Affiliation of authors: Y.-M. Sung, N. L.-S. Tang (Department of Chemical Pathology), P. B.-S. Lai (Department of Surgery), P. K.-S. Chan (Department of Microbiology), F. K.-L. Chan (Department of Medicine and Therapeutics, Faculty of Medicine), The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Correspondence to: Nelson Leung-Sang Tang, M.D., F.R.C.P.A., Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China (e-mail: nelsontang{at}cuhk.edu.hk).
Steroid 5-reductase type II (SRD5A2) catalyzes the conversion of testosterone to a more potent androgen, dihydrotestosterone, and plays an important role in steroidogenesis. One hypothesis for a hormonal etiology in hepatocellular carcinoma (HCC) was raised by a study that showed a positive association between testosterone levels and the incidence of HCC in Taiwan (1), in which the V allele of V89L in SRD5A2 was statistically significantly associated with an increased risk of HCC. Because V89L is a functional allele that encodes for an enzyme with enhanced activity (2), polymorphisms in SRD5A2 might play an important role in the pathogenesis of HCC. However, Yu et al. (1) analyzed only two SRD5A2 polymorphisms, one of which is not present among the Chinese population. Here, we genotyped five additional single nucleotide polymorphisms (SNPs), which span most of the SRD5A2 gene, to assess whether such polymorphisms predispose men to HCC.
Six SRD5A2 SNPs were studied. Three were coding SNPs, C5R and R227Q, which had been studied for predisposition to prostate cancer (3,4), and V89L. The other three were intronic SNPs, IVS1+6181T>C (dbSNP rs#2300703), IVS1+17627C>G (dbSNP rs#2300702), and IVS120568T>A (dbSNP rs#2268794). DNA from peripheral white blood cells of 117 male hepatitis B virus (HBV)-related HCC patients (case patients) and 102 male chronic HBV carriers (control subjects) was extracted and genotyped by using the polymerase chain reactionrestriction fragment length polymorphism technique (5). All subjects provided written informed consent, and the study received approval from the institutional research ethics committee.
We found a statistically significant association between the V allele of V89L and HCC (chi-square P = .030), with 57.8% of control subjects and 71.8% of case patients carrying at least one V allele. Compared with that of subjects homozygous for the LL genotype, the odds ratio for HCC case subjects carrying one or more V allele was 1.86 (95% confidence interval = 1.02 to 3.39). All subjects carried the wild-type C5R and R227Q alleles. IVS1+6181T>C, IVS1+17627C>G, and IVS120568T>A are all located within the 51-kb intron 1 of SRD5A2. The frequencies of minor alleles IVS1+6181C, IVS1+17627G, and IVS120568A were similar among case patients and control subjects (35.3% and 32.8%, 36.6% and 38.3%, 8.0% and 6.3%, respectively) and were not associated with an increased risk of HCC (Table 1). These results suggest that, among the six SRD5A2 SNPs, only V89L is associated with a statistically significant risk of HCC among Chinese men. Our data support the hypothesis that SRD5A2 plays an important role in the predisposition to HCC in chronic hepatitis B carriers and that V89L may be the primary functional allele accounting for the increased risk associated with this gene.
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NOTES
Editors note: Yu et al. declined to respond.
REFERENCES
1 Yu MW, Yang YC, Yang SY, Cheng SW, Liaw YF, Lin SM, et al. Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested casecontrol study among men. J Natl Cancer Inst 2001;93:164451.
2 Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res 1993;53:7904.[Abstract]
3 Hsing AW, Chen C, Chokkalingam AP, Gao YT, Dightman DA, Nguyen HT, et al. Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case control study. Cancer Epidemiol Biomarkers Prev 2001;10:107782.
4 Makridakis NM, di Salle E, Reichardt JK. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 2000;10:40713.[CrossRef][Medline]
5 Rapley R. Restriction fragment length polymorphism. In: Enayat MS, editor. The nucleic acid protocols handbook. Totowa (NJ): Humana Press; 2000. p. 67985.
6 Schlesselman JJ, Stolley PD. Casecontrol studies: design, conduct, analysis. New York (NY): Oxford University Press; 1982. p. 68497.
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