Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers

Abstract

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 x 10(-18)). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

Polymorphisms in the kinesin-like factor 1 B gene and risk of epithelial ovarian cancer in Eastern Chinese women

“…These lead to a speculation that other kinesins, including KIF1B, may function in ovarian carcinogenesis and progression. Recently, a GWAS study reported that the KIF1B-rs17401966 G allele was significantly associated with the decreased risk of HCC [21]. Since then, considerable efforts have been devoted to validating this association, but the underlying mechanisms remain controversial [22][23][24].…”

“…A GWAS firstly identified KIF1B polymorphisms to be significantly associated with the risk of hepatocellular carcinoma (HCC) [21], but several subsequent studies did not find any associations between KIF1B polymorphisms and HCC risk [22][23][24]. Nevertheless, two recent meta-analysis studies summarized all published association data and found that the KIF1B-rs17401966 G allele significantly reduced the risk of HCC [25,26], which indicating a potentially important effect of KIF1B SNPs on the etiology of human cancers, such as ovarian cancer.…”

Host genetic factors in hepatitis B infection, liver cancer and vaccination response: A review with a focus on Africa

“…Recently, a GWAS has been conducted in Chinese, identifying a region on chromosome 1p33.26 (KIF1B, UBE4B and PGD) as susceptibility locus for HCC in individuals persistently infected with HBV [pic] (Zhang et al, 2010). The meta-analysis by Qin et al on TNFA polymorphisms (see above) concluded that the -308 promoter variant is associated with liver cancer in Asians and Caucasians when patients were compared to healthy controls, but not when compared to HBV infection cases (Qin et al, 2010).…”

Recent updates of genetic and genomic alterations in hepatocellular carcinoma

“…[21] In a GWAS of HCC in chronic HBV carriers of Chinese ancestry, one intronic SNP (rs17401966) in kinesin family member 1B was identified to be highly associated with HBV-related HCC. [22] In addition, SNP (rs9679162) in polypeptide N-acetylgalactosaminyl transferase 14 (GALNT14) have been shown to be associated with chemotherapy response in patients with advanced HCC; for advanced HCC patients treated with FMP (fluorouracil oxantrone cisplatin) chemotherapy, GALNT14 genotype (rs9679162) was an effective predictor of the therapeutic outcome. [23,24] GENOMIC ALTERATION: GENOMIC IMBALANCES Copy number variation-genomic gain or loss Chromosomal abnormalities in HCC have been well reported, and comparative genomic hybridization (CGH) has revealed a consistent pattern of genomic gains and losses involved in the development and progression of HCC.…”