure and HBV infection develop HCC eventually, which indicates a possible role of genetic factors in the etiology of this malignancy. In this study, we performed a systematic screening of single nucleotide polymorphisms (SNPs) in genes related to AFB1-response in Chinese, and then, by means of molecular evolutionary analysis, pharmacogenetics investigation, and case-control study as well, we evaluated the possible role of natural selection in shaping the nucleotide diversity patterns in human CYP3A locus, and investigated the association of CYP1A2 genetic polymorphisms with caffeine metabolic phenotype in a Chinese population, and pinpointed the association of SNPs in five genes, including CYP3A4, CYP3A5, CYP1A2, XRCC1 and ADPRT, with susceptibility to HCC with cases and controls recruited from Fusui, an HCC high risk region in China. The major conclusions were as follows: (1) We obtained strong evidence of positive natural selection on the entire CYP3A gene cluster in non-Africans. Sliding-window analyses suggested that CYP3A4 and CYP3A7 were under a recent or an ongoing selective sweep in the overall population, while CYP3A43 and CYP3A5 were underwent a recent selective sweep in non-Africans and Caucasians, respectively; (2) The CYP1A2 G-3113A polymorphism was associated with decreased in vivo caffeine metabolic activity, two and five haplotype pairs or haplotype combined genotypes in CYP1A2 were responsible for high and low in vivo caffeine metabolic activity, respectively, in a Chinese population. (3) We found for the first time that genetic polymorphism in CYP3A5 was associated with HCC risk in the high risk region in China. As compared with individuals carrying CYP3A5*3 homozygous genotype associated with CYP3A5 low activity, carriers of at least one wild-type CYP3A5*1 allele showed significantly decreasedHCC risk, with an odds ratio (OR) of 0.70 (95% Confidence Interval [CI]: 0.53-0.91, P=0.009); 4) We observed for the first time that CYP1A2 genetic polymorphism was associated with HCC risk in the Fusui endemic region in China. Homozygotes of the haplotype -3860G/-3113G/5347C showed significantly increased risk for HCC (OR=1.65, 95% CI: 1.11-2.46, p=0.014), especially for HBsAg seronegative subjects (OR=2.69, 95% CI: 1.43-5.06, P=0.002) and smokers (OR=2.00, 95% CI: 1.13-3.53, p=0.017). The identification of susceptibility loci for HCC in our study might provide ideal genetic markers for early screening of high risk individuals as well as potential targets for chemoprevention of HCC in the endemic regions. In addition, our findings will provide the basis for both the development of optimal dosage regiment for drug therapy in clinic and the realization of individualized medicine in future.